Obesity Resistance Promotes Mild Contractile Dysfunction Associated with Intracellular Ca2+ Handling

PubMed Central

de Sá, Felipe Gonçalves dos Santos; Lima-Leopoldo, Ana Paula; Jacobsen, Bruno Barcellos; Ferron, Artur Junio Togneri; Estevam, Wagner Muller; Campos, Dijon Henrique Salomé; Castardeli, Edson; da Cunha, Márcia Regina Holanda; Cicogna, Antonio Carlos; Leopoldo, André Soares

2015-01-01

Background Diet-induced obesity is frequently used to demonstrate cardiac dysfunction. However, some rats, like humans, are susceptible to developing an obesity phenotype, whereas others are resistant to that. Objective To evaluate the association between obesity resistance and cardiac function, and the impact of obesity resistance on calcium handling. Methods Thirty-day-old male Wistar rats were distributed into two groups, each with 54 animals: control (C; standard diet) and obese (four palatable high-fat diets) for 15 weeks. After the experimental protocol, rats consuming the high-fat diets were classified according to the adiposity index and subdivided into obesity-prone (OP) and obesity-resistant (OR). Nutritional profile, comorbidities, and cardiac remodeling were evaluated. Cardiac function was assessed by papillary muscle evaluation at baseline and after inotropic maneuvers. Results The high-fat diets promoted increase in body fat and adiposity index in OP rats compared with C and OR rats. Glucose, lipid, and blood pressure profiles remained unchanged in OR rats. In addition, the total heart weight and the weight of the left and right ventricles in OR rats were lower than those in OP rats, but similar to those in C rats. Baseline cardiac muscle data were similar in all rats, but myocardial responsiveness to a post-rest contraction stimulus was compromised in OP and OR rats compared with C rats. Conclusion Obesity resistance promoted specific changes in the contraction phase without changes in the relaxation phase. This mild abnormality may be related to intracellular Ca2+ handling. PMID:26761369

Aerobic Exercise Training Prevents Heart Failure-Induced Skeletal Muscle Atrophy by Anti-Catabolic, but Not Anabolic Actions

PubMed Central

Souza, Rodrigo W. A.; Piedade, Warlen P.; Soares, Luana C.; Souza, Paula A. T.; Aguiar, Andreo F.; Vechetti-Júnior, Ivan J.; Campos, Dijon H. S.; Fernandes, Ana A. H.; Okoshi, Katashi; Carvalho, Robson F.; Cicogna, Antonio C.; Dal-Pai-Silva, Maeli

2014-01-01

Background Heart failure (HF) is associated with cachexia and consequent exercise intolerance. Given the beneficial effects of aerobic exercise training (ET) in HF, the aim of this study was to determine if the ET performed during the transition from cardiac dysfunction to HF would alter the expression of anabolic and catabolic factors, thus preventing skeletal muscle wasting. Methods and Results We employed ascending aortic stenosis (AS) inducing HF in Wistar male rats. Controls were sham-operated animals. At 18 weeks after surgery, rats with cardiac dysfunction were randomized to 10 weeks of aerobic ET (AS-ET) or to an untrained group (AS-UN). At 28 weeks, the AS-UN group presented HF signs in conjunction with high TNF-α serum levels; soleus and plantaris muscle atrophy; and an increase in the expression of TNF-α, NFκB (p65), MAFbx, MuRF1, FoxO1, and myostatin catabolic factors. However, in the AS-ET group, the deterioration of cardiac function was prevented, as well as muscle wasting, and the atrophy promoters were decreased. Interestingly, changes in anabolic factor expression (IGF-I, AKT, and mTOR) were not observed. Nevertheless, in the plantaris muscle, ET maintained high PGC1α levels. Conclusions Thus, the ET capability to attenuate cardiac function during the transition from cardiac dysfunction to HF was accompanied by a prevention of skeletal muscle atrophy that did not occur via an increase in anabolic factors, but through anti-catabolic activity, presumably caused by PGC1α action. These findings indicate the therapeutic potential of aerobic ET to block HF-induced muscle atrophy by counteracting the increased catabolic state. PMID:25330387

Naked mole-rats maintain healthy skeletal muscle and Complex IV mitochondrial enzyme function into old age

PubMed Central

Stoll, Elizabeth A; Karapavlovic, Nevena; Rosa, Hannah; Woodmass, Michael; Rygiel, Karolina; White, Kathryn; Turnbull, Douglass M; Faulkes, Chris G

2016-01-01

The naked mole-rat (NMR) Heterocephalus glaber is an exceptionally long-lived rodent, living up to 32 years in captivity. This extended lifespan is accompanied by a phenotype of negligible senescence, a phenomenon of very slow changes in the expected physiological characteristics with age. One of the many consequences of normal aging in mammals is the devastating and progressive loss of skeletal muscle, termed sarcopenia, caused in part by respiratory enzyme dysfunction within the mitochondria of skeletal muscle fibers. Here we report that NMRs avoid sarcopenia for decades. Muscle fiber integrity and mitochondrial ultrastructure are largely maintained in aged animals. While mitochondrial Complex IV expression and activity remains stable, Complex I expression is significantly decreased. We show that aged naked mole-rat skeletal muscle tissue contains some mitochondrial DNA rearrangements, although the common mitochondrial DNA deletions associated with aging in human and other rodent skeletal muscles are not present. Interestingly, NMR skeletal muscle fibers demonstrate a significant increase in mitochondrial DNA copy number. These results have intriguing implications for the role of mitochondria in aging, suggesting Complex IV, but not Complex I, function is maintained in the long-lived naked mole rat, where sarcopenia is avoided and healthy muscle function is maintained for decades. PMID:27997359

Roles of polyuria and hyperglycemia in bladder dysfunction in diabetes.

PubMed

Xiao, Nan; Wang, Zhiping; Huang, Yexiang; Daneshgari, Firouz; Liu, Guiming

2013-03-01

Diabetes mellitus causes diabetic bladder dysfunction. We identified the pathogenic roles of polyuria and hyperglycemia in diabetic bladder dysfunction in rats. A total of 72 female Sprague-Dawley® rats were divided into 6 groups, including age matched controls, and rats with sham urinary diversion, urinary diversion, streptozotocin induced diabetes mellitus after sham urinary diversion, streptozotocin induced diabetes mellitus after urinary diversion and 5% sucrose induced diuresis after sham urinary diversion. Urinary diversion was performed by ureterovaginostomy 10 days before diabetes mellitus induction. Animals were evaluated 20 weeks after diabetes mellitus or diuresis induction. We measured 24-hour drinking and voiding volumes, and cystometry. Bladders were harvested to quantify smooth muscle, urothelium and collagen. We measured nitrotyrosine and Mn superoxide dismutase in the bladder. Diabetes and diuresis caused increases in drinking and voiding volume, and bladder weight. Bladder weight decreased in the urinary diversion group and the urinary diversion plus diabetes group. The intercontractile interval, voided volume and compliance increased in the diuresis and diabetes groups, decreased in the urinary diversion group and further decreased in the urinary diversion plus diabetes group. Total cross-sectional tissue, smooth muscle and urothelium areas increased in the diuresis and diabetes groups, and decreased in the urinary diversion and urinary diversion plus diabetes groups. As a percent of total tissue area, collagen decreased in the diuresis and diabetes groups, and increased in the urinary diversion and urinary diversion plus diabetes groups. Smooth muscle and urothelium decreased in the urinary diversion and urinary diversion plus diabetes groups. Nitrotyrosine and Mn superoxide dismutase increased in rats with diabetes and urinary diversion plus diabetes. Polyuria induced bladder hypertrophy, while hyperglycemia induced substantial oxidative stress in the bladder, which may have a pathogenic role in late stage diabetic bladder dysfunction. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia.

PubMed

Pannérec, Alice; Springer, Margherita; Migliavacca, Eugenia; Ireland, Alex; Piasecki, Mathew; Karaz, Sonia; Jacot, Guillaume; Métairon, Sylviane; Danenberg, Esther; Raymond, Frédéric; Descombes, Patrick; McPhee, Jamie S; Feige, Jerome N

2016-04-01

Declining muscle mass and function is one of the main drivers of loss of independence in the elderly. Sarcopenia is associated with numerous cellular and endocrine perturbations, and it remains challenging to identify those changes that play a causal role and could serve as targets for therapeutic intervention. In this study, we uncovered a remarkable differential susceptibility of certain muscles to age-related decline. Aging rats specifically lose muscle mass and function in the hindlimbs, but not in the forelimbs. By performing a comprehensive comparative analysis of these muscles, we demonstrate that regional susceptibility to sarcopenia is dependent on neuromuscular junction fragmentation, loss of motoneuron innervation, and reduced excitability. Remarkably, muscle loss in elderly humans also differs in vastus lateralis and tibialis anterior muscles in direct relation to neuromuscular dysfunction. By comparing gene expression in susceptible and non-susceptible muscles, we identified a specific transcriptomic signature of neuromuscular impairment. Importantly, differential molecular profiling of the associated peripheral nerves revealed fundamental changes in cholesterol biosynthetic pathways. Altogether our results provide compelling evidence that susceptibility to sarcopenia is tightly linked to neuromuscular decline in rats and humans, and identify dysregulation of sterol metabolism in the peripheral nervous system as an early event in this process.

Treatment of stress urinary incontinence with adipose tissue-derived stem cells.

PubMed

Lin, Guiting; Wang, Guifang; Banie, Lia; Ning, Hongxiu; Shindel, Alan W; Fandel, Thomas M; Lue, Tom F; Lin, Ching-Shwun

2010-01-01

Effective treatment for stress urinary incontinence (SUI) is lacking. This study investigated whether transplantation of adipose tissue-derived stem cells (ADSC) can treat SUI in a rat model. Rats were induced to develop SUI by postpartum vaginal balloon dilation and bilateral ovariectomy. ADSC were isolated from the peri-ovary fat, examined for stem cell properties, and labeled with thymidine analog BrdU or EdU. Ten rats received urethral injection of saline as a control. Twelve rats received urethral injection of EdU-labeled ADSC and six rats received intravenous injection of BrdU-labeled ADSC through the tail vein. Four weeks later, urinary voiding function was assessed by conscious cystometry. The rats were then killed and their urethras harvested for tracking of ADSC and quantification of elastin, collagen and smooth muscle contents. Cystometric analysis showed that eight out 10 rats in the control group had abnormal voiding, whereas four of 12 (33.3%) and two of six (33.3%) rats in the urethra-ADSC and tail vein-ADSC groups, respectively, had abnormal voiding. Histologic analysis showed that the ADSC-treated groups had significantly higher elastin content than the control group and, within the ADSC-treated groups, rats with normal voiding pattern also had significantly higher elastin content than rats with voiding dysfunction. ADSC-treated normal-voiding rats had significantly higher smooth muscle content than control or ADSC-treated rats with voiding dysfunction. Transplantation of ADSC via urethral or intravenous injection is effective in the treatment and/or prevention of SUI in a pre-clinical setting.

Long-term high-fat-diet feeding induces skeletal muscle mitochondrial biogenesis in rats in a sex-dependent and muscle-type specific manner

PubMed Central

2012-01-01

Background Mitochondrial dysfunction is thought to play a crucial role in the etiology of insulin resistance, in which skeletal muscle is the main tissue contributor. Sex differences in skeletal muscle insulin and antioxidant responses to high-fat-diet (HFD) feeding have been described. The aim of this study was to elucidate whether there is a sex dimorphism in the effects of HFD feeding on skeletal muscle mitochondrial biogenesis and on the adiponectin signaling pathway, as well as the influence of the muscle type (oxidative or glycolytic). Methods Gastrocnemius and soleus muscles of male and female Wistar rats of 2 months of age fed with a high-fat-diet (HFD) or a low fat diet for 26 weeks were used. Mitochondrial biogenesis and oxidative damage markers, oxidative capacity and antioxidant defences were analyzed. Serum insulin sensitivity parameters and the levels of proteins involved in adiponectin signaling pathway were also determined. Results HFD feeding induced mitochondrial biogenesis in both sexes, but to a higher degree in male rats. Although HFD female rats showed greater antioxidant protection and maintained a better insulin sensitivity profile than their male counterparts, both sexes showed an impaired response to adiponectin, which was more evident in gastrocnemius muscle. Conclusions We conclude that HFD rats may induce skeletal muscle mitochondrial biogenesis as an attempt to compensate the deleterious consequences of adiponectin and insulin resistance on oxidative metabolism, and that the effects of HFD feeding are sex-dependent and muscle-type specific. PMID:22353542

Berberine alleviates the cerebrovascular contractility in streptozotocin-induced diabetic rats through modulation of intracellular Ca²⁺ handling in smooth muscle cells.

PubMed

Ma, Yu-Guang; Zhang, Yin-Bin; Bai, Yun-Gang; Dai, Zhi-Jun; Liang, Liang; Liu, Mei; Xie, Man-Jiang; Guan, Hai-Tao

2016-04-12

Vascular dysfunction is a distinctive phenotype in diabetes mellitus. Current treatments mostly focus on the tight glycemic control and few of these treatments have been designed to directly recover the vascular dysfunction in diabetes. As a classical natural medicine, berberine has been explored as a possible therapy for DM. In addition, it is reported that berberine has an extra-protective effect in diabetic vascular dysfunction. However, little is known whether the berberine treatment could ameliorate the smooth muscle contractility independent of a functional endothelium under hyperglycemia. Furthermore, it remains unknown whether berberine affects the arterial contractility by regulating the intracellular Ca(2+) handling in vascular smooth cells (VSMCs) under hyperglycemia. Sprague-Dawley rats were used to establish the diabetic model with a high-fat diet plus injections of streptozotocin (STZ). Berberine (50, 100, and 200 mg/kg/day) were intragastrically administered to control and diabetic rats for 8 weeks since the injection of STZ. The intracellular Ca(2+) handling of isolated cerebral VSMCs was investigated by recording the whole-cell L-type Ca(2+) channel (CaL) currents, assessing the protein expressions of CaL channel, and measuring the intracellular Ca(2+) in response to caffeine. Our results showed that chronic administration of 100 mg/kg/day berberine not only reduced glucose levels, but also inhibited the augmented contractile function of cerebral artery to KCl and 5-hydroxytryptamine (5-HT) in diabetic rats. Furthermore, chronic administration of 100 mg/kg/day berberine significantly inhibited the CaL channel current densities, reduced the α1C-subunit expressions of CaL channel, decreased the resting intracellular Ca(2+) ([Ca(2+)]i) level, and suppressed the Ca(2+) releases from RyRs in cerebral VSMCs isolated from diabetic rats. Correspondingly, acute application of 10 μM berberine could directly inhibit the hyperglycemia-induced CaL currents and suppress the hyperglycemia-induced Ca(2+) releases from RyRs in cerebral VSMCs isolated from normal control rats. Our study indicated that berberine alleviated the cerebral arterial contractility in the rat model of streptozotocin-induced diabetes via regulating the intracellular Ca(2+) handling of smooth muscle cells.

Short-term muscle atrophy caused by botulinum toxin-A local injection impairs fracture healing in the rat femur.

PubMed

Hao, Yongqiang; Ma, Yongcheng; Wang, Xuepeng; Jin, Fangchun; Ge, Shengfang

2012-04-01

Damaged bone is sensitive to mechanical stimulation throughout the remodeling phase of bone healing. Muscle damage and muscular atrophy associated with open fractures and subsequent fixation are not beneficial to maintaining optimum conditions for mechanical stability. The aim of this study was to investigate whether local muscle atrophy and dysfunction affect fracture healing in a rat femur fracture model. We combined the rat model of a short period atrophy of the quadriceps with femur fracture. Forty-four-month-old male Wistar rats were adopted for this study. Two units of botulinum toxin-A (BXTA) were administered locally into the right side of the quadriceps of each rat, while the same dose of saline was injected into the contralateral quadriceps. After BXTA had been fully absorbed by the quadriceps, osteotomy was performed in both femurs with intramedullary fixation. Gross observation and weighing of muscle tissue, X-ray analysis, callus histology, and bone biomechanical testing were performed at different time points up to 8 weeks post-surgery. Local injection of BXTA led to a significant decrease in the volume and weight of the quadriceps compared to the control side. At the eighth week, the left side femurs of the saline-injected quadriceps almost reached bony union, and fibrous calluses were completely calcified into woven bone. However, a gap was still visible in the BXTA-treated side on X-ray images. As showed by bone histology, there were no mature osseous calluses or woven bone on the BXTA-treated side, but a resorption pattern was evident. Biomechanical testing indicated that the femurs of the BXTA-treated side exhibited inferior mechanical properties compared with the control side. The inferior outcome following BXTA injection, compared with saline injection, in terms of callus resistance may be the consequence of unexpected load and mechanical unsteadiness caused by muscle atrophy and dysfunction. Copyright © 2011 Orthopaedic Research Society.

The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure.

PubMed

Hwee, Darren T; Kennedy, Adam R; Hartman, James J; Ryans, Julie; Durham, Nickie; Malik, Fady I; Jasper, Jeffrey R

2015-04-01

Heart failure-mediated skeletal myopathy, which is characterized by muscle atrophy and muscle metabolism dysfunction, often manifests as dyspnea and limb muscle fatigue. We have previously demonstrated that increasing Ca(2+) sensitivity of the sarcomere by a small-molecule fast skeletal troponin activator improves skeletal muscle force and exercise performance in healthy rats and models of neuromuscular disease. The objective of this study was to investigate the effect of a novel fast skeletal troponin activator, CK-2127107 (2-aminoalkyl-5-N-heteroarylpyrimidine), on skeletal muscle function and exercise performance in rats exhibiting heart failure-mediated skeletal myopathy. Rats underwent a left anterior descending coronary artery ligation, resulting in myocardial infarction and a progressive decline in cardiac function [left anterior descending coronary artery heart failure (LAD-HF)]. Compared with sham-operated control rats, LAD-HF rat hindlimb and diaphragm muscles exhibited significant muscle atrophy. Fatigability was increased during repeated in situ isokinetic plantar flexor muscle contractions. CK-2127107 produced a leftward shift in the force-Ca(2+) relationship of skinned, single diaphragm, and extensor digitorum longus fibers. Exercise performance, which was assessed by rotarod running, was lower in vehicle-treated LAD-HF rats than in sham controls (116 ± 22 versus 193 ± 31 seconds, respectively; mean ± S.E.M.; P = 0.04). In the LAD-HF rats, a single oral dose of CK-2127107 (10 mg/kg p.o.) increased running time compared with vehicle treatment (283 ± 47 versus 116 ± 22 seconds; P = 0.0004). In summary, CK-2127107 substantially increases exercise performance in this heart failure model, suggesting that modulation of skeletal muscle function by a fast skeletal troponin activator may be a useful therapeutic in heart failure-associated exercise intolerance. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Different responses of mesenteric artery from normotensive and spontaneously hypertensive rats to nitric oxide and its redox congeners.

PubMed

Orescanin, Zorana S; Milovanović, Slobodan R; Spasić, Snezana D; Jones, David R; Spasić, Mihajlo B

2007-01-01

The conversion of nitric oxide (NO*) into its congeners nitrosonium (NO(+)) and nitroxyl (HNO/NO(-)) ions may have important consequences for signal transduction and physiological responses. Manganese-containing superoxide dismutase (MnSOD) may convert NO. into its redox congeners. In our current work, we have examined the mechanism of sodium nitroprusside (SNP)-induced relaxation of arteries, with or without endothelium, from both normotensive and spontaneously hypertensive (SH) rats in the absence and presence of MnSOD. SNP induced a greater degree of relaxation in normotensive than in SH rats. MnSOD antagonized SNP-induced relaxation and effect was greater in normotensive than hypertensive rats. However, MnSOD even potentiated SNP-induced relaxation in mesenteric arteries with endothelium from SH rats. Our results indicate that HNO/NO(-)-mediated relaxation is more effective in mesenteric artery smooth muscle from SH rats than from normotensive rats and that vascular dysfunction in SH rats is not solely endothelium-derived but involves changes in vascular smooth muscles.

Flk-1+Sca-1- mesenchymal stem cells: functional characteristics in vitro and regenerative capacity in vivo

PubMed Central

Li, Yugang; Pan, Enshan; Wang, Yu; Zhu, Xiaoguang; Wei, Anyang

2015-01-01

Objectives: Mesenchymal stem cells (MSCs) represent a powerful tool in regenerative medicine because of their differentiation and migration capacities. We aimed to investigate the possibility of Flk-1+Sca-1- mesenchymal stem cells (Flk-1+Sca-1- MSCs) transplantation to repair erectile function in patients suffering from diabetes mellitus (DM)-associated erectile dysfunction (ED). Methods: In this study, we isolated Flk-1+Sca-1- MSCs from bone marrow (bMSCs). Then, newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine for the purpose of tracking endogenous Flk-1+Sca-1- MSCs. Eight weeks later, 8 of these rats were randomly chosen to serve as normal control (N group). The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce DM. Eight of these rats were randomly chosen to serve as DM control (DM group) while another 8 rats were subject to Flk-1+Sca-1- MSCs treatment (DM+MSC group). All rats were evaluated for erectile function by intracavernous pressure (ICP) measurement. Afterward, their penile tissues were examined by histology. Results: Flk-1+Sca-1- MSCs could differentiate into skeletal muscle cells and endothelial cells in vivo and in vitro. Engrafted Flk-1+Sca-1- MSCs were shown to home to injured muscle, participate in myofibers repair and could partially reconstitute the sarcolemmal expression of myocardin and ameliorate the level of related specific pathological markers. Conclusion: Flk-1+Sca-1- MSCs could be used in the treatment erectile function in diabetes mellitus associated erectile dysfunction by promoting regeneration of nNOS-positive nerves, endothelium, and smooth muscle in the penis. PMID:26617697

Cavernous neurotomy in the rat is associated with the onset of an overt condition of hypogonadism.

PubMed

Vignozzi, Linda; Filippi, Sandra; Morelli, Annamaria; Marini, Mirca; Chavalmane, Aravinda; Fibbi, Benedetta; Silvestrini, Enrico; Mancina, Rosa; Carini, Marco; Vannelli, G Barbara; Forti, Gianni; Maggi, Mario

2009-05-01

Most men following radical retropubic prostatectomy (RRP) are afflicted by erectile dysfunction (ED). RRP-related ED occurs as a result of surgically elicited neuropraxia, leading to histological changes in the penis, including collagenization of smooth muscle and endothelial damage. To verify whether hypogonadism could contribute to the pathogenesis of RRP-ED. Effects of testosterone (T), alone or in association with long-term tadalafil (Tad) treatment in a rat model of bilateral cavernous neurotomy (BCN). Penile tissues from rats were harvested for vasoreactivity studies 3 months post-BCN. Penile oxygenation was evaluated by hypoxyprobe immunostaining. Phosphodiesterase type 5 (PDE5), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expression were quantified by Real Time quantitative reverse transcription polymerase chain reaction (qRT-PCR). In BCN rats, we observed the onset of an overt condition of hypogonadism, characterized by reduced T plasma level, reduced ventral prostate weight, reduced testis function (including testis weight and number of Leydig cells), with an inadequate compensatory increase of luteinizing hormone. BCN induced massive penile hypoxia, decreased muscle/fiber ratio, nNOS, eNOS, PDE5 expression, increased sensitivity to the nitric oxide donor, sodium nitroprusside (SNP), and reduced the relaxant response to acetylcholine (Ach), as well as unresponsiveness to acute Tad dosing. In BCN rats, chronic Tad-administration normalizes penile oxygenation, smooth muscle loss, PDE5 expression, SNP sensitivity, and the responsiveness to the acute Tad administration. Chronic Tad treatment was ineffective in counteracting the reduction of nNOS and eNOS expression, along with Ach responsiveness. T supplementation, in combination with Tad, reverted some of the aforementioned alterations, restoring smooth muscle content, eNOS expression, as well as the relaxant response of penile strips to Ach, but not nNOS expression. BCN was associated with hypogonadism, probably of central origin. T supplementation in hypogonadal BCN rats ameliorates some aspects of BCN-induced ED, including collagenization of penile smooth muscle and endothelial dysfunction, except surgically induced altered nNOS expression.

Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses

PubMed Central

Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

2015-01-01

Abstract Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague–Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ∼60%. However, supplementing gAd fully rescued insulin’s microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin’s metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats. Key points Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin’s metabolic action via an AMPK- and nitric oxide-dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. PMID:26108677

Effect of chronic, extrinsic denervation on functional NANC innervation with vasoactive intestinal polypeptide and substance P in longitudinal muscle of rat jejunum.

PubMed

Kasparek, M S; Fatima, J; Iqbal, C W; Duenes, J A; Sarr, M G

2008-03-01

Intestinal denervation contributes to enteric motor dysfunction after intestinal transplantation [small bowel transplantation (SBT)]. Our aim was to determine long-term effects of extrinsic denervation on functional non-adrenergic, non-cholinergic innervation with vasoactive intestinal polypeptide (VIP) and substance P. Contractile activity of jejunal longitudinal muscle from six age-matched, naïve control rats (NC) and eight rats 1 year after syngeneic SBT were studied in tissue chambers. Spontaneous contractile activity did not differ between groups. Exogenous VIP inhibited contractile activity dose-dependently in both groups, greater in NC than in SBT. The VIP antagonist ([D-p-Cl-Phe(6),Leu(17)]-VIP) and the nitric oxide synthase inhibitor l-N(G)-nitro arginine prevented inhibition by exogenous VIP and electrical field stimulation (EFS) in both groups. Exogenous substance P increased contractile activity dose-dependently, greater in NC than in SBT. The substance P antagonist ([D-Pro(2),D-Trp(7,9)]-substance P) inhibited effects of exogenous substance P and increased the EFS-induced inhibitory response. Immunohistofluorescence showed staining for tyrosine hydroxylase in the jejunoileum 1 year after SBT suggesting sympathetic reinnervation. In rat jejunal longitudinal muscle after chronic denervation, response to exogenous VIP and substance P is decreased, while endogenous release of both neurotransmitters is preserved. These alterations in excitatory and inhibitory pathways occur despite extrinsic reinnervation and might contribute to enteric motor dysfunction after SBT.

Effect of chronic, extrinsic denervation on functional NANC innervation with vasoactive intestinal polypeptide and substance P in longitudinal muscle of rat jejunum1

PubMed Central

KASPAREK, M. S.; FATIMA, J.; IQBAL, C. W.; DUENES, J. A.; SARR, M. G.

2008-01-01

Intestinal denervation contributes to enteric motor dysfunction after intestinal transplantation [small bowel transplantation (SBT)]. Our aim was to determine long-term effects of extrinsic denervation on functional non-adrenergic, non-cholinergic innervation with vasoactive intestinal polypeptide (VIP) and substance P. Contractile activity of jejunal longitudinal muscle from six age-matched, naïve control rats (NC) and eight rats 1 year after syngeneic SBT were studied in tissue chambers. Spontaneous contractile activity did not differ between groups. Exogenous VIP inhibited contractile activity dose-dependently in both groups, greater in NC than in SBT. The VIP antagonist ([D-p-Cl-Phe6,Leu17]-VIP) and the nitric oxide synthase inhibitor L-NG-nitro arginine prevented inhibition by exogenous VIP and electrical field stimulation (EFS) in both groups. Exogenous substance P increased contractile activity dose-dependently, greater in NC than in SBT. The substance P antagonist ([D-Pro2,D-Trp7,9]-substance P) inhibited effects of exogenous substance P and increased the EFS-induced inhibitory response. Immunohistofluorescence showed staining for tyrosine hydroxylase in the jejunoileum 1 year after SBT suggesting sympathetic reinnervation. In rat jejunal longitudinal muscle after chronic denervation, response to exogenous VIP and substance P is decreased, while endogenous release of both neurotransmitters is preserved. These alterations in excitatory and inhibitory pathways occur despite extrinsic reinnervation and might contribute to enteric motor dysfunction after SBT. PMID:17971029

Improved penile histology by phalloidin stain: circular and longitudinal cavernous smooth muscles, dual-endothelium arteries, and erectile dysfunction-associated changes.

PubMed

Lin, Guiting; Qiu, Xuefeng; Fandel, Thomas M; Albersen, Maarten; Wang, Zhong; Lue, Tom F; Lin, Ching-Shwun

2011-10-01

To investigate whether fluorochrome-conjugated phalloidin can delineate cavernous smooth muscle (CSM) cells and whether it can be combined with immunofluorescence (IF) staining to quantify erectile dysfunction (ED)-associated changes. ED was induced by cavernous nerve crush in rats. Penile tissues of control and ED rats were stained with Alexa-488-conjugated phalloidin and/or with antibodies against rat endothelial cell antigen (RECA), CD31, neuronal nitric oxide synthase (nNOS), and collagen-IV (Col-IV). Phalloidin was able to delineate CSM as composed of a circular and a longitudinal compartment. When combined with IF stain for CD31 or RECA, it helped the identification of the helicine arteries as covered by endothelial cells on both sides of the smooth muscle layer. When combined with IF stain for nNOS, it helped the identification that nNOS-positive nerves were primarily localized within the dorsal nerves and in the adventitia of dorsal arteries. When combined with IF stain for Col-IV, it helped identify that Col-IV was localized around smooth muscles and beneath the endothelium. Phalloidin also facilitated the quantitative analysis of ED-related changes in the penis. In rats with cavernous nerve injury, RECA or Col-IV expression did not change significantly, but CSM and nNOS nerve contents decreased significantly. Phalloidin stain improved penile histology, enabling the visualization of the circular and longitudinal compartments in the CSM. It also worked synergistically with IF stain, permitting the visualization of the dual endothelial covering in helicine arteries, and facilitating the quantification of ED-related histologic changes. Copyright © 2011 Elsevier Inc. All rights reserved.

Gene therapy strategies for urological dysfunction.

PubMed

Chancellor, M B; Yoshimura, N; Pruchnic, R; Huard, J

2001-07-01

Novel molecular techniques such as conventional and ex vivo gene therapy, and tissue engineering have only recently been introduced to the field of urology. The lower urinary tract is ideally suited for minimally invasive therapy, and also ex vivo approaches would limit the risk of systemic side effects. Muscle-derived stem cells have been used successfully to treat stress incontinence, and rats with diabetic bladder dysfunction benefited from nerve growth factor (NGF)-based gene therapy. Nitric oxide synthase and capase-7 might provide suitable gene therapy targets for erectile dysfunction and benign prostatic hyperplasia, respectively.

(p-ClPhSe)2 stimulates carbohydrate metabolism and reverses the metabolic alterations induced by high fructose load in rats.

PubMed

Quines, Caroline B; Rosa, Suzan G; Chagas, Pietro M; Velasquez, Daniela; Prado, Vinicius C; Nogueira, Cristina W

2017-09-01

The modern life leads to excess consumption of food rich in fructose; however, the long-term changes in carbohydrate and lipid metabolism could lead to metabolic dysfunction in humans. The present study evaluated the in vitro insulin-mimetic action of p-chloro-diphenyl diselenide (p-ClPhSe) 2 . The second aim of this study was to investigate if (p-ClPhSe) 2 reverses metabolic dysfunction induced by fructose load in Wistar rats. The insulin-mimetic action of (p-ClPhSe) 2  at concentrations of 50 and 100 μM was determined in slices of rat skeletal muscle. (p-ClPhSe) 2  at a concentration of 50 μM stimulated the glucose uptake by 40% in skeletal muscle. A dose-response curve revealed that (p-ClPhSe) 2  at a dose of 25 mg/kg reduced (∼20%) glycemia in rats treated with fructose (5 g/kg, i.g.). The administration of fructose impaired the liver homeostasis and (p-ClPhSe) 2 (25 mg/kg) protected against the increase (∼25%) in the G-6-Pase and isocitrate dehydrogenase activities and reduced the triglyceride content (∼25%) in the liver. (p-ClPhSe) 2 regulated the liver homeostasis by stimulating hexokinase activity (∼27%), regulating the TCA cycle activity (increased the ATP and citrate synthase activity (∼15%)) and increasing the glycogen levels (∼67%). In conclusion, (p-ClPhSe) 2 stimulated carbohydrate metabolism and reversed metabolic dysfunction in rats fed with fructose. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Sodium ferulate treatment and interventional mechanism reverse erectile dysfunction in streptozotocin-induced diabetic rats].

PubMed

Xu, Xiao-Hong; Tan, Fu-Qing; Zhao, Tong-Feng; Hu, Hua; Xiao, Kun; Gu, Wei

2009-06-23

To investigate the effect and mechanism of sodium ferulate (SF) on reversing erectile dysfunction in diabetes mellitus (DM) rats. Forty-four male adult Sprague-Dawley rats were induced for diabetes by an intraperitoneal injection of streptozotocin. Then the successful models were randomly divided into DM + SF group and DM group (22 rats each respectively). The rats in DM +SF group were treated with sodium ferulate (100 mg x kg(-1) x d(-1)) through a daily gastric lavage. At Week 12, the erectile function of all rats was evaluated and serum samples were harvested. The SOD, CAT, NOS, MDA and NO levels in corpus cavernosum and serum were all measured. The pathologic change in penile cavernous body was observed microscopically. The diabetic rat models were successfully established. The erectile function was much better in normal control group and DM + SF group than that in DM group. And the penile erection rates in three groups were 100%, 66% and 22% respectively. The activity levels of SOD, CAT and NOS were markedly decreased in DM group as compared to those in normal control group and DM + SF group (P < 0.01). The NO content was approximately equal in normal control group and DM + SF group (112 +/- 28) nmol/ml vs (137 +/- 25) nmol/ml. But both were much higher than that in DM group (56 +/- 10) nmol/ml, both P < 0.01. The MDA content was markedly increased in DM group as compared to those in normal control group and DM + SF group (both P < 0.01). Microscopically, muscle fibers in penile cavernous body arranged disorderly, muscular mantle damaged and desmoplasia scattered among muscle fibers in DM group. Sodium ferulate may play interventional roles in reversing diabetic erectile dysfunction through metabolic regulation of free radicals, antagonism of oxidative insults and enhancement of NO production.

Long-term effects of extrinsic denervation on VIP and substance P innervation in circular muscle of rat jejunum.

PubMed

Kasparek, Michael S; Fatima, Javairiah; Iqbal, Corey W; Duenes, Judith A; Sarr, Michael G

2007-10-01

Intestinal denervation contributes to enteric motor dysfunction after small bowel transplantation (SBT). Our aim was to determine long-term effects of extrinsic denervation on function of nonadrenergic, noncholinergic innervation with substance P and vasoactive intestinal polypeptide (VIP). Contractile activity of jejunal circular muscle strips from six age-matched, naive control rats (NC) and eight rats 1 year after syngeneic SBT was studied in tissue chambers. Spontaneous contractile activity did not differ between groups. Exogenous VIP inhibited contractile activity dose-dependently to a comparable degree in both groups. The VIP antagonist ([D-p-Cl-Phe(6),Leu(17)]-VIP) and the nitric oxide synthase inhibitor L-NG-nitro-arginine did not affect VIP-induced inhibition but increased contractile activity during electrical field stimulation (EFS) in both groups. Exogenous substance P increased contractile activity dose-dependently, greater in NC than SBT. The substance P antagonist ([D-Pro(2),D-Trp(7,9)]-substance P) inhibited effects of exogenous substance P and decreased the excitatory EFS response. Immunohistofluorescence showed tyrosine hydroxylase staining after SBT indicating sympathetic reinnervation. In jejunal circular muscle after chronic denervation, response to exogenous substance P, but not VIP, is decreased, whereas endogenous release of both neurotransmitters is preserved. Alterations in balance of excitatory and inhibitory pathways occur despite extrinsic reinnervation and might contribute to enteric motor dysfunction after SBT.

Beneficial Effects of Scutellaria baicalensis on Penile Erection in Streptozotocin-Induced Diabetic Rats.

PubMed

Li, Xiang; Lee, Yun Jung; Kim, Hye Yoom; Tan, Rui; Park, Min Cheol; Kang, Dae Gill; Lee, Ho Sub

2016-01-01

We have reported that ethanol extracts of the root from Scutellaria baicalensis Georgi (ESB) relax cavernous smooth muscles via the NO/cGMP system and Ca[Formula: see text]-sensitive K[Formula: see text] channels in the rabbit corpus cavernosum. In the present study, erectile function was assessed by intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrical stimulation of the cavernous nerve. The ICP/MAP ratio was dose-dependently increased by the treatment of ESB in normal SD rats ([Formula: see text]). To investigate the beneficial effect of ESB on erectile dysfunction in a diabetic animal model, male SD rats were injected with streptozotocin (60[Formula: see text]mg/kg) and then 300[Formula: see text]mg/kg/day ESB was administered daily for eight weeks. In our in vivo study, administration of ESB in STZ rats significantly increased the ICP, ICP/MAP ratio, area under the curve (AUC), as well as the cavernous cGMP levels. Morphometric analyses showed that ESB administration increased both smooth muscle volume and the regular arrangement of collagen fibers compared to the STZ group. The protein expression levels of endothelial nitric oxide synthase (eNOS) and SM [Formula: see text]-actin from penile tissues were also significantly increased in the ESB-treated rats. Taken together, these results suggest that ESB ameliorates penile erectile dysfunction via the activation of the NO/cGMP pathways of the penile corpus cavernosum in a streptozotocin-induced diabetic rat model.

Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure.

PubMed

Delp, M D; Duan, C; Mattson, J P; Musch, T I

1997-10-01

One of the primary consequences of left ventricular dysfunction (LVD) after myocardial infarction is a decrement in exercise capacity. Several factors have been hypothesized to account for this decrement, including alterations in skeletal muscle metabolism and aerobic capacity. The purpose of this study was to determine whether LVD-induced alterations in skeletal muscle enzyme activities, fiber composition, and fiber size are 1) generalized in muscles or specific to muscles composed primarily of a given fiber type and 2) related to the severity of the LVD. Female Wistar rats were divided into three groups: sham-operated controls (n = 13) and rats with moderate (n = 10) and severe (n = 7) LVD. LVD was surgically induced by ligating the left main coronary artery and resulted in elevations (P < 0.05) in left ventricular end-diastolic pressure (sham, 5 +/- 1 mmHg; moderate LVD, 11 +/- 1 mmHg; severe LVD, 25 +/- 1 mmHg). Moderate LVD decreased the activities of phosphofructokinase (PFK) and citrate synthase in one muscle composed of type IIB fibers but did not modify fiber composition or size of any muscle studied. However, severe LVD diminished the activity of enzymes involved in terminal and beta-oxidation in muscles composed primarily of type I fibers, type IIA fibers, and type IIB fibers. In addition, severe LVD induced a reduction in the activity of PFK in type IIB muscle, a 10% reduction in the percentage of type IID/X fibers, and a corresponding increase in the portion of type IIB fibers. Atrophy of type I fibers, type IIA fibers, and/or type IIB fibers occurred in soleus and plantaris muscles of rats with severe LVD. These data indicate that rats with severe LVD after myocardial infarction exhibit 1) decrements in mitochondrial enzyme activities independent of muscle fiber composition, 2) a reduction in PFK activity in type IIB muscle, 3) transformation of type IID/X to type IIB fibers, and 4) atrophy of type I, IIA, and IIB fibers.

Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure

NASA Technical Reports Server (NTRS)

Delp, M. D.; Duan, C.; Mattson, J. P.; Musch, T. I.

1997-01-01

One of the primary consequences of left ventricular dysfunction (LVD) after myocardial infarction is a decrement in exercise capacity. Several factors have been hypothesized to account for this decrement, including alterations in skeletal muscle metabolism and aerobic capacity. The purpose of this study was to determine whether LVD-induced alterations in skeletal muscle enzyme activities, fiber composition, and fiber size are 1) generalized in muscles or specific to muscles composed primarily of a given fiber type and 2) related to the severity of the LVD. Female Wistar rats were divided into three groups: sham-operated controls (n = 13) and rats with moderate (n = 10) and severe (n = 7) LVD. LVD was surgically induced by ligating the left main coronary artery and resulted in elevations (P < 0.05) in left ventricular end-diastolic pressure (sham, 5 +/- 1 mmHg; moderate LVD, 11 +/- 1 mmHg; severe LVD, 25 +/- 1 mmHg). Moderate LVD decreased the activities of phosphofructokinase (PFK) and citrate synthase in one muscle composed of type IIB fibers but did not modify fiber composition or size of any muscle studied. However, severe LVD diminished the activity of enzymes involved in terminal and beta-oxidation in muscles composed primarily of type I fibers, type IIA fibers, and type IIB fibers. In addition, severe LVD induced a reduction in the activity of PFK in type IIB muscle, a 10% reduction in the percentage of type IID/X fibers, and a corresponding increase in the portion of type IIB fibers. Atrophy of type I fibers, type IIA fibers, and/or type IIB fibers occurred in soleus and plantaris muscles of rats with severe LVD. These data indicate that rats with severe LVD after myocardial infarction exhibit 1) decrements in mitochondrial enzyme activities independent of muscle fiber composition, 2) a reduction in PFK activity in type IIB muscle, 3) transformation of type IID/X to type IIB fibers, and 4) atrophy of type I, IIA, and IIB fibers.

Exercise training increases protein O-GlcNAcylation in rat skeletal muscle.

PubMed

Hortemo, Kristin Halvorsen; Lunde, Per Kristian; Anonsen, Jan Haug; Kvaløy, Heidi; Munkvik, Morten; Rehn, Tommy Aune; Sjaastad, Ivar; Lunde, Ida Gjervold; Aronsen, Jan Magnus; Sejersted, Ole M

2016-09-01

Protein O-GlcNAcylation has emerged as an important intracellular signaling system with both physiological and pathophysiological functions, but the role of protein O-GlcNAcylation in skeletal muscle remains elusive. In this study, we tested the hypothesis that protein O-GlcNAcylation is a dynamic signaling system in skeletal muscle in exercise and disease. Immunoblotting showed different protein O-GlcNAcylation pattern in the prototypical slow twitch soleus muscle compared to fast twitch EDL from rats, with greater O-GlcNAcylation level in soleus associated with higher expression of the modulating enzymes O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine fructose-6-phosphate amidotransferase isoforms 1 and 2 (GFAT1, GFAT2). Six weeks of exercise training by treadmill running, but not an acute exercise bout, increased protein O-GlcNAcylation in rat soleus and EDL There was a striking increase in O-GlcNAcylation of cytoplasmic proteins ~50 kDa in size that judged from mass spectrometry analysis could represent O-GlcNAcylation of one or more key metabolic enzymes. This suggests that cytoplasmic O-GlcNAc signaling is part of the training response. In contrast to exercise training, postinfarction heart failure (HF) in rats and humans did not affect skeletal muscle O-GlcNAcylation level, indicating that aberrant O-GlcNAcylation cannot explain the skeletal muscle dysfunction in HF Human skeletal muscle displayed extensive protein O-GlcNAcylation that by large mirrored the fiber-type-related O-GlcNAcylation pattern in rats, suggesting O-GlcNAcylation as an important signaling system also in human skeletal muscle. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Phenotypic modulation of corpus cavernosum smooth muscle cells in a rat model of cavernous neurectomy.

PubMed

Yang, Fan; Zhao, Jian F; Shou, Qi Y; Huang, Xiao J; Chen, Gang; Yang, Ke B; Zhang, Shi G; Lv, Bo D; Fu, Hui Y

2014-01-01

Patients undergoing radical prostatectomy (RP) are at high risk for erectile dysfunction (ED) due to potential cavernous nerve (CN) damage during surgery. Penile hypoxia after RP is thought to significantly contribute to ED pathogenesis. We previously showed that corpora cavernosum smooth muscle cells (CCSMCs) undergo phenotypic modulation under hypoxic conditions in vitro. Here, we studied such changes in an in vivo post-RP ED model by investigating CCSMCs in bilateral cavernous neurectomy (BCN) rats. Sprague-Dawley rats underwent sham (n = 12) or BCN (n = 12) surgery. After 12 weeks, they were injected with apomorphine to determine erectile function. The penile tissues were harvested and assessed for fibrosis using Masson trichrome staining and for molecular markers of phenotypic modulation using immunohistochemistry and western blotting. CCSMC morphological structure was evaluated by hematoxylin-eosin (H&E) staining and transmission electron microscopy (TEM). Erectile function was significantly lower in BCN rats than in sham rats. BCN increased hypoxia-inducible factor-1α and collagen protein expression in corpora cavernous tissue. H&E staining and TEM showed that CCSMCs in BCN rats underwent hypertrophy and showed rough endoplasmic reticulum formation. The expression of CCSMC phenotypic markers, such as smooth muscle α-actin, smooth muscle myosin heavy chain, and desmin, was markedly lower, whereas vimentin protein expression was significantly higher in BCN rats than in control rats. CCSMCs undergo phenotype modulation in rats with cavernous neurectomy. The results have unveiled physiological transformations that occur at the cellular and molecular levels and have helped characterize CN injury-induced ED.

ORAL BISPHENOL A (BPA) GIVEN TO RATS AT MODERATE DOSES IS ASSOCIATED WITH ERECTILE DYSFUNCTION, CAVERNOSAL LIPOFIBROSIS, AND ALTERATIONS OF GLOBAL GENE TRANSCRIPTION

PubMed Central

Kovanecz, I; Gelfand, R; Masouminia, M; Gharib, S; Segura, D; Vernet, D; Rajfer, J; Li, DK; Kannan, K; Gonzalez-Cadavid, NF

2013-01-01

Introduction Bisphenol A (BPA), a suspected reproductive biohazard and endocrine disruptor released from plastics is associated with erectile dysfunction (ED) in occupationally exposed workers. However, in rats, despite the induction of hypogonadism, apoptosis of the penile corporal smooth muscle, fat infiltration into the cavernosal tissue, and changes in global gene expression with the intraperitoneal administration of high dose BPA, ED was not observed. Aims We investigated whether BPA administered orally rather than intraperitoneally to rats for longer periods and lower doses will lead to ED. Main Outcomes Measures ED, histological, and biochemical markers in rat penile tissues. Methods 2.5-month old rats were given drinking water daily without and with BPA at 1 and 0.1 mg/kg/day. Two months later, erectile function was determined by cavernosometry (DIC) and electrical field stimulation (EFS) and serum levels of testosterone (T), estradiol (E2), and BPA were measured. Penile tissue sections were assayed by Masson (smooth muscle (SM)/collagen), Oil Red O (fat), TUNEL (apoptosis), immunohistochemistry for Oct 4 (stem cells), and α-SM actin/ calponin (SM and myofibroblasts), applying quantitative image analysis. Other markers were assayed by western blots. DNA microarrays/microRNA assays defined transcription profiles. Results Orally administered BPA did not affect body weight, but: 1) decreased serum T and E2; 2) reduced the EFS response and increased the DIC drop rate; 3) increased within the corporal tissue the presence of fat, myofibroblasts and apoptosis; 4) lowered the contents of SM and stem cells, but not nerve terminals; and 5) caused alterations of the transcriptional profiles for both mRNA and microRNAs within the penile shaft. Conclusions Long-term exposure of rats to oral BPA,caused a moderate corporal veno-occlusive dysfunction (CVOD), possibly due to alterations within the corporal tissue that pose gene transcriptional changes related to inflammation, fibrosis and epithelial/ mesenchymal transition (EMT). PMID:24305612

Vascular smooth muscle cell apoptosis is an early trigger for hypothyroid atherosclerosis.

PubMed

Wang, Pei; Xu, Tian-Ying; Guan, Yun-Feng; Zhao, Yan; Li, Zhi-Yong; Lan, Xiao-Hong; Wang, Xia; Yang, Peng-Yuan; Kang, Zhi-Min; Vanhoutte, Paul M; Miao, Chao-Yu

2014-06-01

Endothelial dysfunction is an initial and vascular smooth muscle cell (VSMC) apoptosis, a later step of atherosclerosis. Hypothyroidism accelerates atherosclerosis. However, the early events responsible for this pro-atherosclerotic effect are unclear. Rats were resistant to induction of atherosclerosis by high cholesterol diet alone, but became susceptible in hypothyroid state achieved by administration of propylthiouracil (PTU) for 6 weeks. VSMC dysfunction and apoptosis were obvious within 1 week after PTU treatment, without signs of endothelial dysfunction. This early VSMC damage was caused by hypothyroidism but not the high cholesterol diet. In ApoE knockout mice, PTU-induced hypothyroidism triggered early VSMC apoptosis, increased oxidative stress, and accelerated atherosclerosis development. Thyroid hormone supplementation (T4, 10, or 50 μg/kg) prevented atherogenic phenotypes in hypothyroid rats and mice. In rats, thyroidectomy caused severe hypothyroidism 5 days after operation, which also led to rapid VSMC dysfunction and apoptosis. In vitro studies did not show a direct toxic effect of PTU on VSMCs. In contrast, thyroid hormone (T3, 0.75 μg/L plus T4, 50 nmol/L) exerted a direct protection against VSMC apoptosis, which was reduced by knockdown of TRα1, rather than TRβ1 and TRβ2 receptors. TRα1-mediated inhibition of apoptotic signalling of JNKs and caspase-3 contributed to the anti-apoptotic action of thyroid hormone. These findings provide an in vivo example for VSMC apoptosis as an early trigger of hypothyroidism-associated atherosclerosis, and reveal activation of TRα1 receptors to prevent VSMC apoptosis as a therapeutic strategy in this disease. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

4-Phenylbutyrate Benefits Traumatic Hemorrhagic Shock in Rats by Attenuating Oxidative Stress, Not by Attenuating Endoplasmic Reticulum Stress.

PubMed

Yang, Guangming; Peng, Xiaoyong; Hu, Yi; Lan, Dan; Wu, Yue; Li, Tao; Liu, Liangming

2016-07-01

Vascular dysfunction such as vascular hyporeactivity following severe trauma and shock is a major cause of death in injured patients. Oxidative stress and endoplasmic reticulum stress play an important role in vascular dysfunction. The objective of the present study was to determine whether or not 4-phenylbutyrate can improve vascular dysfunction and elicit antishock effects by inhibiting oxidative and endoplasmic reticulum stress. Prospective, randomized, controlled laboratory experiment. State key laboratory of trauma, burns, and combined injury. Five hundred and fifty-two Sprague-Dawley rats. Rats were anesthetized, and a model of traumatic hemorrhagic shock was established by left femur fracture and hemorrhage. The effects of 4-phenylbutyrate (5, 20, 50, 100, 200, and 300 mg/kg) on vascular reactivity, animal survival, hemodynamics, and vital organ function in traumatic hemorrhagic shock rats and cultured vascular smooth muscle cells, and the relationship to oxidative stress and endoplasmic reticulum stress was observed. Lower doses of 4-phenylbutyrate significantly improved the vascular function, stabilized the hemodynamics, and increased the tissue blood flow and vital organ function in traumatic hemorrhagic shock rats, and markedly improved the survival outcomes. Among all dosages observed in the present study, 20 mg/kg of 4-phenylbutyrate had the best effect. Further results indicated that 4-phenylbutyrate significantly inhibited the oxidative stress, decreased shock-induced oxidative stress index such as the production of reactive oxygen species, increased the antioxidant enzyme levels such as superoxide dismutase, catalase, and glutathione, and improved the mitochondrial function by inhibiting the opening of the mitochondrial permeability transition pore in rat artery and vascular smooth muscle cells. In contrast, 4-phenylbutyrate did not affect the changes of endoplasmic reticulum stress markers following traumatic hemorrhagic shock. Furthermore, 4-phenylbutyrate increased the nuclear levels of nuclear factor-E2-related factor 2, and decreased the nuclear levels of nuclear factor κB in hypoxic vascular smooth muscle cells. 4-phenylbutyrate has beneficial effects for traumatic hemorrhagic shock including improving animal survival and protecting organ function. These beneficial effects of 4-phenylbutyrate in traumatic hemorrhagic shock result from its vascular function protection via attenuation of the oxidative stress and mitochondrial permeability transition pore opening. Nuclear factor-E2-related factor 2 and nuclear factor-κB may be involved in 4-phenylbutyrate-mediated inhibition of oxidative stress.

Chronic prostatitis/chronic pelvic pain syndrome impairs erectile function through increased endothelial dysfunction, oxidative stress, apoptosis, and corporal fibrosis in a rat model.

PubMed

Hu, Y; Niu, X; Wang, G; Huang, J; Liu, M; Peng, B

2016-11-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an independent risk factor for the development of erectile dysfunction (ED). But the molecular mechanisms underlying the relationship between CP/CPPS and ED are still unclear. The aim of this study was to investigate the effect of CP/CPPS on erectile function in a rat model and the possible mechanisms. A rat model of experimental autoimmune prostatitis (EAP) was established to mimic human CP⁄CPPS. Then twenty 2-month-old male Sprague-Dawley rats were divided into EAP group and control group. Intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured during cavernous nerve electrostimulation, the ratio of max ICP/MAP was calculated. Blood was collected to measure the levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and testosterone, respectively. The expression of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in corpus cavernosum were detected. We also evaluated the smooth muscle/collagen ratio and apoptotic index (AI). The ratio of max ICP/MAP in EAP group were significantly lower than that in control group. The levels of serum CRP, TNF-α, IL-1β, and IL-6 in EAP group were all significantly higher than these in control group. The expression of eNOS and cGMP levels in corpus cavernosum of EAP rats were significantly downregulated. Furthermore, decreased SOD activity and smooth muscle/collagen ratio, increased MDA levels and AI were found in corpus cavernosum of EAP rats. In conclusion, CP/CPPS impaired penile erectile function in a rat model. The declines of eNOS expression and cGMP levels in corpus cavernosum may be an important mechanism of CP/CPPS-induced ED. CP/CPPS also increased oxidative stress, cell apoptosis and decreased smooth muscle/collagen ratio in corpus cavernosum of rats, which were all important for erectile function. © 2016 American Society of Andrology and European Academy of Andrology.

Defects in oxygen supply to skeletal muscle of prediabetic ZDF rats

PubMed Central

Goldman, Daniel; Hanson, Madelyn; Stephenson, Alan H.; Milkovich, Stephanie; Benlamri, Amina; Ellsworth, Mary L.; Sprague, Randy S.

2010-01-01

In humans, prediabetes is characterized by marked increases in plasma insulin and near normal blood glucose levels as well as microvascular dysfunction of unknown origin. Using the extensor digitorum longus muscle of 7-wk inbred male Zucker diabetic fatty rats fed a high-fat diet as a model of prediabetes, we tested the hypothesis that hyperinsulinemia contributes to impaired O2 delivery in skeletal muscle. Using in vivo video microscopy, we determined that the total O2 supply to capillaries in the extensor digitorum longus muscle of prediabetic rats was reduced to 64% of controls with a lower O2 supply rate per capillary and higher O2 extraction resulting in a decreased O2 saturation at the venous end of the capillary network. These findings suggest a lower average tissue Po2 in prediabetic animals. In addition, we determined that insulin, at concentrations measured in humans and Zucker diabetic fatty rats with prediabetes, inhibited the O2-dependent release of ATP from rat red blood cells (RBCs). This inability to release ATP could contribute to the impaired O2 delivery observed in rats with prediabetes, especially in light of the finding that the endothelium-dependent relaxation of resistance arteries from these animals is not different from controls and is not altered by insulin. Computational modeling confirmed a significant 8.3-mmHg decrease in average tissue Po2 as well as an increase in the heterogeneity of tissue Po2, implicating a failure of a regulatory system for O2 supply. The finding that insulin attenuates the O2-dependent release of ATP from RBCs suggests that this defect in RBC physiology could contribute to a failure in the regulation of O2 supply to meet the demand in skeletal muscle in prediabetes. PMID:20207810

Dietary nitrate supplementation: impact on skeletal muscle vascular control in exercising rats with chronic heart failure

PubMed Central

Ferguson, Scott K.; Holdsworth, Clark T.; Colburn, Trenton D.; Wright, Jennifer L.; Craig, Jesse C.; Fees, Alex; Jones, Andrew M.; Allen, Jason D.; Musch, Timothy I.

2016-01-01

Chronic heart failure (CHF) results in central and peripheral derangements that ultimately reduce skeletal muscle O2 delivery and impair exercise tolerance. Dietary nitrate (NO3−) supplementation improves skeletal muscle vascular function and tolerance to exercise. We tested the hypothesis that NO3− supplementation would elevate exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats. Myocardial infarction (MI) was induced (coronary artery ligation) in young adult male rats. After 21 days of recovery, rats randomly received 5 days of NO3−-rich beetroot juice (CHF + BR, n = 10) or a placebo (CHF, n = 10). Mean arterial pressure (carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% grade). CHF-induced dysfunction, as determined by myocardial infarction size (29 ± 3% and 33 ± 4% in CHF and CHF + BR, respectively) and left ventricular end-diastolic pressure (18 ± 2 and 18 ± 2 mmHg in CHF and CHF + BR, respectively), and exercising mean arterial pressure (131 ± 3 and 128 ± 4 mmHg in CHF and CHF + BR, respectively) were not different (P > 0.05) between groups. Total exercising hindlimb skeletal muscle BF (95 ± 5 and 116 ± 9 ml·min−1·100 g−1 in CHF and CHF + BR, respectively) and VC (0.75 ± 0.05 and 0.90 ± 0.05 ml·min−1·100 g−1·mmHg−1 in CHF and CHF + BR, respectively) were 22% and 20% greater in BR-supplemented rats, respectively (P < 0.05). During exercise, BF in 9 and VC in 10 hindlimb muscles and muscle portions were significantly greater in the CHF + BR group. These results provide strong evidence that dietary NO3− supplementation improves skeletal muscle vascular function during exercise in rats with CHF and, thus, support the use of BR as a novel therapeutic modality for the treatment of CHF. PMID:27445296

Dietary nitrate supplementation: impact on skeletal muscle vascular control in exercising rats with chronic heart failure.

PubMed

Ferguson, Scott K; Holdsworth, Clark T; Colburn, Trenton D; Wright, Jennifer L; Craig, Jesse C; Fees, Alex; Jones, Andrew M; Allen, Jason D; Musch, Timothy I; Poole, David C

2016-09-01

Chronic heart failure (CHF) results in central and peripheral derangements that ultimately reduce skeletal muscle O2 delivery and impair exercise tolerance. Dietary nitrate (NO3 (-)) supplementation improves skeletal muscle vascular function and tolerance to exercise. We tested the hypothesis that NO3 (-) supplementation would elevate exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats. Myocardial infarction (MI) was induced (coronary artery ligation) in young adult male rats. After 21 days of recovery, rats randomly received 5 days of NO3 (-)-rich beetroot juice (CHF + BR, n = 10) or a placebo (CHF, n = 10). Mean arterial pressure (carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% grade). CHF-induced dysfunction, as determined by myocardial infarction size (29 ± 3% and 33 ± 4% in CHF and CHF + BR, respectively) and left ventricular end-diastolic pressure (18 ± 2 and 18 ± 2 mmHg in CHF and CHF + BR, respectively), and exercising mean arterial pressure (131 ± 3 and 128 ± 4 mmHg in CHF and CHF + BR, respectively) were not different (P > 0.05) between groups. Total exercising hindlimb skeletal muscle BF (95 ± 5 and 116 ± 9 ml·min(-1)·100 g(-1) in CHF and CHF + BR, respectively) and VC (0.75 ± 0.05 and 0.90 ± 0.05 ml·min(-1)·100 g(-1)·mmHg(-1) in CHF and CHF + BR, respectively) were 22% and 20% greater in BR-supplemented rats, respectively (P < 0.05). During exercise, BF in 9 and VC in 10 hindlimb muscles and muscle portions were significantly greater in the CHF + BR group. These results provide strong evidence that dietary NO3 (-) supplementation improves skeletal muscle vascular function during exercise in rats with CHF and, thus, support the use of BR as a novel therapeutic modality for the treatment of CHF. Copyright © 2016 the American Physiological Society.

Analysis of testosterone effects on sonic hedgehog signaling in juvenile, adolescent and adult sprague dawley rat penis.

PubMed

Bond, Christopher W; Angeloni, Nicholas L; Podlasek, Carol A

2010-03-01

Smooth muscle apoptosis is a major contributing factor to erectile dysfunction (ED) development in prostatectomy and diabetic patients and animal models. A critical regulator of penile smooth muscle and apoptosis is Sonic hedgehog (SHH). The SHH protein is decreased in ED models and SHH treatment of cavernous nerve (CN) injured rats prevents smooth muscle apoptosis. A close association between androgen deficiency and ED has been suggested in the literature, but few studies have examined the molecular effects on penile smooth muscle and on known signaling mechanisms that regulate morphology. Aim. Examine testosterone and SHH interaction in eugonadal adult, adolescent and juvenile rats by performing castration studies and treatment with supraphysiological testosterone. The eugonadal adult Sprague Dawley rats were either treated with testosterone for 7 or 14 days (N = 14) or were castrated for 4 or 7 days (N = 12). The juvenile rats were treated with testosterone for 8 days (N = 7). The adolescent rats were castrated and sacrificed at P88 (N = 8). The control rats had empty vehicle (N = 22) or sham surgery (N = 20). The active form of SHH protein and mRNA were quantified by semi-quantitative immunohistochemical analysis and real-time reverse transcriptase polymerase chain reaction (RT-PCR). Testosterone treatment did not alter SHH signaling in juvenile rats. Shh mRNA increased 3.2-fold and SHH protein increased 1.2-fold in rats castrated during puberty. In adult rats, castration decreased Shh mRNA 3.2-fold but did not alter SHH protein. Testosterone supplement in adult rats increased Shh mRNA 2.3-fold and decreased SHH protein 1.3-fold. SHH signaling is independent of testosterone in normal juvenile rats and is sensitive to testosterone during adolescence, while testosterone supplement in the adult adversely impacts SHH signaling in a very similar manner to that observed with CN injury.

Radiation-induced erectile dysfunction using prostate-confined modern radiotherapy in a rat model.

PubMed

Kimura, Masaki; Yan, Hui; Rabbani, Zahid; Satoh, Takefumi; Baba, Shiro; Yin, Fang-fang; Polascik, Thomas J; Donatucci, Craig F; Vujaskovic, Zeljko; Koontz, Bridget F

2011-08-01

The mechanisms of radiation-induced erectile dysfunction (ED) are unclear, as clinical studies are limited, and previous animal models were based on wide-field irradiation, which does not model current radiotherapy (RT) techniques. To perform functional and morphological analyses of erectile function (EF) utilizing image-guided stereotactic prostate-confined RT in a rat model. Sixty young adult male rats aged 10-12 weeks old were divided into age-matched sham and RT groups. A single 20-Gy fraction to the prostate was delivered to RT animals. Penile bulb, shaft, and testes were excluded from treatment fields. Bioassay and intracavernous pressure (ICP) measurements were conducted at 2, 4, and 9 weeks following RT. Perfusion analysis of the corpora cavernosa (CC) was conducted using Hoechst injected prior to sacrifice. Penile shaft and cavernous nerve (CN) were evaluated by immunohistochemistry. Plasma testosterone level was analyzed using a testosterone enzyme-linked immunosorbent assay (ELISA) assay kit. Irradiated animals demonstrated statistically significant time-dependent functional impairment of EF by bioassay and ICP measurement from 4 weeks. Neuronal nitric oxide synthase (NOS) expression was decreased in CN by 4 weeks. In CC, expression levels of anti-alpha smooth muscle actin and endothelial NOS were significantly decreased at 9 weeks. In penile dorsal vessels, smooth muscle/collagen ratio was significantly decreased at 4 and 9 weeks. Additionally, Hoechst perfusion showed time-dependent decrease in CC of RT animals, whereas CD31 expression was not affected. No toxicities were noted; testosterone levels were similar in both groups. We demonstrated time-dependent ED following image-guided stereotactic RT. Our results imply that reduction of neuronal NOS expression in cavernous nerve could trigger consecutive reduction of smooth muscle content as well as blood perfusion in CC that resulted in corporal veno-occlusive dysfunction. Present study could be a cornerstone to future research that may bring comprehensive scientific understanding of radiation-induced ED. © 2011 International Society for Sexual Medicine.

Tong Xie Yao Fang relieves irritable bowel syndrome in rats via mechanisms involving regulation of 5-hydroxytryptamine and substance P

PubMed Central

Yin, Yue; Zhong, Lei; Wang, Jian-Wei; Zhao, Xue-Ying; Zhao, Wen-Jing; Kuang, Hai-Xue

2015-01-01

AIM: To investigate whether the Chinese medicine Tong Xie Yao Fang (TXYF) improves dysfunction in an irritable bowel syndrome (IBS) rat model. METHODS: Thirty baby rats for IBS modeling were separated from mother rats (1 h per day) from days 8 to 21, and the rectum was expanded by angioplasty from days 8 to 12. Ten normal rats were used as normal controls. We examined the effects of TXYF on defection frequency, colonic transit function and smooth muscle contraction, and the expression of 5-hydroxytryptamine (5-HT) and substance P (SP) in colonic and hypothalamus tissues by Western blot and RT-PCT techniques in both normal rats and IBS model rats with characterized visceral hypersensitivity. RESULTS: Defecation frequency was 1.8 ± 1.03 in normal rats and 4.5 ± 1.58 in IBS model rats (P < 0.001). However, the defecation frequency was significantly decreased (3.0 ± 1.25 vs 4.5 ± 1.58, P < 0.05), while the time (in seconds) of colon transit function was significantly increased (256.88 ± 20.32 vs 93.36 ± 17.28, P < 0.001) in IBS + TXYF group rats than in IBS group rats. Increased colonic smooth muscle tension and contract frequency in IBS model rats were significantly decreased by administration of TXYF. Exogenous agonist stimulants increased spontaneous activity and elicited contractions of colon smooth muscle in IBS model rats, and all of these actions were significantly reduced by TXYF involving 5-HT and SP down-regulation. CONCLUSION: TXYF can modulate the activity of the enteric nervous system and alter 5-HT and SP activities, which may contribute to the symptoms of IBS. PMID:25914462

Tong Xie Yao Fang relieves irritable bowel syndrome in rats via mechanisms involving regulation of 5-hydroxytryptamine and substance P.

PubMed

Yin, Yue; Zhong, Lei; Wang, Jian-Wei; Zhao, Xue-Ying; Zhao, Wen-Jing; Kuang, Hai-Xue

2015-04-21

To investigate whether the Chinese medicine Tong Xie Yao Fang (TXYF) improves dysfunction in an irritable bowel syndrome (IBS) rat model. Thirty baby rats for IBS modeling were separated from mother rats (1 h per day) from days 8 to 21, and the rectum was expanded by angioplasty from days 8 to 12. Ten normal rats were used as normal controls. We examined the effects of TXYF on defection frequency, colonic transit function and smooth muscle contraction, and the expression of 5-hydroxytryptamine (5-HT) and substance P (SP) in colonic and hypothalamus tissues by Western blot and RT-PCT techniques in both normal rats and IBS model rats with characterized visceral hypersensitivity. Defecation frequency was 1.8 ± 1.03 in normal rats and 4.5 ± 1.58 in IBS model rats (P < 0.001). However, the defecation frequency was significantly decreased (3.0 ± 1.25 vs 4.5 ± 1.58, P < 0.05), while the time (in seconds) of colon transit function was significantly increased (256.88 ± 20.32 vs 93.36 ± 17.28, P < 0.001) in IBS + TXYF group rats than in IBS group rats. Increased colonic smooth muscle tension and contract frequency in IBS model rats were significantly decreased by administration of TXYF. Exogenous agonist stimulants increased spontaneous activity and elicited contractions of colon smooth muscle in IBS model rats, and all of these actions were significantly reduced by TXYF involving 5-HT and SP down-regulation. TXYF can modulate the activity of the enteric nervous system and alter 5-HT and SP activities, which may contribute to the symptoms of IBS.

Prenatal hypoxia leads to increased muscle sympathetic nerve activity, sympathetic hyperinnervation, premature blunting of neuropeptide Y signaling, and hypertension in adult life.

PubMed

Rook, William; Johnson, Christopher D; Coney, Andrew M; Marshall, Janice M

2014-12-01

Adverse conditions prenatally increase the risk of cardiovascular disease, including hypertension. Chronic hypoxia in utero (CHU) causes endothelial dysfunction, but whether sympathetic vasoconstrictor nerve functioning is altered is unknown. We, therefore, compared in male CHU and control (N) rats muscle sympathetic nerve activity, vascular sympathetic innervation density, and mechanisms of sympathetic vasoconstriction. In young (Y)-CHU and Y-N rats (≈3 months), baseline arterial blood pressure was similar. However, tonic muscle sympathetic nerve activity recorded focally from arterial vessels of spinotrapezius muscle had higher mean frequency in Y-CHU than in Y-N rats (0.56±0.075 versus 0.33±0.036 Hz), and the proportions of single units with high instantaneous frequencies (1-5 and 6-10 Hz) being greater in Y-CHU rats. Sympathetic innervation density of tibial arteries was ≈50% greater in Y-CHU than in Y-N rats. Increases in femoral vascular resistance evoked by sympathetic stimulation at low frequency (2 Hz for 2 minutes) and bursts at 20 Hz were substantially smaller in Y-CHU than in Y-N rats. In Y-N only, the neuropeptide Y Y1-receptor antagonist BIBP3226 attenuated these responses. By contrast, baseline arterial blood pressure was higher in middle-aged (M)-CHU than in M-N rats (≈9 months; 139±3 versus 126±3 mm Hg, respectively). BIBP3226 had no effect on femoral vascular resistance increases evoked by 2 Hz or 20 Hz bursts in M-N or M-CHU rats. These results indicate that fetal programming induced by prenatal hypoxia causes an increase in centrally generated muscle sympathetic nerve activity in youth and hypertension by middle age. This is associated with blunting of sympathetically evoked vasoconstriction and its neuropeptide Y component that may reflect premature vascular aging and contribute to increased risk of cardiovascular disease. © 2014 American Heart Association, Inc.

Sialorphin (the mature peptide product of Vcsa1) relaxes corporal smooth muscle tissue and increases erectile function in the ageing rat.

PubMed

Davies, Kelvin P; Tar, Moses; Rougeot, Catherine; Melman, Arnold

2007-02-01

To determine if the mature peptide product of the Vcsa1 gene, sialorphin, could restore erectile function in ageing rats, and whether these effects are mediated through relaxation of corporal smooth muscle tissue, as we recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in three distinct models of erectile dysfunction, and gene transfer of plasmids expressing Vcsa1 into the corpora of ageing rats restored erectile function. Sialorphin was injected intracorporeally into retired breeder rats, and the effect on the physiology of corporal tissue was analysed by intracorporal/blood pressure (ICP/BP) measurement at different times after injection. In organ-bath studies, the ability of sialorphin (1 microg/mL) to enhance C-type natriuretic peptide (CNP) relaxation of corporal smooth muscle tissue strips was investigated after pre-contraction with 1 microm phenylephrine. Intracorporal injection of 100 microg sialorphin into retired breeder rats resulted in a time-dependent increase in the ICP/BP response to electrostimulation of the cavernosal nerve. After 55-65 min the ICP/BP ratio increased to approximately 0.6, a value associated with normal erectile function. In organ-bath studies after pre-contraction with 1 microm phenylephrine, 1 microm CNP significantly (67%) increased the relaxation rate of corporal tissue. This rate of relaxation was increased by 2.5-fold after incubation with sialorphin (1 microg/mL) compared with carrier alone. These results show that sialorphin has a role in erectile function, probably through a mechanism that involves relaxation of corporal smooth muscle tissue.

Statin-induced myotoxicity is exacerbated by aging: A biophysical and molecular biology study in rats treated with atorvastatin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Camerino, Giulia Maria; De Bellis, Michela; Conte,

Statin-induced skeletal muscle damage in rats is associated to the reduction of the resting sarcolemmal chloride conductance (gCl) and ClC-1 chloride channel expression. These drugs also affect the ClC-1 regulation by increasing protein kinase C (PKC) activity, which phosphorylate and close the channel. Also the intracellular resting calcium (restCa) level is increased. Similar alterations are observed in skeletal muscles of aged rats, suggesting a higher risk of statin myotoxicity. To verify this hypothesis, we performed a 4–5-weeks atorvastatin treatment of 24-months-old rats to evaluate the ClC-1 channel function by the two-intracellular microelectrodes technique as well as transcript and protein expressionmore » of different genes sensitive to statins by quantitative real-time-PCR and western blot analysis. The restCa was measured using FURA-2 imaging, and histological analysis of muscle sections was performed. The results show a marked reduction of resting gCl, in agreement with the reduced ClC-1 mRNA and protein expression in atorvastatin-treated aged rats, with respect to treated adult animals. The observed changes in myocyte-enhancer factor-2 (MEF2) expression may be involved in ClC-1 expression changes. The activity of PKC was also increased and further modulate the gCl in treated aged rats. In parallel, a marked reduction of the expression of glycolytic and mitochondrial enzymes demonstrates an impairment of muscle metabolism. No worsening of restCa or histological features was found in statin-treated aged animals. These findings suggest that a strong reduction of gCl and alteration of muscle metabolism coupled to muscle atrophy may contribute to the increased risk of statin-induced myopathy in the elderly. - Highlights: • This work characterizes the causes of atorvastatin related myotoxicity in aged rats. • Skeletal muscle chloride channel ClC-1 is a target of statin-induced side effects. • ClC-1 dysfunction is worsened by aging process. • Age-related changes of energy production contribute to statin-induced myotoxicity. • These findings suggest caution with statin therapy during aging.« less

Effects of prolonged ingestion of epigallocatechin gallate on diabetes type 1-induced vascular modifications in the erectile tissue of rats.

PubMed

Lombo, C; Morgado, C; Tavares, I; Neves, D

2016-07-01

Diabetes Mellitus type 1 is a metabolic disease that predisposes to erectile dysfunction, partly owing to structural and molecular changes in the corpus cavernosum (CC) vessels. The aim of this study was to determine the effects of early treatment with the antioxidant epigallocatechin gallate (EGCG) in cavernous diabetes-induced vascular modifications. Diabetes was induced in two groups of young Wistar rats; one group was treated with EGCG for 10 weeks. A reduction in smooth muscle content was observed in the CC of diabetic rats, which was significantly attenuated with EGCG consumption. No differences were observed among groups, neither in the expression of VEGF assayed by western blotting nor in the immunofluorescent labeling of vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2). VEGFR2 was restricted to the endothelium, whereas VEGF and VEGFR1 co-localized in the smooth muscle layer. With regard to the Angiopoietin/Tie-2 system, no quantitative differences in Angiopoietin 1 were observed among the experimental groups. Ang1 localization was restricted to the smooth muscle layer, and receptor Tie2 and Angiopoietin 2 were both expressed in the endothelium. In brief, our results suggest that EGCG consumption prevented diabetes-induced loss of cavernous smooth muscle but does not affect vascular growth factor expression in young rats.

Using gene chips to identify organ-specific, smooth muscle responses to experimental diabetes: potential applications to urological diseases.

PubMed

Hipp, Jason D; Davies, Kelvin P; Tar, Moses; Valcic, Mira; Knoll, Abraham; Melman, Arnold; Christ, George J

2007-02-01

To identify early diabetes-related alterations in gene expression in bladder and erectile tissue that would provide novel diagnostic and therapeutic treatment targets to prevent, delay or ameliorate the ensuing bladder and erectile dysfunction. The RG-U34A rat GeneChip (Affymetrix Inc., Sunnyvale, CA, USA) oligonucleotide microarray (containing approximately 8799 genes) was used to evaluate gene expression in corporal and male bladder tissue excised from rats 1 week after confirmation of a diabetic state, but before demonstrable changes in organ function in vivo. A conservative analytical approach was used to detect alterations in gene expression, and gene ontology (GO) classifications were used to identify biological themes/pathways involved in the aetiology of the organ dysfunction. In all, 320 and 313 genes were differentially expressed in bladder and corporal tissue, respectively. GO analysis in bladder tissue showed prominent increases in biological pathways involved in cell proliferation, metabolism, actin cytoskeleton and myosin, as well as decreases in cell motility, and regulation of muscle contraction. GO analysis in corpora showed increases in pathways related to ion channel transport and ion channel activity, while there were decreases in collagen I and actin genes. The changes in gene expression in these initial experiments are consistent with the pathophysiological characteristics of the bladder and erectile dysfunction seen later in the diabetic disease process. Thus, the observed changes in gene expression might be harbingers or biomarkers of impending organ dysfunction, and could provide useful diagnostic and therapeutic targets for a variety of progressive urological diseases/conditions (i.e. lower urinary tract symptoms related to benign prostatic hyperplasia, erectile dysfunction, etc.).

Effects of exercise training on brain-derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction.

PubMed

Lee, Heow Won; Ahmad, Monir; Wang, Hong-Wei; Leenen, Frans H H

2017-03-01

What is the central question of this study? Exercise training increases brain-derived neurotrophic factor (BDNF) in the hippocampus, which depends on a myokine, fibronectin type III domain-containing protein 5 (FNDC5). Whether exercise training after myocardial infarction induces parallel increases in FNDC5 and BDNF expression in skeletal muscle and the heart has not yet been studied. What is the main finding and its importance? Exercise training after myocardial infarction increases BDNF protein in skeletal muscle and the non-infarct area of the LV without changes in FNDC5 protein, suggesting that BDNF is not regulated by FNDC5 in skeletal muscle and heart. An increase in cardiac BDNF may contribute to the improvement of cardiac function by exercise training. Exercise training after myocardial infarction (MI) attenuates progressive left ventricular (LV) remodelling and dysfunction, but the peripheral stimuli induced by exercise that trigger these beneficial effects are still unclear. We investigated as possible mediators fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the skeletal muscle and heart. Male Wistar rats underwent either sham surgery or ligation of the left descending coronary artery, and surviving MI rats were allocated to either a sedentary (Sed-MI) or an exercise group (ExT-MI). Exercise training was done for 4 weeks on a motor-driven treadmill. At the end, LV function was evaluated, and FNDC5 and BDNF mRNA and protein were assessed in soleus muscle, quadriceps and non-, peri- and infarct areas of the LV. At 5 weeks post MI, FNDC5 mRNA was decreased in soleus muscle and all areas of the LV, but FNDC5 protein was increased in the soleus muscle and the infarct area. Mature BDNF (mBDNF) protein was decreased in the infarct area without a change in mRNA. Exercise training attenuated the decrease in ejection fraction and the increase in LV end-diastolic pressure post MI. Exercise training had no effect on FNDC5 mRNA and protein, but increased mBDNF protein in soleus muscle, quadriceps and the non-infarct area of the LV. The mBDNF protein in the non-infarct area correlated positively with ejection fraction and inversely with LV end-diastolic pressure. In conclusion, mBDNF is induced by exercise training in skeletal muscle and the non-infarct area of the LV, which may contribute to improvement of muscle dysfunction and cardiac function post MI. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Hyperammonaemia‐induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress

PubMed Central

Davuluri, Gangarao; Allawy, Allawy; Thapaliya, Samjhana; Rennison, Julie H.; Singh, Dharmvir; Kumar, Avinash; Sandlers, Yana; Van Wagoner, David R.; Flask, Chris A.; Hoppel, Charles; Kasumov, Takhar

2016-01-01

Key points Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia.We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD+/NADH ratio and ATP content.During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids.Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell‐permeable ester of αKG reversed the lower TCA cycle intermediate concentrations and increased ATP content.Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS. Abstract Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non‐hepatic ammonia disposal. Non‐hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from α‐ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD+/NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell‐permeable ester of α‐ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia‐induced mitochondrial dysfunction is a novel therapeutic approach. PMID:27558544

Longitudinal studies of time-dependent changes in both bladder and erectile function after streptozotocin-induced diabetes in Fischer 344 male rats.

PubMed

Melman, Arnold; Zotova, Elena; Kim, Mimi; Arezzo, Joseph; Davies, Kelvin; DiSanto, Michael; Tar, Moses

2009-11-01

To provide sensitive physiological endpoints for the onset and long-term progression of deficits induced by diabetes mellitus (DM) in bladder and erectile function in male rats, and to evaluate parallel changes in urogenital and nerve function induced by hyperglycaemia over a protracted period as a model for chronic deficits in patients with diabetes. The study comprised in 877 male, 3-month-old, Fischer 344 rats; 666 were injected intraperitoneally with 35 mg/kg streptozotocin (STZ) and divided into insulin-treated and untreated diabetic groups. The rats were studied over 8 months and measurements made of both erectile and bladder function, as well as nerve conduction studies over the duration of the study. There was an early (first month) abnormality of both erectile and bladder function that persisted through the 8 months of the study. The erectile dysfunction was manifest as reduced intracavernous pressure/blood pressure ratio, and the bladder dysfunction as a persistent increase in detrusor overactivity with no detrusor decompensation. Insulin treatment prevented or modified the abnormality in each organ. Hyperglycaemia caused a progressive decrease in caudal nerve conduction velocity. The mean digital sensory and tibial motor nerve conduction velocity did not deteriorate over time. Correlation measurements of nerve and organ function were not consistent. The results of this extensive long-term study show early and profound effects of hyperglycaemia on the smooth muscle of the penis and bladder, that were persistent and stable in surviving rats over the 8 months. The physiological changes did not correlate well with neurological measurements of those organs. Significantly, diverse smooth-muscle cellular and subcellular events antedated the measured neurological manifestations of the hyperglycaemia by several months. Although autonomic diabetic neuropathy is a primary life-threatening complication of long-term diabetes in humans, this rat model of STZ-induced diabetes showed that the rapid onset of physiological manifestations was based on many molecular changes in the smooth muscle cells in this model of type 1 DM.

Hyperexcitability to electrical stimulation and accelerated muscle fatiguability of taut bands in rats.

PubMed

Wang, Yong-Hui; Yin, Ming-Jing; Fan, Zhen-Zhen; Arendt-Nielsen, Lars; Ge, Hong-You; Yue, Shou-Wei

2014-04-01

Myofascial trigger points contribute significantly to musculoskeletal pain and motor dysfunction and may be associated with accelerated muscle fatiguability. The aim of this study was to investigate the electrically induced force and fatigue characteristics of muscle taut bands in rats. Muscle taut bands were dissected out and subjected to trains of electrical stimulation. The electrical threshold intensity for muscle contraction and maximum contraction force (MCF), electrical intensity dependent fatigue and electrical frequency dependent fatigue characteristics were assessed in three different sessions (n=10 each) and compared with non-taut bands in the biceps femoris muscle. The threshold intensity for muscle contraction and MCF at the 10th, 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those of non-taut bands (all p<0.05). The MCF at the 15th and 20th intensity dependent fatigue stimuli of taut bands were significantly lower than those at the 1st and 5th stimuli (all p<0.01). The MCF in the frequency dependent fatigue test was significantly higher and the stimulus frequency that induced MCF was significantly lower for taut bands than for non-taut bands (both p<0.01). The present study demonstrates that the muscle taut band itself was more excitable to electrical stimulation and significantly less fatigue resistant than normal muscle fibres.

Effects of the peroxisome proliferator-activated receptor (PPAR)-δ agonist GW501516 on bone and muscle in ovariectomized rats.

PubMed

Mosti, M P; Stunes, A K; Ericsson, M; Pullisaar, H; Reseland, J E; Shabestari, M; Eriksen, E F; Syversen, U

2014-06-01

Estrogen deficiency promotes bone loss and skeletal muscle dysfunction. Peroxisome proliferator-activated receptors (PPARs) have 3 subtypes (α, δ, and γ). PPARγ agonists induce bone loss, whereas PPARα agonists increase bone mass. Although PPARδ agonists are known to influence skeletal muscle metabolism, the skeletal effects are unsettled. This study investigated the musculoskeletal effects of the PPARδ agonist GW501516 in ovariectomized (OVX) rats. Female Sprague Dawley rats, 12 weeks of age, were allocated to a sham-operated group and 3 OVX groups; high-dose GW501516 (OVX-GW5), low-dose GW501516 (OVX-GW1), and a control group (OVX-CTR), respectively (n = 12 per group). Animals received GW501516 or vehicle (methylcellulose) daily for 4 months by gavage. Bone mineral density (BMD) was assessed by dual x-ray absorptiometry at the femur, spine, and whole body. Bone microarchitecture at the proximal tibia was assessed by microcomputed tomography, and dynamic histomorphometry was performed. Quadriceps muscle morphology and the relative expression of mitochondrial proteins were analyzed. Bone metabolism markers and metabolic markers were measured in plasma. After 4 months, the OVX-GW5 group displayed lower femoral BMD than OVX-CTR. Trabecular separation was higher in the GW-treated groups, compared with OVX-CTR. The OVX-GW5 group also exhibited lower cortical area fraction and a higher structure model index than OVX-CTR. These effects coincided with impaired bone formation in both GW groups. The OVX-GW5 group displayed elevated triglyceride levels and reduced adiponectin levels, whereas no effects on muscle morphology or mitochondrial gene expression appeared. In summary, the PPARδ agonist GW501516 negatively affected bone properties in OVX rats, whereas no effects were detected in skeletal muscle.

COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats.

PubMed

Muñoz, Mercedes; Sánchez, Ana; Pilar Martínez, María; Benedito, Sara; López-Oliva, Maria-Elvira; García-Sacristán, Albino; Hernández, Medardo; Prieto, Dolores

2015-07-01

Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS. Copyright © 2015 Elsevier Inc. All rights reserved.

Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction

PubMed Central

Padilla, Jaume; Park, Young-Min; Welly, Rebecca J.; Scroggins, Rebecca J.; Britton, Steven L.; Koch, Lauren G.; Jenkins, Nathan T.; Crissey, Jacqueline M.; Zidon, Terese; Morris, E. Matthew; Meers, Grace M. E.; Thyfault, John P.

2015-01-01

Ovariectomized rodents model human menopause in that they rapidly gain weight, reduce spontaneous physical activity (SPA), and develop metabolic dysfunction, including insulin resistance. How contrasting aerobic fitness levels impacts ovariectomy (OVX)-associated metabolic dysfunction is not known. Female rats selectively bred for high and low intrinsic aerobic fitness [high-capacity runners (HCR) and low-capacity runners (LCR), respectively] were maintained under sedentary conditions for 39 wk. Midway through the observation period, OVX or sham (SHM) operations were performed providing HCR-SHM, HCR-OVX, LCR-SHM, and LCR-OVX groups. Glucose tolerance, energy expenditure, and SPA were measured before and 4 wk after surgery, while body composition via dual-energy X-ray absorptiometry and adipose tissue distribution, brown adipose tissue (BAT), and skeletal muscle phenotype, hepatic lipid content, insulin resistance via homeostatic assessment model of insulin resistance and AdipoIR, and blood lipids were assessed at death. Remarkably, HCR were protected from OVX-associated increases in adiposity and insulin resistance, observed only in LCR. HCR rats were ∼30% smaller, had ∼70% greater spontaneous physical activity (SPA), consumed ∼10% more relative energy, had greater skeletal muscle proliferator-activated receptor coactivator 1-alpha, and ∼40% more BAT. OVX did not increase energy intake and reduced SPA to the same extent in both HCR and LCR. LCR were particularly affected by an OVX-associated reduction in resting energy expenditure and experienced a reduction in relative BAT; resting energy expenditure correlated positively with BAT across all animals (r = 0.6; P < 0.001). In conclusion, despite reduced SPA following OVX, high intrinsic aerobic fitness protects against OVX-associated increases in adiposity and insulin resistance. The mechanism may involve preservation of resting energy expenditure. PMID:25608751

Sialorphin (the mature peptide product of Vcsa1) relaxes corporal smooth muscle tissue and increases erectile function in the ageing rat

PubMed Central

Davies, Kelvin P.; Tar, Moses; Rougeot, Catherine; Melman, Arnold

2007-01-01

OBJECTIVE To determine if the mature peptide product of the Vcsa1 gene, sialorphin, could restore erectile function in ageing rats, and whether these effects are mediated through relaxation of corporal smooth muscle tissue, as we recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in three distinct models of erectile dysfunction, and gene transfer of plasmids expressing Vcsa1 into the corpora of ageing rats restored erectile function. MATERIALS AND METHODS Sialorphin was injected intracorporeally into retired breeder rats, and the effect on the physiology of corporal tissue was analysed by intracorporal/blood pressure (ICP/BP) measurement at different times after injection. In organ-bath studies, the ability of sialorphin (1 μg/mL) to enhance C-type natriuretic peptide (CNP) relaxation of corporal smooth muscle tissue strips was investigated after pre-contraction with 1 μM phenylephrine. RESULTS Intracorporal injection of 100 μg sialorphin into retired breeder rats resulted in a time-dependent increase in the ICP/BP response to electrostimulation of the cavernosal nerve. After 55–65 min the ICP/BP ratio increased to ≈ 0.6, a value associated with normal erectile function. In organ-bath studies after pre-contraction with 1 μM phenylephrine, 1 μM CNP significantly (67%) increased the relaxation rate of corporal tissue. This rate of relaxation was increased by 2.5-fold after incubation with sialorphin (1 μg/mL) compared with carrier alone. CONCLUSION These results show that sialorphin has a role in erectile function, probably through a mechanism that involves relaxation of corporal smooth muscle tissue. PMID:17026587

Importance of neural mechanisms in colonic mucosal and muscular dysfunction in adult rats following neonatal colonic irritation.

PubMed

Chaloner, A; Rao, A; Al-Chaer, E D; Greenwood-Van Meerveld, B

2010-02-01

Previous studies have shown that early life trauma induced by maternal separation or colonic irritation leads to hypersensitivity to colorectal distension in adulthood. We tested the hypothesis that repetitive colorectal distension in neonates leads to abnormalities in colonic permeability and smooth muscle function in the adult rat. In neonatal rats, repetitive colorectal distension was performed on days 8, 10, and 12. As adults, stool consistency was graded from 0 (formed stool) to 3 (liquid stool). Colonic tissue was isolated for histology and myeloperoxidase levels. The colonic mucosa was placed in modified Ussing chambers for measurements of permeability and short-circuit current responses to forskolin, electrical field stimulation, and carbachol. Segments of colonic musculature were placed in organ baths and contractile response to potassium chloride, electrical field stimulation, and carbachol were determined. In adult rats that experienced neonatal colonic irritation, no significant changes in colonic histology or myeloperoxidase activity were observed; however, stool consistency scores were increased. Mucosal permeability, measured as an increase in basal conductance, was significantly increased but no changes in short-circuit current responses were observed. In adulthood, rats that underwent colorectal distension as neonates exhibited an elevated smooth muscle contractile response to potassium chloride, but no changes in response to electrical field stimulation or carbachol. In summary, neonatal colonic irritation, shown previously to produce colonic hypersensitivity, leads to significant alterations in colonic mucosal and smooth muscle function characterized by loose stools, increased mucosal permeability, and increased smooth muscle contractility in the absence of colon inflammation in adulthood. Published by Elsevier Ltd.

Exogenous skeletal muscle satellite cells promote the repair of levator palpebrae superioris mechanical damage in rat.

PubMed

Ye, Lin; Yao, Yuanyuan; Guo, Hui; Peng, Yun

2018-05-17

Blepharoptosis is a drooping of the upper eyelid, usually due to dysfunction of the levator palpebrae superioris (LPS). Recently, skeletal muscle satellite cells (SSCs) have been reported to promote the repair of damaged skeletal muscle. This study aims to investigate the potential contribution of exogenous SSCs to the regeneration of mechanically damaged LPS. Thirty-two rats were randomly divided into four groups, including control group, SSCs-treated group, SSCs-treated injury group and non-treated injury group. After rats in injury groups were artificially lacerated on both the left and right LPS, HBBS (Hank's Balanced Salt Solution) containing SSCs was injected into upper eyelid tissue. After 7 days, the LPS muscle tissues were excised. In addition, skeletal muscle cells (SMCs) and SSCs were cocultured for use as an in vitro model, and the protective effects of SSCs on cultured SMCs were also investigated. Histological staining revealed that exogenous SSCs repaired the damaged muscle fibers and attenuated the fibrosis of LPS, possibly due to the increased level of IGF-1. In contrast, the level of IL-1β, IL-6, TGF-β1 and Smad2/3 (phospho-T8) were significantly reduced in the SSCs-treated group. The in vitro model using coculture of skeletal muscle cells (SMCs) and SSCs also revealed an increased level of IGF-1 and reduced level of inflammatory factors, resulting in a better cell survival rate. This study found that exogenous SSCs can promote the repair of LPS mechanical damage and provides new insight into the development of novel therapeutic approaches for blepharoptosis.

Nanoparticle inhalation augments particle-dependent systemic microvascular dysfunction

PubMed Central

Nurkiewicz, Timothy R; Porter, Dale W; Hubbs, Ann F; Cumpston, Jared L; Chen, Bean T; Frazer, David G; Castranova, Vincent

2008-01-01

Background We have shown that pulmonary exposure to fine particulate matter (PM) impairs endothelium dependent dilation in systemic arterioles. Ultrafine PM has been suggested to be inherently more toxic by virtue of its increased surface area. The purpose of this study was to determine if ultrafine PM (or nanoparticle) inhalation produces greater microvascular dysfunction than fine PM. Rats were exposed to fine or ultrafine TiO2 aerosols (primary particle diameters of ~1 μm and ~21 nm, respectively) at concentrations which do not alter bronchoalveolar lavage markers of pulmonary inflammation or lung damage. Results By histopathologic evaluation, no significant inflammatory changes were seen in the lung. However, particle-containing macrophages were frequently seen in intimate contact with the alveolar wall. The spinotrapezius muscle was prepared for in vivo microscopy 24 hours after inhalation exposures. Intraluminal infusion of the Ca2+ ionophore A23187 was used to evaluate endothelium-dependent arteriolar dilation. In control rats, A23187 infusion produced dose-dependent arteriolar dilations. In rats exposed to fine TiO2, A23187 infusion elicited vasodilations that were blunted in proportion to pulmonary particle deposition. In rats exposed to ultrafine TiO2, A23187 infusion produced arteriolar constrictions or significantly impaired vasodilator responses as compared to the responses observed in control rats or those exposed to a similar pulmonary load of fine particles. Conclusion These observations suggest that at equivalent pulmonary loads, as compared to fine TiO2, ultrafine TiO2 inhalation produces greater remote microvascular dysfunction. PMID:18269765

Roles of Polyuria and Hyperglycemia on Bladder Dysfunction in Diabetes

PubMed Central

Xiao, Nan; Wang, Zhiping; Huang, Yexiang; Daneshgari, Firouz; Liu, Guiming

2014-01-01

Purpose Diabetes mellitus (DM) causes diabetic bladder dysfunction (DBD). We aimed to identify the pathogenic roles of polyuria and hyperglycemia on DBD in rats. Materials and Methods Seventy-two female Sprague-Dawley rats were divided: age-matched controls (control), sham urinary diversion (sham), urinary diversion (UD), streptozotocin-induced diabetes after sham UD (DM), streptozotocin-induced diabetes after UD (UD+DM), and 5% sucrose-induced diuresis after sham UD (DIU). UD was performed by ureterovaginostomy 10d before DM induction. Animals were evaluated 20 wks after DM or diuresis induction. We measured 24-hr drinking and voiding volumes and cystometry (CMG). Bladders were harvested for quantification of smooth muscle, urothelium, and collagen. We measured nitrotyrosine and manganese superoxide dismutase (MnSOD) in bladder. Results Diabetes and diuresis caused increases in drinking volume, voiding volume and bladder weight. Bladder weights decreased in the UD and UD+DM groups. Intercontractile intervals, voided volume, and compliance increased in the DIU and DM groups, decreased in the UD, and further decreased in the UD+DM group. The total cross-sectional tissue, smooth muscle and urothelium areas increased in the DIU and DM groups, and decreased in the UD and UD+DM groups. As percentages of total tissue area, collagen decreased in the DIU and DM groups, and increased in the UD and UD+DM groups, and smooth muscle and urothelium decreased in the UD and UD+DM groups. Nitrotyrosine and MnSOD increased in DM and UD+DM rats. Conclusions Polyuria induced bladder hypertrophy, while hyperglycemia induced substantial oxidative stress in the bladder, which may play a pathogenic role in late stage DBD. PMID:22999997

Exposure to Gulf War Illness chemicals induces functional muscarinic receptor maladaptations in muscle nociceptors.

PubMed

Cooper, B Y; Johnson, R D; Nutter, T J

2016-05-01

Chronic pain is a component of the multisymptom disease known as Gulf War Illness (GWI). There is evidence that pain symptoms could have been a consequence of prolonged and/or excessive exposure to anticholinesterases and other GW chemicals. We previously reported that rats exposed, for 8 weeks, to a mixture of anticholinesterases (pyridostigmine bromide, chlorpyrifos) and a Nav (voltage activated Na(+) channel) deactivation-inhibiting pyrethroid, permethrin, exhibited a behavior pattern that was consistent with a delayed myalgia. This myalgia-like behavior was accompanied by persistent changes to Kv (voltage activated K(+)) channel physiology in muscle nociceptors (Kv7, KDR). In the present study, we examined how exposure to the above agents altered the reactivity of Kv channels to a muscarinic receptor (mAChR) agonist (oxotremorine-M). Comparisons between muscle nociceptors harvested from vehicle and GW chemical-exposed rats revealed that mAChR suppression of Kv7 activity was enhanced in exposed rats. Yet in these same muscle nociceptors, a Stromatoxin-insensitive component of the KDR (voltage activated delayed rectifier K(+) channel) exhibited decreased sensitivity to activation of mAChR. We have previously shown that a unique mAChR-induced depolarization and burst discharge (MDBD) was exaggerated in muscle nociceptors of rats exposed to GW chemicals. We now provide evidence that both muscle and vascular nociceptors of naïve rats exhibit MDBD. Examination of the molecular basis of the MDBD in naïve animals revealed that while the mAChR depolarization was independent of Kv7, the action potential burst was modulated by Kv7 status. mAChR depolarizations were shown to be dependent, in part, on TRPA1. We argue that dysfunction of the MDBD could be a functional convergence point for maladapted ion channels and receptors consequent to exposure to GW chemicals. Copyright © 2016 Elsevier Inc. All rights reserved.

Down-regulation of fibroblast growth factor 2 and its co-receptors heparan sulfate proteoglycans by resveratrol underlies the improvement of cardiac dysfunction in experimental diabetes.

PubMed

Strunz, Célia Maria Cássaro; Roggerio, Alessandra; Cruz, Paula Lázara; Pacanaro, Ana Paula; Salemi, Vera Maria Cury; Benvenuti, Luiz Alberto; Mansur, Antonio de Pádua; Irigoyen, Maria Cláudia

2017-02-01

Cardiac remodeling in diabetes involves cardiac hypertrophy and fibrosis, and fibroblast growth factor 2 (FGF2) is an important mediator of this process. Resveratrol, a polyphenolic antioxidant, reportedly promotes the improvement of cardiac dysfunction in diabetic rats. However, little information exists linking the amelioration of the cardiac function promoted by resveratrol and the expression of FGF2 and its co-receptors, heparan sulfate proteoglycans (HSPGs: Glypican-1 and Syndecan-4), in cardiac muscle of Type 2 diabetic rats. Diabetes was induced experimentally by the injection of streptozotocin and nicotinamide, and the rats were treated with resveratrol for 6 weeks. According to our results, there is an up-regulation of the expression of genes and/or proteins of Glypican-1, Syndecan-4, FGF2, peroxisome proliferator-activated receptor gamma and AMP-activated protein kinase in diabetic rats. On the other hand, resveratrol treatment promoted the attenuation of left ventricular diastolic dysfunction and the down-regulation of the expression of all proteins under study. The trigger for the changes in gene expression and protein synthesis promoted by resveratrol was the presence of diabetes. The negative modulation conducted by resveratrol on FGF2 and HSPGs expression, which are involved in cardiac remodeling, underlies the amelioration of cardiac function. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A novel experimental model of erectile dysfunction in rats with heart failure using volume overload

PubMed Central

Silva, Fábio Henrique; Veiga, Frederico José Reis; Mora, Aline Gonçalves; Heck, Rodrigo Sader; De Oliveira, Caroline Candida; Gambero, Alessandra; Franco-Penteado, Carla Fernanda; Antunes, Edson; Gardner, Jason D.; Priviero, Fernanda Bruschi Marinho

2017-01-01

Background Patients with heart failure (HF) display erectile dysfunction (ED). However, the pathophysiology of ED during HF remains poorly investigated. Objective This study aimed to characterize the aortocaval fistula (ACF) rat model associated with HF as a novel experimental model of ED. We have undertaken molecular and functional studies to evaluate the alterations of the nitric oxide (NO) pathway, autonomic nervous system and oxidative stress in the penis. Methods Male rats were submitted to ACF for HF induction. Intracavernosal pressure in anesthetized rats was evaluated. Concentration-response curves to contractile (phenylephrine) and relaxant agents (sodium nitroprusside; SNP), as well as to electrical field stimulation (EFS), were obtained in the cavernosal smooth muscle (CSM) strips from sham and HF rats. Protein expression of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) and phosphodiestarese-5 in CSM were evaluated, as well as NOX2 (gp91phox) and superoxide dismutase (SOD) mRNA expression. SOD activity and thiobarbituric acid reactive substances (TBARs) were also performed in plasma. Results HF rats display erectile dysfunction represented by decreased ICP responses compared to sham rats. The neurogenic contractile responses elicited by EFS were greater in CSM from the HF group. Likewise, phenylephrine-induced contractions were greater in CSM from HF rats. Nitrergic response induced by EFS were decreased in the cavernosal tissue, along with lower eNOS, nNOS and phosphodiestarese-5 protein expressions. An increase of NOX2 and SOD mRNA expression in CSM and plasma TBARs of HF group were detected. Plasma SOD activity was decreased in HF rats. Conclusion ED in HF rats is associated with decreased NO bioavailability in erectile tissue due to eNOS/nNOS dowregulation and NOX2 upregulation, as well as hypercontractility of the penis. This rat model of ACF could be a useful tool to evaluate the molecular alterations of ED associated with HF. PMID:29095897

A novel experimental model of erectile dysfunction in rats with heart failure using volume overload.

PubMed

Silva, Fábio Henrique; Veiga, Frederico José Reis; Mora, Aline Gonçalves; Heck, Rodrigo Sader; De Oliveira, Caroline Candida; Gambero, Alessandra; Franco-Penteado, Carla Fernanda; Antunes, Edson; Gardner, Jason D; Priviero, Fernanda Bruschi Marinho; Claudino, Mário Angelo

2017-01-01

Patients with heart failure (HF) display erectile dysfunction (ED). However, the pathophysiology of ED during HF remains poorly investigated. This study aimed to characterize the aortocaval fistula (ACF) rat model associated with HF as a novel experimental model of ED. We have undertaken molecular and functional studies to evaluate the alterations of the nitric oxide (NO) pathway, autonomic nervous system and oxidative stress in the penis. Male rats were submitted to ACF for HF induction. Intracavernosal pressure in anesthetized rats was evaluated. Concentration-response curves to contractile (phenylephrine) and relaxant agents (sodium nitroprusside; SNP), as well as to electrical field stimulation (EFS), were obtained in the cavernosal smooth muscle (CSM) strips from sham and HF rats. Protein expression of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) and phosphodiestarese-5 in CSM were evaluated, as well as NOX2 (gp91phox) and superoxide dismutase (SOD) mRNA expression. SOD activity and thiobarbituric acid reactive substances (TBARs) were also performed in plasma. HF rats display erectile dysfunction represented by decreased ICP responses compared to sham rats. The neurogenic contractile responses elicited by EFS were greater in CSM from the HF group. Likewise, phenylephrine-induced contractions were greater in CSM from HF rats. Nitrergic response induced by EFS were decreased in the cavernosal tissue, along with lower eNOS, nNOS and phosphodiestarese-5 protein expressions. An increase of NOX2 and SOD mRNA expression in CSM and plasma TBARs of HF group were detected. Plasma SOD activity was decreased in HF rats. ED in HF rats is associated with decreased NO bioavailability in erectile tissue due to eNOS/nNOS dowregulation and NOX2 upregulation, as well as hypercontractility of the penis. This rat model of ACF could be a useful tool to evaluate the molecular alterations of ED associated with HF.

Soluble receptor for advanced glycation end products mitigates vascular dysfunction in spontaneously hypertensive rats.

PubMed

Liu, Yu; Yu, Manli; Zhang, Le; Cao, Qingxin; Song, Ying; Liu, Yuxiu; Gong, Jianbin

2016-08-01

Vascular dysfunction including vascular remodeling and endothelial dysfunction in hypertension often results in poor clinical outcomes and increased risk of vascular accidents. We investigate the effect of treatment with soluble receptor for advanced glycation end products (sRAGE) on vascular dysfunction in spontaneously hypertensive rats (SHR). Firstly, the aortic AGE/RAGE pathway was investigated in SHR. Secondly, SHR received intraperitoneal injections of sRAGE daily for 4 weeks. Effect of sRAGE against vascular dysfunction in SHR and underlying mechanism was investigated. SHR aortas exhibited enhanced activity of aldose reductase, reduced activity of glyoxalase 1, accumulation of methylglyoxal and AGE, and upregulated expression of RAGE. Treatment of SHR with sRAGE had no significant effect on blood pressure, but alleviated aortic hypertrophy and endothelial dysfunction. In vitro, treatment with sRAGE reversed the effect of incubation with AGE on proliferation of smooth muscle cells and endothelial function. Treatment of SHR with sRAGE abated oxidative stress, suppressed inflammation and NF-κB activation, improved the balance between Ang II and Ang-(1-7) through reducing angiotensin-converting enzyme (ACE) activity and enhancing ACE2 expression, and upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in aortas. In conclusion, treatment with sRAGE alleviated vascular adverse remodeling in SHR, possibly via suppression of oxidative stress and inflammation, improvement in RAS balance, and activation of PPAR-γ pathway.

Inhibition of forkhead boxO-specific transcription prevents mechanical ventilation-induced diaphragm dysfunction.

PubMed

Smuder, Ashley J; Sollanek, Kurt J; Min, Kisuk; Nelson, W Bradley; Powers, Scott K

2015-05-01

Mechanical ventilation is a lifesaving measure for patients with respiratory failure. However, prolonged mechanical ventilation results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragm weakness is essential to developing effective countermeasures to combat this important problem. In this regard, the forkhead boxO family of transcription factors is activated in the diaphragm during mechanical ventilation, and forkhead boxO-specific transcription can lead to enhanced proteolysis and muscle protein breakdown. Currently, the role that forkhead boxO activation plays in the development of mechanical ventilation-induced diaphragm weakness remains unknown. This study tested the hypothesis that mechanical ventilation-induced increases in forkhead boxO signaling contribute to ventilator-induced diaphragm weakness. University research laboratory. Young adult female Sprague-Dawley rats. Cause and effect was determined by inhibiting the activation of forkhead boxO in the rat diaphragm through the use of a dominant-negative forkhead boxO adeno-associated virus vector delivered directly to the diaphragm. Our results demonstrate that prolonged (12 hr) mechanical ventilation results in a significant decrease in both diaphragm muscle fiber size and diaphragm-specific force production. However, mechanically ventilated animals treated with dominant-negative forkhead boxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting forkhead boxO transcription attenuated the mechanical ventilation-induced activation of the ubiquitin-proteasome system, the autophagy/lysosomal system, and caspase-3. Forkhead boxO is necessary for the activation of key proteolytic systems essential for mechanical ventilation-induced diaphragm atrophy and contractile dysfunction. Collectively, these results suggest that targeting forkhead boxO transcription could be a key therapeutic target to combat ventilator-induced diaphragm dysfunction.

Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway

PubMed Central

Fan, Jingjing; Yang, Xiaoqi; Li, Jie; Shu, Ziyang; Dai, Jun; Liu, Xingran; Li, Biao; Jia, Shaohui; Kou, Xianjuan; Yang, Yi; Chen, Ning

2017-01-01

The quality control of skeletal muscle is a continuous requirement throughout the lifetime, although its functions and quality present as a declining trend during aging process. Dysfunctional or deficient autophagy and excessive apoptosis may contribute to the atrophy of senescent skeletal muscle. Spermidine, as a natural polyamine, can be involved in important cellular functions for lifespan extension and stress resistance in several model organisms through activating autophagy. Similarly, cellular autophagic responses to exercise have also been extensively investigated. In the present study, in order to confirm the mitigation or amelioration of skeletal muscle atrophy in aging rats through spermidine coupled with exercise intervention and explore corresponding mechanisms, the rat model with aging-related atrophy of skeletal muscle was established by intraperitoneal injection of D-galactose (D-gal) (200 mg/kgd), and model rats were subjected to the intervention with spermidine (5 mg/kgd) or swimming (60 min/d, 5 d/wk) or combination for 42 days. Spermidine coupled with exercise could attenuate D-gal-induced aging-related atrophy of skeletal muscle through induced autophagy and reduced apoptosis with characteristics of more autophagosomes, activated mitophagy, enhanced mitochondrial quality, alleviated cell shrinkage, and less swollen mitochondria under transmission scanning microscopic observation. Meanwhile, spermidine coupled with exercise could induce autophagy through activating AMPK-FOXO3a signal pathway with characterization of increased Beclin1 and LC3-II/LC3-I ratio, up-regulated anti-apoptotic Bcl-2, down-regulated pro-apoptotic Bax and caspase-3, as well as activated AMPK and FOXO3a. Therefore, spermidine combined with exercise can execute the prevention or treatment of D-gal-induced aging-related skeletal muscle atrophy through enhanced autophagy and reduced apoptosis mediated by AMPK-FOXO3a signal pathway. PMID:28407698

Therapeutic effects of adipose-derived stem cells-based microtissues on erectile dysfunction in streptozotocin-induced diabetic rats

PubMed Central

Zhou, Feng; Hui, Yu; Xin, Hua; Xu, Yong-De; Lei, Hong-En; Yang, Bi-Cheng; Guan, Rui-Li; Li, Meng; Hou, Jian-Quan; Xin, Zhong-Cheng

2017-01-01

This study aimed to explore the therapeutic effects of adipose-derived stem cells (ADSCs)-based microtissues (MTs) on erectile dysfunction (ED) in streptozotocin (STZ)-induced diabetic rats. Fifty-six 8-week-old Sprague-Dawley rats received intraperitoneal injection of STZ (60 mg kg−1), and 8 weeks later, the determined diabetic rats randomly received intracavernous (IC) injection of phosphate buffer solution (PBS), ADSCs, or MTs. Another eight normal rats equally got IC injection of PBS. MTs were generated with a hanging drop method, and the injected cells were tracked in ADSC- and MT-injected rats. Four weeks after the treatments, intracavernous pressure (ICP), histopathological changes in corpus cavernosum (CC), and functional proteins were measured. Rat cytokine antibody array was used to detect ADSCs or MTs lysate. The results showed that MTs expressed vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and tumor necrosis factor-stimulated gene-6 (TSG-6). MTs injection had a higher retention than ADSCs injection and MTs treatment improved ICP, neuronal nitric oxide synthase (nNOS) expression, smooth muscle, and endothelial contents in diabetic rats, ameliorated local inflammation in CC better. Thus, our findings demonstrate that IC injection of MTs improves erectile function and histopathological changes in STZ-induced diabetic rats and appears to be more promising than traditional ADSCs. The underlying mechanisms involve increased cell retention accompanied with neuroprotection and anti-inflammatory behaviors of the paracrine factors. PMID:27345005

Association of Exercise Training with Tobacco Smoking Prevents Fibrosis but has Adverse Impact on Myocardial Mechanics.

PubMed

Reis Junior, Dermeval; Antonio, Ednei Luiz; de Franco, Marcello Fabiano; de Oliveira, Helenita Antonia; Tucci, Paulo José Ferreira; Serra, Andrey Jorge

2016-12-01

There was no data for cardiac repercussion of exercise training associated with tobacco smoking. This issue is interesting because some smoking people can be enrolled in an exercise-training program. Thus, we evaluated swimming training effects on the function and structural myocardial in rats exposed to tobacco smoking. Male Wistar rats were assigned to one of four groups: C, untrained rats without exposure to tobacco smoking; E, exercised rats without exposure to tobacco smoking; CS, untrained rats exposed to tobacco smoking; ECS, exercised rats exposed to tobacco smoking. Rats swam five times a week twice daily (60min per session) for 8 weeks. Before each bout exercise, rats breathed smoke from 20 cigarettes for 60min. Twenty-four hours after the last day of the protocol, papillary muscles were isolated for in vitro analysis of myocardial mechanics. The myocardial mass and nuclear cardiomyocyte volume were used as hypertrophy markers, and collagen content was determined by picrosirius red staining. There was a well-pronounced myocardial hypertrophic effect for two interventions. The exercise blunted myocardial collagen increases induced by tobacco smoking. However, exercise and tobacco-smoking association was deleterious to myocardial performance. Thereby, in vitro experiments with papillary muscles contracting in isometric showed impairment myocardial inotropism in exercised rats exposed to tobacco smoking. This work presents novel findings on the role of exercise training on cardiac remodeling induced by tobacco smoking. Although exercise has mitigated tissue fibrosis, their association with tobacco smoking exacerbated hypertrophy and in vitro myocardial dysfunction. This is first study to show that the association of an aerobic exercise training with tobacco smoking intensifies the phenotype of pathological cardiac hypertrophy. Therefore, the combination of interventions resulted in exacerbated myocardial hypertrophy and contractility dysfunction. These findings have significant clinical implication because some smoking people can be enrolled in an exercise-training program. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Gestational Protein Restriction Impairs Glucose Disposal in the Gastrocnemius Muscles of Female Rats

PubMed Central

Blesson, Chellakkan S.; Chinnathambi, Vijayakumar; Kumar, Sathish

2017-01-01

Gestational low-protein (LP) diet causes hyperglycemia and insulin resistance in adult offspring, but the mechanism is not clearly understood. In this study, we explored the role of insulin signaling in gastrocnemius muscles of gestational LP-exposed female offspring. Pregnant rats were fed a control (20% protein) or an isocaloric LP (6%) diet from gestational day 4 until delivery. Normal diet was given to mothers after delivery and to pups after weaning until necropsy. Offspring were euthanized at 4 months, and gastrocnemius muscles were treated with insulin ex vivo for 30 minutes. Messenger RNA and protein levels of molecules involved in insulin signaling were assessed at 4 months. LP females were smaller at birth but showed rapid catchup growth by 4 weeks. Glucose tolerance test in LP offspring at 3 months showed elevated serum glucose levels (P < 0.01; glycemia Δ area under the curve 342 ± 28 in LP vs 155 ± 23 in controls, mmol/L * 120 minutes) without any change in insulin levels. In gastrocnemius muscles, LP rats showed reduced tyrosine phosphorylation of insulin receptor substrate 1 upon insulin stimulation due to the overexpression of tyrosine phosphatase SHP-2, but serine phosphorylation was unaffected. Furthermore, insulin-induced phosphorylation of Akt, glycogen synthase kinase (GSK)–3α, and GSK-3β was diminished in LP rats, and they displayed an increased basal phosphorylation (inactive form) of glycogen synthase. Our study shows that gestational protein restriction causes peripheral insulin resistance by a series of phosphorylation defects in skeletal muscle in a mechanism involving insulin receptor substrate 1, SHP-2, Akt, GSK-3, and glycogen synthase causing dysfunctional GSK-3 signaling and increased stored glycogen, leading to distorted glucose homeostasis. PMID:28324067

Sex differences in the metabolic dysfunction and insulin resistance of skeletal muscle glucose transport following high fructose ingestion.

PubMed

Rattanavichit, Yupaporn; Chukijrungroat, Natsasi; Saengsirisuwan, Vitoon

2016-12-01

The role of high fructose ingestion (HFI) in the development of conditions mimicking human metabolic syndrome has mostly been demonstrated in male animals; however, the extent of HFI-induced metabolic alterations in females remains unclear. The present study investigated whether HFI-induced metabolic perturbations differ between sexes and whether HFI aggravates the metabolic disturbances under ovarian hormone deprivation. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were given either water or liquid fructose (10% wt/vol) for 6 wk. Blood pressure, glucose tolerance, insulin-stimulated glucose transport activity and signaling proteins, including insulin receptor (IR), insulin receptor substrate 1 (IRS-1), Akt, Akt substrate of 160 kDa (AS160), AMPKα, JNK, p38 MAPK, angiotensin-converting enzyme (ACE), ANG II type 1 receptor (AT 1 R), ACE2, and Mas receptor (MasR) in skeletal muscle, were evaluated. We found that HFI led to glucose intolerance and hypertension in male and OVX rats but not in female rats with intact ovaries. Moreover, HFI did not induce insulin resistance in the skeletal muscle of female and OVX rats but impaired the insulin-stimulated glucose transport activity in the skeletal muscle of male rats, which was accompanied by lower insulin-stimulated IRS-1 Tyr 989 (44%), Akt Ser 473 (30%), and AS160 Ser 588 (43%), and increases in insulin-stimulated IRS-1 Ser 307 (78%), JNK Thr 183 /Tyr 185 (69%), and p38 MAPK Thr 180 /Tyr 182 (81%). The results from the present study show sex differences in the development of metabolic syndrome-like conditions and indicate the protective role of female sex hormones against HFI-induced cardiometabolic abnormalities. Copyright © 2016 the American Physiological Society.

Reversal of diabetic vasculopathy in a rat model of type 1 diabetes by opiorphin-related peptides

PubMed Central

Calenda, Giulia; Tong, Yuehong; Kanika, Nirmala D.; Tar, Moses T.; Suadicani, Sylvia O.; Zhang, Xinhua; Melman, Arnold; Rougeot, Catherine

2011-01-01

Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma. In the present study, we investigated if diabetes induced changes in plasma sialorphin levels and if changes in these levels could modulate the biochemistry and physiology of vascular smooth muscle. We show that circulating sialorphin levels are reduced in a rat model of type I diabetes. Intracorporal injection of plasmids expressing sialorphin into diabetic rats restores sialorphin levels to those seen in the blood of nondiabetic animals and results in both improved erectile function and blood pressure. Sialorphin modulated the ability of C-type natriuretic peptide to relax both corporal and aortic smooth muscle strips and of bradykinin to regulate intracellular calcium levels in both corporal and aortic smooth muscle cells. We have previously shown that expression of genes encoding opiorphins is increased when erectile function is improved. Our findings thus suggest that by affecting circulating levels of opiorphin-related peptides, proper erectile function is not only an indicator but also a modulator of overall vascular health of a man. PMID:21784987

Reversal of diabetic vasculopathy in a rat model of type 1 diabetes by opiorphin-related peptides.

PubMed

Calenda, Giulia; Tong, Yuehong; Kanika, Nirmala D; Tar, Moses T; Suadicani, Sylvia O; Zhang, Xinhua; Melman, Arnold; Rougeot, Catherine; Davies, Kelvin P

2011-10-01

Diabetes results in a myriad of vascular complications, often referred to as diabetic vasculopathy, which encompasses both microvascular [erectile dysfunction (ED), retinopathy, neuropathy, and nephropathy] and macrovascular complications (hypertension, coronary heart disease, and myocardial infarction). In diabetic animals and patients with ED, there is decreased opiorphin or opiorphin-related gene expression in corporal tissue. Both opiorphin and the rat homologous peptide sialorphin are found circulating in the plasma. In the present study, we investigated if diabetes induced changes in plasma sialorphin levels and if changes in these levels could modulate the biochemistry and physiology of vascular smooth muscle. We show that circulating sialorphin levels are reduced in a rat model of type I diabetes. Intracorporal injection of plasmids expressing sialorphin into diabetic rats restores sialorphin levels to those seen in the blood of nondiabetic animals and results in both improved erectile function and blood pressure. Sialorphin modulated the ability of C-type natriuretic peptide to relax both corporal and aortic smooth muscle strips and of bradykinin to regulate intracellular calcium levels in both corporal and aortic smooth muscle cells. We have previously shown that expression of genes encoding opiorphins is increased when erectile function is improved. Our findings thus suggest that by affecting circulating levels of opiorphin-related peptides, proper erectile function is not only an indicator but also a modulator of overall vascular health of a man.

Pelvic muscles' mechanical response to strains in the absence and presence of pregnancy-induced adaptations in a rat model.

PubMed

Catanzarite, Tatiana; Bremner, Shannon; Barlow, Caitlin L; Bou-Malham, Laura; O'Connor, Shawn; Alperin, Marianna

2018-05-01

Maternal birth trauma to the pelvic floor muscles is thought to be consequent to mechanical demands placed on these muscles during fetal delivery that exceed muscle physiological limits. The above is consistent with studies of striated limb muscles that identify hyperelongation of sarcomeres, the functional muscle units, as the primary cause of mechanical muscle injury and resultant muscle dysfunction. However, pelvic floor muscles' mechanical response to strains have not been examined at a tissue level. Furthermore, we have previously demonstrated that during pregnancy, rat pelvic floor muscles acquire structural and functional adaptations in preparation for delivery, which likely protect against mechanical muscle injury by attenuating the strain effect. We sought to determine the mechanical impact of parturition-related strains on pelvic floor muscles' microstructure, and test the hypothesis that pregnancy-induced adaptations modulate muscle response to strains associated with vaginal delivery. Three-month-old Sprague-Dawley late-pregnant (N = 20) and nonpregnant (N = 22) rats underwent vaginal distention, replicating fetal crowning, with variable distention volumes. Age-matched uninjured pregnant and nonpregnant rats served as respective controls. After sacrifice, pelvic floor muscles, which include coccygeus, iliocaudalis, and pubocaudalis, were fixed in situ and harvested for fiber and sarcomere length measurements. To ascertain the extent of physiological strains during spontaneous vaginal delivery, analogous measurements were obtained in intrapartum rats (N = 4) sacrificed during fetal delivery. Data were compared with repeated measures and 2-way analysis of variance, followed by pairwise comparisons, with significance set at P < .05. Gross anatomic changes were observed in the pelvic floor muscles following vaginal distention, particularly in the entheseal region of pubocaudalis, which appeared translucent. The above appearance resulted from dramatic stretch of the myofibers, as indicated by significantly longer fiber length compared to controls. Stretch ratios, calculated as fiber length after vaginal distention divided by baseline fiber length, increased gradually with increasing distention volume. Paralleling these macroscopic changes, vaginal distention resulted in acute and progressive increase in sarcomere length with rising distention volume. The magnitude of strain effect varied by muscle, with the greatest sarcomere elongation observed in coccygeus, followed by pubocaudalis, and a smaller increase in iliocaudalis, observed only at higher distention volumes. The average fetal rat volume approximated 3 mL. Pelvic floor muscle sarcomere lengths in pregnant animals undergoing vaginal distention with 3 mL were similar to intrapartum sarcomere lengths in all muscles (P > .4), supporting the validity of our experimental approach. Vaginal distention resulted in dramatically longer sarcomere lengths in nonpregnant compared to pregnant animals, especially in coccygeus and pubocaudalis (P < .0001), indicating significant attenuation of sarcomere elongation in the presence of pregnancy-induced adaptations in pelvic floor muscles. Delivery-related strains lead to acute sarcomere elongation, a well-established cause of mechanical injury in skeletal muscles. Sarcomere hyperelongation resultant from mechanical strains is attenuated by pregnancy-induced adaptations acquired by the pelvic floor muscles prior to parturition. Copyright © 2018 Elsevier Inc. All rights reserved.

An animal model to study lower urinary tract symptoms and erectile dysfunction: the hyperlipidaemic rat.

PubMed

Rahman, Nadeem U; Phonsombat, Surat; Bochinski, Derek; Carrion, Rafael E; Nunes, Lora; Lue, Tom F

2007-09-01

To present evidence that rats fed a high-fat diet could serve as a useful animal model to study both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED), as recent epidemiological studies have shown a strong association between LUTS and ED but the physiological basis behind this relationship is unknown. In all, 24 male Sprague-Dawley rats were divided into two groups: nine controls were fed a 'normal' diet and 15 were fed a high-fat diet (hyperlipidaemic rats). After 6 months all the rats had bladder and erectile functions evaluated using awake cystometry and cavernosal nerve electrostimulation, respectively. After the functional studies were completed, the penis, prostate and bladder were collected for immunohistochemical analysis. The hyperlipidaemic rats had significantly higher serum cholesterol and low-density lipoprotein than the controls (P < 0.05). The hyperlipidaemic rats also had significantly worse erectile function (P = 0.004) and developed more bladder overactivity (P = 0.004) than the controls. In the hyperlipidaemic rats there was significant muscle hypertrophy in the peri-urethral lobe of the prostate (P < 0.001) and in the bladder (P < 0.05). There was also greater P2X(1) (purinoceptor) staining as well as other molecular changes in the bladder of the hyperlipidaemic rats. In this hyperlipidaemic rat model three abnormalities were consistently detected: prostatic enlargement, bladder overactivity, and ED. This rat model could be a useful research tool for understanding the common causes of LUTS and ED, as well as facilitating the development of preventive measures and better therapies to treat both conditions.

Exercise training decreases NADPH oxidase activity and restores skeletal muscle mass in heart failure rats.

PubMed

Cunha, Telma F; Bechara, Luiz R G; Bacurau, Aline V N; Jannig, Paulo R; Voltarelli, Vanessa A; Dourado, Paulo M; Vasconcelos, Andrea R; Scavone, Cristóforo; Ferreira, Júlio C B; Brum, Patricia C

2017-04-01

We have recently demonstrated that NADPH oxidase hyperactivity, NF-κB activation, and increased p38 phosphorylation lead to atrophy of glycolytic muscle in heart failure (HF). Aerobic exercise training (AET) is an efficient strategy to counteract skeletal muscle atrophy in this syndrome. Therefore, we tested whether AET would regulate muscle redox balance and protein degradation by decreasing NADPH oxidase hyperactivity and reestablishing NF-κB signaling, p38 phosphorylation, and proteasome activity in plantaris muscle of myocardial infarcted-induced HF (MI) rats. Thirty-two male Wistar rats underwent MI or fictitious surgery (SHAM) and were randomly assigned into untrained (UNT) and trained (T; 8 wk of AET on treadmill) groups. AET prevented HF signals and skeletal muscle atrophy in MI-T, which showed an improved exercise tolerance, attenuated cardiac dysfunction and increased plantaris fiber cross-sectional area. To verify the role of inflammation and redox imbalance in triggering protein degradation, circulating TNF-α levels, NADPH oxidase profile, NF-κB signaling, p38 protein levels, and proteasome activity were assessed. MI-T showed a reduced TNF-α levels, NADPH oxidase activity, and Nox2 mRNA expression toward SHAM-UNT levels. The rescue of NADPH oxidase activity induced by AET in MI rats was paralleled by reducing nuclear binding activity of the NF-κB, p38 phosphorylation, atrogin-1, mRNA levels, and 26S chymotrypsin-like proteasome activity. Taken together our data provide evidence for AET improving plantaris redox homeostasis in HF associated with a decreased NADPH oxidase, redox-sensitive proteins activation, and proteasome hyperactivity further preventing atrophy. These data reinforce the role of AET as an efficient therapy for muscle wasting in HF. NEW & NOTEWORTHY This study demonstrates, for the first time, the contribution of aerobic exercise training (AET) in decreasing muscle NADPH oxidase activity associated with reduced reactive oxygen species production and systemic inflammation, which diminish NF-κB overactivation, p38 phosphorylation, and ubiquitin proteasome system hyperactivity. These molecular changes counteract plantaris atrophy in trained myocardial infarction-induced heart failure rats. Our data provide new evidence into how AET may regulate protein degradation and thus prevent skeletal muscle atrophy. Copyright © 2017 the American Physiological Society.

Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis.

PubMed

Deng, Wensheng; Zhu, Yiming; Lin, Jiayun; Zheng, Lei; Zhang, Chihao; Luo, Meng

2017-07-01

Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis. Copyright © 2017 Elsevier Inc. All rights reserved.

RECOMBINANT FACTOR XIII DIMINISHES MULTIPLE ORGAN DYSFUNCTION IN RATS CAUSED BY GUT ISCHEMIA-REPERFUSION INJURY

PubMed Central

Zaets, Sergey B.; Xu, Da-Zhong; Lu, Qi; Feketova, Eleonora; Berezina, Tamara L.; Gruda, Maryann; Malinina, Inga V.; Deitch, Edwin A.; Olsen, Eva H. N.

2010-01-01

Plasma factor XIII (FXIII) is responsible for stabilization of fibrin clot at the final stage of blood coagulation. Because FXIII has also been shown to modulate inflammation and endothelial permeability, we hypothesized that FXIII diminishes multiple organ dysfunction caused by gut I/R injury. A model of superior mesenteric artery occlusion (SMAO) was used to induce gut I/R injury. Rats were subjected to 45-min SMAO or sham SMAO and treated with recombinant human FXIII A2 subunit (rFXIII) or placebo at the beginning of the reperfusion period. Lung permeability, lung and gut myeloperoxidase activity, gut histology, neutrophil respiratory burst, and microvascular blood flow in the liver and muscles were measured after a 3-h reperfusion period. The effect of activated rFXIII on transendothelial resistance of human umbilical vein endothelial cells was tested in vitro. Superior mesenteric artery occlusion–induced lung permeability as well as lung and gut myeloperoxidase activity was significantly lower in rFXIII-treated versus untreated animals. Similarly, rFXIII-treated rats had lower neutrophil respiratory burst activity and ileal mucosal injury. Rats treated with rFXIII also had higher liver microvascular blood flow compared with the placebo group. Superior mesenteric artery occlusion did not cause FXIII consumption during the study period. In vitro, activated rFXIII caused a dose-dependent increase in human umbilical vein endothelial cell monolayer resistance to thrombin-induced injury. Thus, administration of rFXIII diminishes SMAO-induced multiple organ dysfunction in rats, presumably by preservation of endothelial barrier function and the limitation of polymorphonuclear leukocyte activation. PMID:18948851

Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, X-J; Xia, L-L; Xu, T-Y; Zhang, X-H; Zhu, Z-W; Zhang, M-G; Liu, Y; Xu, C; Zhong, S; Shen, Z-J

2016-04-01

There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats. © 2015 Blackwell Verlag GmbH.

Alterations in intrinsic mitochondrial function with aging are fiber type-specific and do not explain differential atrophy between muscles.

PubMed

Picard, Martin; Ritchie, Darmyn; Thomas, Melissa M; Wright, Kathryn J; Hepple, Russell T

2011-12-01

To determine whether mitochondrial dysfunction is causally related to muscle atrophy with aging, we examined respiratory capacity, H(2) O(2) emission, and function of the mitochondrial permeability transition pore (mPTP) in permeabilized myofibers prepared from four rat muscles that span a range of fiber type and degree of age-related atrophy. Muscle atrophy with aging was greatest in fast-twitch gastrocnemius (Gas) muscle (-38%), intermediate in both the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (Sol) muscles (-21%), and non-existent in adductor longus (AL) muscle (+47%). In contrast, indices of mitochondrial dysfunction did not correspond to this differential degree of atrophy. Specifically, despite higher protein expression for oxidative phosphorylation (oxphos) system in fast Gas and EDL, state III respiratory capacity per myofiber wet weight was unchanged with aging, whereas the slow Sol showed proportional decreases in oxphos protein, citrate synthase activity, and state III respiration. Free radical leak (H(2) O(2) emission per O(2) flux) under state III respiration was higher with aging in the fast Gas, whereas state II free radical leak was higher in the slow AL. Only the fast muscles had impaired mPTP function with aging, with lower mitochondrial calcium retention capacity in EDL and shorter time to mPTP opening in Gas and EDL. Collectively, our results underscore that the age-related changes in muscle mitochondrial function depend largely upon fiber type and are unrelated to the severity of muscle atrophy, suggesting that intrinsic changes in mitochondrial function are unlikely to be causally involved in aging muscle atrophy. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Myostatin, a profibrotic factor and the main inhibitor of striated muscle mass, is present in the penile and vascular smooth muscle.

PubMed

Kovanecz, I; Masouminia, M; Gelfand, R; Vernet, D; Rajfer, J; Gonzalez-Cadavid, N F

2017-09-01

Myostatin is present in striated myofibers but, except for myometrial cells, has not been reported within smooth muscle cells (SMC). We investigated in the rat whether myostatin is present in SMC within the penis and the vascular wall and, if so, whether it is transcriptionally expressed and associated with the loss of corporal SMC occurring in certain forms of erectile dysfunction (ED). Myostatin protein was detected by immunohistochemistry/fluorescence and western blots in the perineal striated muscles, and also in the SMC of the penile corpora, arteries and veins, and aorta. Myostatin was found in corporal SMC cultures, and its transcriptional expression (and its receptor) was shown there by DNA microarrays. Myostatin protein was measured by western blots in the penile shaft of rats subjected to bilateral cavernosal nerve resection (BCNR), that were left untreated, or treated (45 days) with muscle-derived stem cells (MDSC), or concurrent daily low-dose sildenafil. Myostatin was not increased by BCNR (compared with sham operated animals), but over expressed after treatment with MDSC. This was reduced by concurrent sildenafil. The presence of myostatin in corporal and vascular SMC, and its overexpression in the corpora by MDSC therapy, may have relevance for the stem cell treatment of corporal fibrosis and ED.

Decreased intracellular [Ca2+ ] coincides with reduced expression of Dhprα1s, RyR1, and diaphragmatic dysfunction in a rat model of sepsis.

PubMed

Wang, Meng-Meng; Hao, Li-Ying; Guo, Feng; Zhong, Bin; Zhong, Xiao-Mei; Yuan, Jing; Hao, Yi-Fei; Zhao, Shuang; Sun, Xue-Fei; Lei, Ming; Jiao, Guang-Yu

2017-12-01

Sepsis can cause decreased diaphragmatic contractility. Intracellular calcium as a second messenger is central to diaphragmatic contractility. However, changes in intracellular calcium concentration ([Ca 2+ ]) and the distribution and co-localization of relevant calcium channels [dihydropyridine receptors, (DHPRα1s) and ryanodine receptors (RyR1)] remain unclear during sepsis. In this study we investigated the effect of changed intracellular [Ca 2+ ] and expression and distribution of DHPRα1s and RyR1 on diaphragm function during sepsis. We measured diaphragm contractility and isolated diaphragm muscle cells in a rat model of sepsis. The distribution and co-localization of DHPRα1s and RyR1 were determined using immunohistochemistry and immunofluorescence, whereas intracellular [Ca 2+ ] was measured by confocal microscopy and fluorescence spectrophotometry. Septic rat diaphragm contractility, expression of DHPRα1s and RyR1, and intracellular [Ca 2+ ] were significantly decreased in the rat sepsis model compared with controls. Decreased intracellular [Ca 2+ ] coincides with diaphragmatic contractility and decreased expression of DHPRα1s and RyR1 in sepsis. Muscle Nerve 56: 1128-1136, 2017. © 2017 Wiley Periodicals, Inc.

Mild aerobic training with blood flow restriction increases the hypertrophy index and MuSK in both slow and fast muscles of old rats: Role of PGC-1α.

PubMed

Bahreinipour, Mohammad-Ali; Joukar, Siyavash; Hovanloo, Fariborz; Najafipour, Hamid; Naderi, Vida; Rajiamirhasani, Alireza; Esmaeili-Mahani, Saeed

2018-06-01

Existing evidence emphasize the role of mitochondrial dysfunction in sarcopenia which is revealed as loss of skeletal muscle mass and neuromuscular junction remodeling. We assessed the effect of low-intensity aerobic training along with blood flow restriction on muscle hypertrophy index, muscle-specific kinase (MuSK), a pivotal protein of the neuromuscular junction and Peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) in aged male rats. Animals groups were control (CTL), sham (Sh), leg blood flow restriction (BFR), exercise (Ex), sham + exercise (Sh + Ex), and BFR plus exercise (BFR + Ex) groups. The exercise groups were trained with low intensity exercise for 10 weeks. 48 h after the last training session, animals were sacrificed under anesthesia. Soleus and EDL muscles were isolated, hypertrophy index was estimated and MuSK and PGC-1α were measured by western blot method. Hypertrophy index enhanced in soleus and Extensor digitorum longus (EDL) muscles of BFR + Ex group (P < 0.01 versus CTL and Sh groups, and P < 0.001 versus other groups). The MuSK protein of soleus and EDL muscles increased in BFR + Ex group (P < 0.01 and P < 0.001, respectively) in comparison with CTL and Sh groups. In BFR + Ex group, the PGC-1α protein increased in both soleus and EDL (P < 0.001 compared to other groups). Also the PGC-1α of soleus muscle was higher in Ex and Sh + Ex groups versus CTL and Sh groups (P < 0.05). Findings suggest that low endurance exercise plus BFR improves the MuSK and hypertrophy index of both slow and fast muscles of elderly rats probably through the rise of PGC-1α expression. Copyright © 2018. Published by Elsevier Inc.

Expression of Hsp27 correlated with rat detrusor contraction after acute urinary retention.

PubMed

Xiong, Zhiyong; Wang, Yongquan; Gong, Wei; Zhou, Zhansong; Lu, Gensheng

2013-09-01

Heat shock protein 27 (Hsp27) can regulate actin cytoskeleton dynamics and contractile protein activation. This study investigates whether Hsp27 expression is related to bladder contractile dysfunction after acute urinary retention (AUR). Female rats were randomized either to AUR by urethral ligation or to normal control group. Bladder and smooth muscle strip contraction at time points from 0 h to 7 days after AUR were estimated by cystometric and organ bath studies. Hsp27 expression in bladder tissue at each time point was detected with immunofluorescence, Western blots, and real-time PCR. Expression of the three phosphorylated forms of Hsp27 was detected by Western blots. Smooth muscle ultrastructure was observed by transmission electron microscopy. Data suggest that maximum detrusor pressure and both carbachol-induced and spontaneous detrusor strip contraction amplitude decreased gradually for the duration from 0 to 6 h, and then increased gradually to near-normal values at 24 h. Treatment of muscle strips with the p38MAK inhibitor, SB203580, inhibited carbachol-induced contractions. Smooth muscle ultrastructure damage was the highest at 6 h after AUR, and then lessened gradually during next 7 days, and ultrastructure was close to normal. Expressions of Hsp27 mRNA and protein and the proteins of the three phosphorylated forms were higher at 0 h, decreased to lower levels up to 6 h, and then gradually increased. Therefore, we conclude that rat bladder contractile function after AUR worsens during 0-6 h, and then gradually recovers. The findings of the current study suggest that Hsp27 modulates bladder smooth muscle contraction after AUR, and that phosphorylation of Hsp27 may be an important pathway modulating actin cytoskeleton dynamics in bladder smooth muscle contraction and reconstruction after injury.

Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity.

PubMed

Varshney, Rohan; Ali, Quaisar; Wu, Chengxiang; Sun, Zhongjie

2016-11-01

The objective of this study is to investigate whether stem cell delivery of secreted Klotho (SKL), an aging-suppressor protein, attenuates monocrotaline-induced pulmonary vascular dysfunction and remodeling. Overexpression of SKL in mesenchymal stem cells (MSCs) was achieved by transfecting MSCs with lentiviral vectors expressing SKL-green fluorescent protein (GFP). Four groups of rats were treated with monocrotaline, whereas an additional group was given saline (control). Three days later, 4 monocrotaline-treated groups received intravenous delivery of nontransfected MSCs, MSC-GFP, MSC-SKL-GFP, and PBS, respectively. Ex vivo vascular relaxing responses to acetylcholine were diminished in small pulmonary arteries (PAs) in monocrotaline-treated rats, indicating pulmonary vascular endothelial dysfunction. Interestingly, delivery of MSCs overexpressing SKL (MSC-SKL-GFP) abolished monocrotaline-induced pulmonary vascular endothelial dysfunction and PA remodeling. Monocrotaline significantly increased right ventricular systolic blood pressure, which was attenuated significantly by MSC-SKL-GFP, indicating improved PA hypertension. MSC-SKL-GFP also attenuated right ventricular hypertrophy. Nontransfected MSCs slightly, but not significantly, improved PA hypertension and pulmonary vascular endothelial dysfunction. MSC-SKL-GFP attenuated monocrotaline-induced inflammation, as evidenced by decreased macrophage infiltration around PAs. MSC-SKL-GFP increased SKL levels, which rescued the downregulation of SIRT1 (Sirtuin 1) expression and endothelial NO synthase (eNOS) phosphorylation in the lungs of monocrotaline-treated rats. In cultured endothelial cells, SKL abolished monocrotaline-induced downregulation of eNOS activity and NO levels and enhanced cell viability. Therefore, stem cell delivery of SKL is an effective therapeutic strategy for pulmonary vascular endothelial dysfunction and PA remodeling. SKL attenuates monocrotaline-induced PA remodeling and PA smooth muscle cell proliferation, likely by reducing inflammation and restoring SIRT1 levels and eNOS activity. © 2016 American Heart Association, Inc.

Maternal High Fat Diet Alters Skeletal Muscle Mitochondrial Catalytic Activity in Adult Male Rat Offspring

PubMed Central

Pileggi, Chantal A.; Hedges, Christopher P.; Segovia, Stephanie A.; Markworth, James F.; Durainayagam, Brenan R.; Gray, Clint; Zhang, Xiaoyuan D.; Barnett, Matthew P. G.; Vickers, Mark H.; Hickey, Anthony J. R.; Reynolds, Clare M.; Cameron-Smith, David

2016-01-01

A maternal high-fat (HF) diet during pregnancy can lead to metabolic compromise, such as insulin resistance in adult offspring. Skeletal muscle mitochondrial dysfunction is one mechanism contributing to metabolic impairments in insulin resistant states. Therefore, the present study aimed to investigate whether mitochondrial dysfunction is evident in metabolically compromised offspring born to HF-fed dams. Sprague-Dawley dams were randomly assigned to receive a purified control diet (CD; 10% kcal from fat) or a high fat diet (HFD; 45% kcal from fat) for 10 days prior to mating, throughout pregnancy and during lactation. From weaning, all male offspring received a standard chow diet and soleus muscle was collected at day 150. Expression of the mitochondrial transcription factors nuclear respiratory factor-1 (NRF1) and mitochondrial transcription factor A (mtTFA) were downregulated in HF offspring. Furthermore, genes encoding the mitochondrial electron transport system (ETS) respiratory complex subunits were suppressed in HF offspring. Moreover, protein expression of the complex I subunit, NDUFB8, was downregulated in HF offspring (36%), which was paralleled by decreased maximal catalytic linked activity of complex I and III (40%). Together, these results indicate that exposure to a maternal HF diet during development may elicit lifelong mitochondrial alterations in offspring skeletal muscle. PMID:27917127

ANIMAL MODELS OF DYSTONIA: LESSONS FROM A MUTANT RAT

PubMed Central

LeDoux, Mark S.

2010-01-01

Dystonia is a motor sign characterized by involuntary muscle contractions which produce abnormal postures. Genetic factors contribute significantly to primary dystonia. In comparison, secondary dystonia can be caused by a wide variety of metabolic, structural, infectious, toxic and inflammatory insults to the nervous system. Although classically ascribed to dysfunction of the basal ganglia, studies of diverse animal models have pointed out that dystonia is a network disorder with important contributions from abnormal olivocerebellar signaling. In particular, work with the dystonic (dt) rat has engendered dramatic paradigm shifts in dystonia research. The dt rat manifests generalized dystonia caused by deficiency of the neuronally-restricted protein caytaxin. Electrophysiological and biochemical studies have shown that defects at the climbing fiber-Purkinje cell synapse in the dt rat lead to abnormal bursting firing patterns in the cerebellar nuclei, which increases linearly with postnatal age. In a general sense, the dt rat has shown the scientific and clinical communities that dystonia can arise from dysfunctional cerebellar cortex. Furthermore, work with the dt rat has provided evidence that dystonia (1) is a neurodevelopmental network disorder and (2) can be driven by abnormal cerebellar output. In large part, work with other animal models has expanded upon studies in the dt rat and shown that primary dystonia is a multi-nodal network disorder associated with defective sensorimotor integration. In addition, experiments in genetically-engineered models have been used to examine the underlying cellular pathologies that drive primary dystonia. PMID:21081162

Glial cell-derived neurotrophic factor alleviates sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nicotinic acetylcholine receptors in an experimental rat model of neuromyopathy.

PubMed

Wang, Xin; Min, Su; Xie, Fei; Yang, Jun; Li, Liang; Chen, Jingyuan

2018-02-05

Sepsis-induced neuromuscular dysfunction results from up-regulation of the expression of γ- and α7-nicotinic acetylcholine receptors (nAChR). Although glial cell derived neurotrophic factor (GDNF) has been implicated in repairing and supporting neurons, little is known about the effects of GDNF on demyelination of nerves in sepsis. In this study, we tested the hypothesis that GDNF could alleviate sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nAChR in an experimental rat model of neuromyopathy. Rats were randomly divided into a sham group and a sepsis group. Levels of inflammatory factors, muscle function, and nicotinic acetylcholine receptors were tested in rats after cecal ligation and puncture (CLP). At 24 h after CLP, GDNF was injected around the sciatic nerve of sepsis rats, cytokines were detected by enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining was used to detect the expression of nAChRs. GDNF and its downstream effector (Erk1/2 and GFR-α), neuregulin-1 (NRG-1) and γ- and α7-nAChR were measured using Western blot analysis. The expression of GDNF reached a minimum at 24 h after CLP. Compared with the sham group, the release of cytokines and the expression of γ- and α7-nAChR were significantly increased in the sepsis group. The administration of GDNF significantly alleviated sepsis-induced neuromuscular dysfunction, as well as reducing the expression of γ- and α7-nAChR. In addition, the expression of Erk1/2, GFR-α, NRG-1 were significantly increased after GDNF treatment. GDNF administration may improve patient outcomes by reducing the demyelination of nerves and the expression of γ- and α7-nAChR. Copyright © 2018. Published by Elsevier Inc.

Antidiabetic effect of Euterpe oleracea Mart. (açaí) extract and exercise training on high-fat diet and streptozotocin-induced diabetic rats: A positive interaction

PubMed Central

de Bem, Graziele Freitas; Costa, Cristiane Aguiar; Santos, Izabelle Barcellos; Cristino Cordeiro, Viviane da Silva; de Carvalho, Lenize Costa Reis Marins; de Souza, Marcelo Augusto Vieira; Soares, Ricardo de Andrade; Sousa, Pergentino José da Cunha; Ognibene, Dayane Teixeira; de Moura, Roberto Soares

2018-01-01

A growing body of evidence suggests a protective role of polyphenols and exercise training on the disorders of type 2 diabetes mellitus (T2DM). We aimed to assess the effect of the açaí seed extract (ASE) associated with exercise training on diabetic complications induced by high-fat (HF) diet plus streptozotocin (STZ) in rats. Type 2 diabetes was induced by feeding rats with HF diet (55% fat) for 5 weeks and a single dose of STZ (35 mg/kg i.p.). Control (C) and Diabetic (D) animals were subdivided into four groups each: Sedentary, Training, ASE Sedentary, and ASE Training. ASE (200 mg/kg/day) was administered by gavage and the exercise training was performed on a treadmill (30min/day; 5 days/week) for 4 weeks after the diabetes induction. In type 2 diabetic rats, the treatment with ASE reduced blood glucose, insulin resistance, leptin and IL-6 levels, lipid profile, and vascular dysfunction. ASE increased the expression of insulin signaling proteins in skeletal muscle and adipose tissue and plasma GLP-1 levels. ASE associated with exercise training potentiated the reduction of glycemia by decreasing TNF-α levels, increasing pAKT and adiponectin expressions in adipose tissue, and IR and pAMPK expressions in skeletal muscle of type 2 diabetic rats. In conclusion, ASE treatment has an antidiabetic effect in type 2 diabetic rats by activating the insulin-signaling pathway in muscle and adipose tissue, increasing GLP-1 levels, and an anti-inflammatory action. Exercise training potentiates the glucose-lowering effect of ASE by activating adiponectin-AMPK pathway and increasing IR expression. PMID:29920546

The corpus cavernosum after treatment with dutasteride or finasteride: A histomorphometric study in a benign prostatic hyperplasia rodent model.

PubMed

Da Silva, Marcello H A; Costa, Waldemar S; B Sampaio, Francisco J; De Souza, Diogo B

2018-06-08

Erectile dysfunction is a common side effect of finasteride and dutasteride treatments. The objective of this study was to investigate the structural changes in the penis using a benign prostatic hyperplasia (BPH) rodent model treated with dutasteride or finasteride. Sixty male rats were divided into the following groups: C, untreated control rats; C + D, control rats receiving dutasteride; C + F, control rats receiving finasteride; H, untreated spontaneously hypertensive rats (SHRs); H + D, SHRs treated with dutasteride; and H + F, SHRs treated with finasteride. Treatments were performed for 40 days, and penises were collected immediately thereafter. The organs were analyzed using histomorphometric methods to determine the cross-sectional penile area, as well as the surface density (Sv) of smooth muscle fibers, connective tissue, elastic system fibers, and sinusoidal spaces of the corpus cavernosum. The results were compared using a one-way ANOVA with Bonferroni's posttest. Groups C + D and C + F had a significantly smaller penile cross-sectional area, but more elastic system fiber Sv compared to Group C. Group C + D showed less smooth muscle Sv, and Group H showed more connective tissue but a smaller sinusoidal space Sv in the corpus cavernosum compared to Group C. Groups H + D and H + F had less smooth muscle Sv than Group H. Group H + D also had more connective tissue and elastic system fiber Sv than Group H. Both dutasteride and finasteride promoted penile modifications in the control rat penis, although this affect was greater in Group H animals. In this rodent model, dutasteride was the drug that most affected the corpus cavernosum.

Hypothyroidism leads to increased collagen-based stiffness and re-expression of large cardiac titin isoforms with high compliance.

PubMed

Wu, Yiming; Peng, Jun; Campbell, Kenneth B; Labeit, Siegfried; Granzier, Henk

2007-01-01

Because long-term hypothyroidism results in diastolic dysfunction, we investigated myocardial passive stiffness in hypothyroidism and focused on the possible role of titin, an important determinant of diastolic stiffness. A rat model of hypothyroidism was used, obtained by administering propylthiouracil (PTU) for times that varied from 1 month (short-term) to 4 months (long-term). Titin expression was determined by transcript analysis, gel electrophoresis and immunoelectron microscopy. Diastolic function was measured at the isolated heart, skinned muscle, and cardiac myocyte levels. We found that hypothyroidism resulted in expression of a large titin isoform, the abundance of which gradually increased with time to become the most dominant isoform in long-term hypothyroid rats. This isoform co-migrates on high-resolution gels with fetal cardiac titin. Transcript analysis on myocardium of long-term PTU rats, provided evidence for expression of additional PEVK and Ig domain exons, similar to what has been described in fetal myocardium. Consistent with the expression of a large titin isoform, titin-based restoring and passive forces were significantly reduced in single cardiac myocytes and muscle strips of long-term hypothyroid rats. Overall muscle stiffness and LV diastolic wall stiffness were increased, however, due to increased collagen-based stiffness. We conclude that long term hypothyroidism triggers expression of a large cardiac titin isoform and that the ensuing reduction in titin-based passive stiffness functions as a compensatory mechanism to reduce LV wall stiffness.

Effects of natural mineral-rich water consumption on the expression of sirtuin 1 and angiogenic factors in the erectile tissue of rats with fructose-induced metabolic syndrome

PubMed Central

Pereira, Cidália D; Severo, Milton; Rafael, Luísa; Martins, Maria João; Neves, Delminda

2014-01-01

Consuming a high-fructose diet induces metabolic syndrome (MS)-like features, including endothelial dysfunction. Erectile dysfunction is an early manifestation of endothelial dysfunction and systemic vascular disease. Because mineral deficiency intensifies the deleterious effects of fructose consumption and mineral ingestion is protective against MS, we aimed to characterize the effects of 8 weeks of natural mineral-rich water consumption on the structural organization and expression of vascular growth factors and receptors on the corpus cavernosum (CC) in 10% fructose-fed Sprague-Dawley rats (FRUCT). Differences were not observed in the organization of the CC either on the expression of vascular endothelial growth factor (VEGF) or the components of the angiopoietins/Tie2 system. However, opposing expression patterns were observed for VEGF receptors (an increase and a decrease for VEGFR1 and VEGFR2, respectively) in FRUCT animals, with these patterns being strengthened by mineral-rich water ingestion. Mineral-rich water ingestion (FRUCTMIN) increased the proportion of smooth muscle cells compared with FRUCT rats and induced an upregulatory tendency of sirtuin 1 expression compared with the control and FRUCT groups. Western blot results were consistent with the dual immunofluorescence evaluation. Plasma oxidized low-density lipoprotein and plasma testosterone levels were similar among the experimental groups, although a tendency for an increase in the former was observed in the FRUCTMIN group. The mineral-rich water-treated rats presented changes similar to those observed in rats treated with MS-protective polyphenol-rich beverages or subjected to energy restriction, which led us to hypothesize that the effects of mineral-rich water consumption may be more vast than those directly observed in this study. PMID:24625878

The effect of vascular endothelial growth factor on a rat model of traumatic arteriogenic erectile dysfunction.

PubMed

Lee, Ming-Chan; El-Sakka, Ahmed I; Graziottin, Tulio M; Ho, Hao-Chung; Lin, Ching-Shwun; Lue, Tom F

2002-02-01

We tested the hypothesis that intracavernous injection of vascular endothelial growth factor (VEGF) can restore erectile function in a rat model of traumatic arteriogenic erectile dysfunction. Exploration of bilateral internal iliac arteries was performed in 50, 3-month-old male rats. A total of 44 rats underwent bilateral ligation of the internal iliac arteries and 6 that underwent exploration only served as the sham operated group. Minutes later intracavernous injection of phosphate buffered saline (PBS) plus bovine serum albumin in 16 rats, 2 microg. VEGF plus PBS plus BSA in 12 and 4 microg. VEGF plus PBS plus BSA in 16 was performed. At weeks 1, 2 and 6 about a third of the rats in each group underwent electrostimulation of the cavernous nerves to assess erectile function and were then sacrificed. Penile tissues were collected for histochemical and electron microscopy examinations. No impairment of erectile function was noted in sham operated rats. Immediately after arterial ligation all rats showed little or no erectile response to neurostimulation. In PBS treated rats modest recovery of erectile function was noted at week 6. Significant recovery of erectile function was noted in VEGF treated rats at weeks 1 and 2 in the 4 microg. group only and at week 6 in the 2 and 4 microg. groups. Neuronal nitric oxide synthase staining showed a reduction in neuronal nitric oxide synthase positive nerve fibers in the dorsal or intracavernous nerves at week 1. Moderate recovery of neuronal nitric oxide synthase positive nerve fibers was noted in the 2 and 4microg. VEGF treated groups but not in the PBS treated group. Electron microscopy revealed no pathological change in sham operated rats. In dorsal nerves the atrophy of myelinated and nonmyelinated nerve fibers was noted in ligated plus PBS treated rats. Partial recovery was observed in VEGF treated rats. Scattered atrophic smooth muscle cells were seen in PBS and occasionally in VEGF treated rats but not in the sham operated group. The most dramatic findings in VEGF treated rats were hypertrophy and hyperplasia of the endothelial cells, especially those lining the small capillaries. Ligation of bilateral internal iliac arteries produced a reliable animal model of traumatic arteriogenic erectile dysfunction. Intracavernous injection of VEGF minutes after arterial ligation facilitated the recovery of erectile function.

The relationship between hamstring length and gluteal muscle strength in individuals with sacroiliac joint dysfunction

PubMed Central

Massoud Arab, Amir; Reza Nourbakhsh, Mohammad; Mohammadifar, Ali

2011-01-01

It has been suggested that tight hamstring muscle, due to its anatomical connections, could be a compensatory mechanism for providing sacroiliac (SI) joint stability in patients with gluteal muscle weakness and SIJ dysfunction. The purpose of this study was to determine the relationship between hamstring muscle length and gluteal muscle strength in subjects with sacroiliac joint dysfunction. A total of 159 subjects with and without low back pain (LBP) between the ages of 20 and 65 years participate in the study. Subjects were categorized into three groups: LBP without SIJ involvement (n = 53); back pain with SIJ dysfunction (n = 53); and no low back pain (n = 53). Hamstring muscle length and gluteal muscle strength were measured in all subjects. The number of individuals with gluteal weakness was significantly (P = 0.02) higher in subjects with SI joint dysfunction (66%) compared to those with LBP without SI joint dysfunctions (34%). In pooled data, there was no significant difference (P = 0.31) in hamstring muscle length between subjects with SI joint dysfunction and those with back pain without SI involvement. In subjects with SI joint dysfunction, however, those with gluteal muscle weakness had significantly (P = 0.02) shorter hamstring muscle length (mean = 158±11°) compared to individuals without gluteal weakness (mean = 165±10°). There was no statistically significant difference (P>0.05) in hamstring muscle length between individuals with and without gluteal muscle weakness in other groups. In conclusion, hamstring tightness in subjects with SI joint dysfunction could be related to gluteal muscle weakness. The slight difference in hamstring muscle length found in this study, although statistically significant, was not sufficient for making any definite conclusions. Further studies are needed to establish the role of hamstring muscle in SI joint stability. PMID:22294848

The relationship between hamstring length and gluteal muscle strength in individuals with sacroiliac joint dysfunction.

PubMed

Massoud Arab, Amir; Reza Nourbakhsh, Mohammad; Mohammadifar, Ali

2011-02-01

It has been suggested that tight hamstring muscle, due to its anatomical connections, could be a compensatory mechanism for providing sacroiliac (SI) joint stability in patients with gluteal muscle weakness and SIJ dysfunction. The purpose of this study was to determine the relationship between hamstring muscle length and gluteal muscle strength in subjects with sacroiliac joint dysfunction. A total of 159 subjects with and without low back pain (LBP) between the ages of 20 and 65 years participate in the study. Subjects were categorized into three groups: LBP without SIJ involvement (n = 53); back pain with SIJ dysfunction (n = 53); and no low back pain (n = 53). Hamstring muscle length and gluteal muscle strength were measured in all subjects. The number of individuals with gluteal weakness was significantly (P = 0.02) higher in subjects with SI joint dysfunction (66%) compared to those with LBP without SI joint dysfunctions (34%). In pooled data, there was no significant difference (P = 0.31) in hamstring muscle length between subjects with SI joint dysfunction and those with back pain without SI involvement. In subjects with SI joint dysfunction, however, those with gluteal muscle weakness had significantly (P = 0.02) shorter hamstring muscle length (mean = 158±11°) compared to individuals without gluteal weakness (mean = 165±10°). There was no statistically significant difference (P>0.05) in hamstring muscle length between individuals with and without gluteal muscle weakness in other groups. In conclusion, hamstring tightness in subjects with SI joint dysfunction could be related to gluteal muscle weakness. The slight difference in hamstring muscle length found in this study, although statistically significant, was not sufficient for making any definite conclusions. Further studies are needed to establish the role of hamstring muscle in SI joint stability.

Peroxisome proliferator-activated receptor γ agonism attenuates endotoxaemia-induced muscle protein loss and lactate accumulation in rats.

PubMed

Crossland, Hannah; Constantin-Teodosiu, Dumitru; Gardiner, Sheila M; Greenhaff, Paul L

2017-07-01

The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats were fed either standard chow (control) or standard chow containing Rosi (8.5 ± 0.1 mg·kg -1 ·day -1 ) for 2 weeks before and during 24 h continuous intravenous infusion of LPS (15 μg·kg -1 ·h -1 ) or saline. Rosi blunted LPS-induced increases in muscle tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA by 70% ( P <0.05) and 64% ( P <0.01) respectively. Furthermore, Rosi suppressed the LPS-induced reduction in phosphorylated AKT and phosphorylated Forkhead box O (FOXO) 1 protein, as well as the up-regulation of muscle RING finger 1 (MuRF1; P <0.01) mRNA and the LPS-induced increase in 20S proteasome activity ( P <0.05). Accordingly, LPS reduced the muscle protein:DNA ratio (∼30%, P <0.001), which Rosi offset. Increased muscle pyruvate dehydrogenase kinase 4 (PDK4) mRNA ( P <0.001) and muscle lactate accumulation ( P <0.001) during endotoxaemia were suppressed by Rosi. Thus, pre-treatment with Rosi reduced muscle cytokine accumulation and blunted muscle protein loss and lactate accumulation during endotoxaemia, and at least in part by reducing activation of molecular events known to increase muscle protein breakdown and mitochondrial pyruvate use. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Morphological modification of female bladder after prolonged use of soy-based diets.

PubMed

da Silva Faria, Tatiane; Soares, Lavínia Leal; Medeiros, Jorge L; Boaventura, Gilson T; Sampaio, Francisco J B; da Fonte Ramos, Cristiane

2009-01-20

The aim of this study was to compare the effects of a prolonged use of organic and transgenic soy upon the lipid profile and the collagen/muscle ratio of the detrusor muscle of the bladder. Wistar rats were fed three different diets from weaning until sacrifice (15 months old): control group (CG) casein-based diet; organic soy group (OSG) organic soy-based diet; genetically modified soy group (GMSG) transgenic soy-based diet. There was no difference in the food consumption or in the diet isoflavone components among the groups. Comparing to CG, both OSG and GMSG groups presented a significant (p<0.05) reduction in the body weight, triglycerides, cholesterol and the smooth muscle of the detrusor and a significant (p<0.05) increase of collagen fibers number of the detrusor muscle. These findings call into question that, the prolonged use of soy-based diets can be deleterious to the bladder by altering the collagen/muscle ratio what can cause bladder dysfunctions similar with that occurring during menopause.

Pharmacological Prevention and Reversion of Erectile Dysfunction after Radical Prostatectomy, By Modulation of Nitric Oxide/Cgmp Pathways

DTIC Science & Technology

2008-03-01

Figure 3. Time course of the effect of bilateral cavernosal nerve resection on the smooth muscle cell content in the rat corpora cavernosa. Penile...iindicates the apoptotic cells in the corpora cavernosa. Bottom: QIA for TUNEL ***Pɘ.001 Figure 7: Time course of the effect of bilateral...Figure 6 Effect of unilateral and bilateral cavernosal nerve resection and long-term sildenafil treatment on cell proliferation and turnover in the

Aerobic training and l-arginine supplementation promotes rat heart and hindleg muscles arteriogenesis after myocardial infarction.

PubMed

Ranjbar, Kamal; Rahmani-Nia, Farhad; Shahabpour, Elham

2016-09-01

Arteriogenesis is a main defense mechanism to prevent heart and local tissues dysfunction in occlusive artery disease. TGF-β and angiostatin have a pivotal role in arteriogenesis. We tested the hypothesis that aerobic training and l-arginine supplementation promotes cardiac and skeletal muscles arteriogenesis after myocardial infarction (MI) parallel to upregulation of TGF-β and downregulation of angiostatin. For this purpose, 4 weeks after LAD occlusion, 50 male Wistar rats were randomly distributed into five groups: (1) sham surgery without MI (sham, n = 10), (2) control-MI (Con-MI, n = 10), (3) l-arginine-MI (La-MI, n = 10), (4) exercise training-MI (Ex-MI, n = 10), and (5) exercise and l-arginine-MI (Ex + La-MI). Exercise training groups running on a treadmill for 10 weeks with moderate intensity. Rats in the l-arginine-treated groups drank water containing 4 % l-arginine. Arteriolar density with different diameters (11-25, 26-50, 51-75, and 76-150 μm), TGF-β, and angiostatin gene expression were measured in cardiac (area at risk) and skeletal (soleus and gastrocnemius) muscles. Smaller arterioles decreased in cardiac after MI. Aerobic training and l-arginine increased the number of cardiac arterioles with 11-25 and 26-50 μm diameters parallel to TGF-β overexpression. In gastrocnemius muscle, the number of arterioles/mm(2) was only increased in the 11 to 25 μm in response to training with and without l-arginine parallel to angiostatin downregulation. Soleus arteriolar density with different size was not different between experimental groups. Results showed that 10 weeks aerobic exercise training and l-arginine supplementation promotes arteriogenesis of heart and gastrocnemius muscles parallel to overexpression of TGF-β and downregulation of angiostatin in MI rats.

Endogenous Stem Cells Were Recruited by Defocused Low-Energy Shock Wave in Treating Diabetic Bladder Dysfunction.

PubMed

Jin, Yang; Xu, Lina; Zhao, Yong; Wang, Muwen; Jin, Xunbo; Zhang, Haiyang

2017-04-01

Defocused low-energy shock wave (DLSW) has been shown effects on activating mesenchymal stromal cells (MSCs) in vitro. In this study, recruitment of endogenous stem cells was firstly examined as an important pathway during the healing process of diabetic bladder dysfunction (DBD) treated by DLSW in vivo. Neonatal rats received intraperitoneal injection of 5-ethynyl-2-deoxyuridine (EdU) and then DBD rat model was created by injecting streptozotocin. Four weeks later, DLSW treatment was performed. Afterward, their tissues were examined by histology. Meanwhile, adipose tissue-derived stem cells (ADSCs) were treated by DLSW in vitro. Results showed DLSW ameliorated voiding function of diabetic rats by recruiting EdU + Stro-1 + CD34 - endogenous stem cells to release abundant nerve growth factor (NGF) and vascular endothelial growth factor (VEGF). Some EdU + cells overlapped with staining of smooth muscle actin. After DLSW treatment, ADSCs showed higher migration ability, higher expression level of stromal cell-derived factor-1 and secreted more NGF and VEGF. In conclusion, DLSW could ameliorate DBD by recruiting endogenous stem cells. Beneficial effects were mediated by secreting NGF and VEGF, resulting into improved innervation and vascularization in bladder.

[Effect of enalapril on nitric oxide synthesis, oxidative metabolism, and vascular tone in aging rats].

PubMed

Sahach, V F; Baziliuk, O V; Stepanenko, L H; Korkach, Iu P; Kotsiuruba, A V

2007-01-01

Endothelium-dependent and endothelium-independent reactions of relaxations of vascular smooth muscle (VSM) were examined in the aorta preparations of the two groups (6-8 and 21-22 month). The studies also two NO synthase (NOS) isoform activity--inducible (iNOS) and constitutive (cNOS), activity of arginase and nitrate reductase and the content of high-molecular nitrosothiols (HMNT) and low-molecular nitrosothiols (LMNT) and stable metabolites of NO (NO(-)2, NO(-)3). Aging rats demonstrated only endothelium-dependent responses of VSM to acethylcholine lowering. This endothelial dysfunction depend on high activity of arginase, iNOS and salvage (by nitrate reductase) NO synthesis, both reactive oxigen species (ROS) (by xanthine oxidase) and peroxynitrite generation, as well as low activity of constitutive (eNOS, nNOS) NO synthesis. Angiotensin-converting enzyme inhibitor (enalapril) administration (20 mg/kg, 30 or 55 days) up regalate constitutive NO synthesis by arginase, iNOS, nitrate reductase activity and ROS and peroxynitrite generation inhibition thus restore endothelium-dependent relaxations of VSM in aging rats. The result obtained suggest a new roles for the renin-angiotensin system in vascular tone regulation. Thus enalapril might serve as a novel tool to prevent aging-associated endothelial dysfunction.

Transcription of G-protein coupled receptors in corporeal smooth muscle is regulated by the endogenous neutral endopeptidase inhibitor sialorphin.

PubMed

Tong, Yuehong; Tiplitsky, Scott I; Tar, Moses; Melman, Arnold; Davies, Kelvin P

2008-08-01

Several reports suggest that the rat Vcsa1 gene is down-regulated in models of erectile dysfunction. The Vcsa protein product sialorphin is an endogenous neutral endopeptidase inhibitor and its down-regulation could result in prolonged activation of G-protein activated signaling pathways by their peptide agonists. We investigated whether Vcsa1 down-regulation could result in an adaptive change in GPCR (G-protein coupled receptor) expression. Gene expression in cultured rat corporeal smooth muscle cells following treatment with siRNA directed against Vcsa1 or the neutral endopeptidase gene was analyzed using microarray and quantitative reverse transcriptase-polymerase chain reaction. In rats Vcsa1 is one of the most down-regulated genes following bilateral transection of the cavernous nerves. In that animal model we also investigated whether Vcsa1 down-regulation was accompanied by similar changes in gene expression in corporeal smooth muscle cells in which Vcsa1 was knocked down in vitro. Microarray analysis and quantitative reverse transcriptase-polymerase chain reaction demonstrated that corporeal smooth muscle cells treated in vitro with siRNA against Vcsa1 resulted in GPCR up-regulation as a functional group. In contrast, treatment of corporeal smooth muscle cells that lowered neutral endopeptidase activity resulted in decreased GPCR expression. These results suggest that the peptide product of Vcsa1, sialorphin, can effect GPCR expression by acting on neutral endopeptidase. In animals with bilaterally transected cavernous nerves the decreased Vcsa1 expression is accompanied by increased GPCR expression in cavernous tissue. These experiments suggest that the mechanism by which Vcsa1 modulates erectile function is partly mediated through changes in GPCR expression.

The platelet-derived growth factor receptor/STAT3 signaling pathway regulates the phenotypic transition of corpus cavernosum smooth muscle in rats.

PubMed

Yan, Jun-Feng; Huang, Wen-Jie; Zhao, Jian-Feng; Fu, Hui-Ying; Zhang, Gao-Yue; Huang, Xiao-Jun; Lv, Bo-Dong

2017-01-01

Erectile dysfunction (ED) is a common clinical disease that is difficult to treat. We previously found that hypoxia modulates the phenotype of primary corpus cavernosum smooth muscle cells (CCSMCs) in rats, but the underlying molecular mechanism is still unknown. Platelet-derived growth factor receptor (PDGFR)-related signaling pathways are correlated with cell phenotypic transition, but research has been focused more on vascular smooth muscle and tracheal smooth muscle and less on CCSMCs. Here, we investigated the role of PDGFR-related signaling pathways in penile CCSMCs, which were successfully isolated from rats and cultured in vitro. PDGF-BB at 5, 10, or 20 ng/ml altered CCSMC morphology from the original elongated, spindle shape to a broader shape and promoted the synthetic phenotype and expression of the related proteins vimentin and collagen-I, while inhibiting the contractile phenotype and expression of the related proteins smooth muscle (SM) α-actin (α-SMA) and desmin. Inhibition of PDGFR activity via siRNA or the PDGFR inhibitor crenolanib inhibited vimentin and collagen-I expression, increased α-SMA and desmin expression, and considerably inhibited serine-threonine protein kinase (AKT) and signal transducer and activator of transcription 3 (STAT3) phosphorylation. STAT3 knockdown promoted the contractile phenotype, inhibited vimentin and collagen-I expression, and increased α-SMA and desmin expression, whereas AKT knockdown did not affect phenotype-associated proteins. STAT3 overexpression in CCSMC cells weakened the suppressive effect of PDGFR inhibition on the morphology and phenotypic transformation induced by PDGF-BB. Through activation of the PDGFR/STAT3 signaling pathway, PDGF promoted the synthetic phenotype transition; thus, regulation of this pathway might contribute to ED therapy.

The relaxant actions of ethanolic extract of Tridax procumbens (Linn.) on rat corpus cavernosum smooth muscle contraction.

PubMed

Salahdeen, Hussein M; Idowu, Gbolahan O; Yemitan, Omoniyi K; Murtala, Babatunde A; Alada, Abdul Rasak A

2015-03-01

The effect of Tridax procumbens aqueous ethanolic extract on the rat corpus cavernosum smooth muscles was evaluated in the present study. Corpus cavernosum strips obtained from healthy, young, adult male Wistar albino rats (250-300 g) were precontracted with phenylephrine (10-7 M) or KCl (60 mM) and then treated with various concentrations of T. procumbens extract (0.15-1.05 mg/mL). The change in corpus cavernosum strip tension was recorded. The interactions between T. procumbens extract with acetylcholine and with sodium nitroprusside were also evaluated. The results indicated that corpus cavernosum strips relaxation induced by T. procumbens extract was concentration-dependent and this was significant (p<0.5). Pre-treatment with a nitric oxide synthase (NOS) inhibitor (N(1) nitro-L-arginine-methyl ester, l-NAME), did not completely inhibit the relaxation. However, T. procumbens extract (0.6 mg/mL) significantly (p<0.5) enhanced both acetylcholine- and sodium nitroprusside-induced corpus cavernosum strips relaxation. RESULTS suggest that T. procumbens extract has a concentration-dependent relaxant effect on the isolated rat corpus cavernosum. The mechanism of action of T. procumbens extract is complex. A part of its relaxing effect is mediated directly by the release of NO from endothelium which may improve erectile dysfunction.

Rosuvastatin safety: An experimental study of myotoxic effects and mitochondrial alterations in rats.

PubMed

El-Ganainy, Samar O; El-Mallah, Ahmed; Abdallah, Dina; Khattab, Mahmoud M; Mohy El-Din, Mahmoud M; El-Khatib, Aiman S

2017-01-04

Myopathy is the most commonly reported adverse effect of statins. All statins are associated with myopathy, though with different rates. Rosuvastatin is a potent statin reported to induce myopathy comparable to earlier statins. However, in clinical practice most patients could tolerate rosuvastatin over other statins. This study aimed to evaluate the myopathic pattern of rosuvastatin in rats using biochemical, functional and histopathological examinations. The possible deleterious effects of rosuvastatin on muscle mitochondria were also examined. The obtained results were compared to myopathy induced by atorvastatin in equimolar dose. Results showed that rosuvastatin induced a rise in CK, a slight increase in myoglobin level together with mild muscle necrosis. Motor activity, assessed by rotarod, showed that rosuvastatin decreased rats' performance. All these manifestations were obviously mild compared to the prominent effects of atorvastatin. Parallel results were obtained in mitochondrial dysfunction parameters. Rosuvastatin only induced a slight increase in LDH and a minor decrease in ATP (∼14%) and pAkt (∼12%). On the other hand, atorvastatin induced an increase in LDH, lactate/pyruvate ratio and a pronounced decline in ATP (∼80%) and pAkt (∼65%). These findings showed that rosuvastatin was associated with mild myotoxic effects in rats, especially when compared to atorvastatin. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Resveratrol recruits rat muscle microvasculature via a nitric oxide-dependent mechanism that is blocked by TNFα

PubMed Central

Wang, Nasui; Ko, Seung-Hyun; Chai, Weidong; Li, Guolian; Barrett, Eugene J.; Tao, Lijian; Cao, Wenhong

2011-01-01

Resveratrol, a polyphenol found in many plants, has antioxidant and anti-inflammatory actions. It also improves endothelial function and may be cardioprotective. Tumor necrosis factor-α (TNFα) causes oxidative stress and microvascular endothelial dysfunction. Whether resveratrol affects microvascular function in vivo and, if so, whether inflammatory cytokines antagonize its microvascular action are not clear. In cultured bovine aortic endothelial cells (BAECs), reserveratrol (100 nM) increased the phosphorylation of protein kinase B (Akt), endothelial nitric oxide (NO) synthase (eNOS), and ERK1/2 within 15 min by more than twofold, and this effect lasted for at least 2 h. Treatment of BAECs with TNFα (10 ng/ml) significantly increased the NADPH oxidase activity and the production of hydrogen peroxide and superoxide. Pretreatment of cells with resveratrol (100 nM) prevented each of these. Injection (ip) of resveratrol in rats potently increased muscle microvascular blood volume (MBV; P = 0.007) and flow (MBF; P < 0.02) within 30 min, and this was sustained for at least 2 h. The phosphorylation of Akt in liver or muscle was unchanged. Superimposed systemic infusion of l-NAME (NOS inhibitor) completely abolished resveratrol-induced increases in MBV and MBF. Similarly, systemic infusion of TNFα prevented resveratrol-induced muscle microvascular recruitment. In conclusion, resveratrol activates eNOS and increases muscle microvascular recruitment via an NO-dependent mechanism. Despite the potent antioxidant effect of resveratrol, TNFα at concentrations that block insulin-mediated muscle microvascular recruitment completely neutralized resveratrol's microvascular action. Thus, chronic inflammation, as seen in type 2 diabetes, may limit resveratrol's vasodilatory actions on muscle microvasculature. PMID:20978231

Molecular and biological pathways of skeletal muscle dysfunction in chronic obstructive pulmonary disease

PubMed Central

Gea, Joaquim

2016-01-01

Chronic obstructive pulmonary disease (COPD) will be a major leading cause of death worldwide in the near future. Weakness and atrophy of the quadriceps are associated with a significantly poorer prognosis and increased mortality in COPD. Despite that skeletal muscle dysfunction may affect both respiratory and limb muscle groups in COPD, the latter are frequently more severely affected. Therefore, muscle dysfunction in COPD is a common systemic manifestation that should be evaluated on routine basis in clinical settings. In the present review, several aspects of COPD muscle dysfunction are being reviewed, with special emphasis on the underlying biological mechanisms. Figures on the prevalence of COPD muscle dysfunction and the most relevant etiologic contributors are also provided. Despite that ongoing research will shed light into the contribution of additional mechanisms to COPD muscle dysfunction, current knowledge points toward the involvement of a wide spectrum of cellular and molecular events that are differentially expressed in respiratory and limb muscles. Such mechanisms are thoroughly described in the article. The contribution of epigenetic events on COPD muscle dysfunction is also reviewed. We conclude that in view of the latest discoveries, from now, on new avenues of research should be designed to specifically target cellular mechanisms and pathways that impair muscle mass and function in COPD using pharmacological strategies and/or exercise training modalities. PMID:27056059

The supplementation of Korean mistletoe water extracts reduces hot flushes, dyslipidemia, hepatic steatosis, and muscle loss in ovariectomized rats.

PubMed

Kim, Min Jung; Park, Jong-Heum; Kwon, Dae Young; Yang, Hye Jeong; Kim, Da Sol; Kang, Suna; Shin, Bae Keun; Moon, Na Rang; Song, Beom-Seok; Kim, Jae-Hun; Park, Sunmin

2015-04-01

Since Korean mistletoe (Viscum album) has been used for alleviating metabolic diseases, it may also prevent the impairment of energy, glucose, lipid, and bone metabolisms in an estrogen-deficient animal model. We determined that long-term consumption of Korean mistletoe water extract (KME) can alleviate menopausal symptoms such as hot flush, increased abdominal fat mass, dyslipidemia, hyperglycemia, and decreased bone mineral density in ovariectomized (OVX) rats fed a high-fat diet, and explored the mechanisms of the effects. OVX rats were divided into four groups and fed high-fat diets supplemented with either 0.6% dextrin (control), 0.2% lyophilized KME + 0.4% dextrin (KME-L), or 0.6% lyophilized KME (KME-H). Sham rats were fed with the high-fat diets with 0.6% dextrin as a normal-control without estrogen deficiency. After eight weeks, OVX rats exhibited impaired energy, glucose and lipid metabolism, and decreased uterine and bone masses. KME-L did not alleviate energy dysfunction. However, KME-H lowered serum levels of total-, LDL-cholesterol, and triglycerides and elevated serum HDL-cholesterol levels in OVX rats with dyslipidemia, to similar levels as normal-control rats. Furthermore, KME-H improved HOMA-IR, an indicator of insulin resistance, in OVX rats. Surprisingly, KME-H fed rats had greater lean mass in the abdomen and leg without differences in fat mass but neither dosage of KME altered bone mineral density in the lumbar spine and femur. The increased lean mass was related to greater phosphorylation of mTOR and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in the quadriceps muscles. Hepatic triglyceride contents were lowered with KME-H in OVX rats by increasing carnitine palmitoyltransferase-1 (CPT-1) expression and decreasing fatty acid synthase (FAS) and sterol regulatory element-binding protein-1c (SREBP-1c) expression. In conclusion, KME may be useful for preventing some menopausal symptoms such as hot flushes, dyslipidemia, hepatic steatosis, and loss of muscle mass in post-menopausal women. © 2014 by the Society for Experimental Biology and Medicine.

The supplementation of Korean mistletoe water extracts reduces hot flushes, dyslipidemia, hepatic steatosis, and muscle loss in ovariectomized rats

PubMed Central

Kim, Min Jung; Park, Jong-Heum; Kwon, Dae Young; Yang, Hye Jeong; Kim, Da Sol; Kang, Suna; Shin, Bae Keun; Moon, Na Rang; Song, Beom-Seok; Kim, Jae-Hun

2015-01-01

Since Korean mistletoe (Viscum album) has been used for alleviating metabolic diseases, it may also prevent the impairment of energy, glucose, lipid, and bone metabolisms in an estrogen-deficient animal model. We determined that long-term consumption of Korean mistletoe water extract (KME) can alleviate menopausal symptoms such as hot flush, increased abdominal fat mass, dyslipidemia, hyperglycemia, and decreased bone mineral density in ovariectomized (OVX) rats fed a high-fat diet, and explored the mechanisms of the effects. OVX rats were divided into four groups and fed high-fat diets supplemented with either 0.6% dextrin (control), 0.2% lyophilized KME + 0.4% dextrin (KME-L), or 0.6% lyophilized KME (KME-H). Sham rats were fed with the high-fat diets with 0.6% dextrin as a normal-control without estrogen deficiency. After eight weeks, OVX rats exhibited impaired energy, glucose and lipid metabolism, and decreased uterine and bone masses. KME-L did not alleviate energy dysfunction. However, KME-H lowered serum levels of total-, LDL-cholesterol, and triglycerides and elevated serum HDL-cholesterol levels in OVX rats with dyslipidemia, to similar levels as normal-control rats. Furthermore, KME-H improved HOMA-IR, an indicator of insulin resistance, in OVX rats. Surprisingly, KME-H fed rats had greater lean mass in the abdomen and leg without differences in fat mass but neither dosage of KME altered bone mineral density in the lumbar spine and femur. The increased lean mass was related to greater phosphorylation of mTOR and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in the quadriceps muscles. Hepatic triglyceride contents were lowered with KME-H in OVX rats by increasing carnitine palmitoyltransferase-1 (CPT-1) expression and decreasing fatty acid synthase (FAS) and sterol regulatory element-binding protein-1c (SREBP-1c) expression. In conclusion, KME may be useful for preventing some menopausal symptoms such as hot flushes, dyslipidemia, hepatic steatosis, and loss of muscle mass in post-menopausal women. PMID:25258426

Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sirvent, P., E-mail: pascal.sirvent@univ-bpclermont.fr; CHRU Montpellier, 34295 Montpellier; Clermont Université, Université Blaise Pascal, EA 3533, Laboratoire des Adaptations Métaboliques à l'Exercice en conditions Physiologiques et Pathologiques

2012-03-01

The most common and problematic side effect of statins is myopathy. To date, the patho-physiological mechanisms of statin myotoxicity are still not clearly understood. In previous studies, we showed that acute application in vitro of simvastatin caused impairment of mitochondrial function and dysfunction of calcium homeostasis in human and rat healthy muscle samples. We thus evaluated in the present study, mitochondrial function and calcium signaling in muscles of patients treated with statins, who present or not muscle symptoms, by oxygraphy and recording of calcium sparks, respectively. Patients treated with statins showed impairment of mitochondrial respiration that involved mainly the complexmore » I of the respiratory chain and altered frequency and amplitude of calcium sparks. The muscle problems observed in statin-treated patients appear thus to be related to impairment of mitochondrial function and muscle calcium homeostasis, confirming the results we previously reported in vitro. -- Highlights: ► The most common and problematic side effect of statins is myopathy. ► Patients treated with statins showed impairment of mitochondrial respiration. ► Statins-treated patients showed altered frequency and amplitude of calcium sparks.« less

Vascular smooth muscle dysfunction induced by monomethylarsonous acid (MMA III): a contributing factor to arsenic-associated cardiovascular diseases.

PubMed

Bae, Ok-Nam; Lim, Eun-Kyung; Lim, Kyung-Min; Noh, Ji-Yoon; Chung, Seung-Min; Lee, Moo-Yeol; Yun, Yeo-Pyo; Kwon, Seong-Chun; Lee, Jun-Ho; Nah, Seung-Yeol; Chung, Jin-Ho

2008-11-01

While arsenic in drinking water is known to cause various cardiovascular diseases in human, exact mechanism still remains elusive. Recently, trivalent-methylated arsenicals, the metabolites of inorganic arsenic, were shown to have higher cytotoxic potential than inorganic arsenic. To study the role of these metabolites in arsenic-induced cardiovascular diseases, we investigated the effect of monomethylarsonous acid (MMA III), a major trivalent-methylated arsenical, on vasomotor tone of blood vessels. In isolated rat thoracic aorta and small mesenteric arteries, MMA III irreversibly suppressed normal vasoconstriction induced by three distinct agonists of phenylephrine (PE), serotonin and endothelin-1. Inhibition of vasoconstriction was retained in aortic rings without endothelium, suggesting that MMA III directly impaired the contractile function of vascular smooth muscle. The effect of MMA III was mediated by inhibition of PE-induced Ca2+ increase as found in confocal microscopy and fluorimeter in-lined organ chamber technique. The attenuation of Ca2+ increase was from concomitant inhibition of release from intracellular store and extracellular Ca2+ influx via L-type Ca2+ channel, which was blocked by MMA III as shown in voltage-clamp assay in Xenopus oocytes. MMA III did not affect downstream process of Ca2+, as shown in permeabilized arterial strips. In in vivo rat model, MMA III attenuated PE-induced blood pressure increase indeed, supporting the clinical relevance of these in vitro findings. In conclusion, MMA III-induced smooth muscle dysfunction through disturbance of Ca2+ regulation, which results in impaired vasoconstriction and aberrant blood pressure change. This study will provide a new insight into the role of trivalent-methylated arsenicals in arsenic-associated cardiovascular diseases.

Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine.

PubMed

de Cavanagh, Elena M V; Toblli, Jorge E; Ferder, León; Piotrkowski, Bárbara; Stella, Inés; Inserra, Felipe

2006-06-01

Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.

Nitric oxide synthase gene transfer for erectile dysfunction in a rat model.

PubMed

Chancellor, M B; Tirney, S; Mattes, C E; Tzeng, E; Birder, L A; Kanai, A J; de Groat, W C; Huard, J; Yoshimura, N

2003-05-01

To determine whether over-expression of nitric oxide synthase (NOS) in the corpus cavernosum of the penis improves erectile function, as NO is an important transmitter for genitourinary tract function, mediating smooth muscle relaxation and being essential for penile erection. The inducible form of the enzyme NOS (iNOS) was introduced into the corpus cavernosum of adult Sprague-Dawley rats (250-300 g) by injecting a solution of plasmid, adenovirus or adenovirus-transduced myoblast cells (adeno-myoblasts). Plasmid, adenovirus and adeno-myoblasts encoding the expression of the beta-galactosidase reporter gene were also injected into rats. Throughout the corpora cavernosum there was expression of beta-galactosidase after injecting each of the three solutions. Maximum staining was greatest for adeno-myoblast, then adenovirus and then plasmid. The mean (sd) basal intracavernosal pressure (ICP) of iNOS-treated animals (adenovirus and adeno-myoblast) increased to 55 (23) cmH2O, compared with naive animals with a basal ICP of 5 (6) cmH2O (P = 0.001). Stimulating the cavernosal nerve (15 Hz, 1.5 ms, 10-40 V, 1 min) resulted in a doubling of the ICP (adenovirus and adeno-myoblast) from the basal level of the iNOS-treated animals. Direct in situ measurement of NO showed the release of 1-1.3 micro mol/L in the adeno-myoblast penis. Myoblast-mediated gene therapy was more successful for delivering iNOS into the corpus cavernosum than direct adenovirus injection or plasmid transfection. Surprisingly, implanting muscle cells into the penis is not only feasible but also beneficial. Gene therapy for NOS may open new avenues of treatment for erectile dysfunction. Control of NOS expression would be necessary to prevent priapism.

Prolonged superficial local cryotherapy attenuates microcirculatory impairment, regional inflammation, and muscle necrosis after closed soft tissue injury in rats.

PubMed

Schaser, Klaus-Dieter; Disch, Alexander C; Stover, John F; Lauffer, Annette; Bail, Herman J; Mittlmeier, Thomas

2007-01-01

Closed soft tissue injury induces progressive microvascular dysfunction and regional inflammation. The authors tested the hypothesis that adverse trauma-induced effects can be reduced by local cooling. While superficial cooling reduces swelling, pain, and cellular oxygen demand, the effects of cryotherapy on posttraumatic microcirculation are incompletely understood. Controlled laboratory study. After a standardized closed soft tissue injury to the left tibial compartment, male rats were randomly subjected to percutaneous perfusion for 6 hours with 0.9% NaCL (controls; room temperature) or cold NaCL (cryotherapy; 8 degrees C) (n = 7 per group). Uninjured rats served as shams (n = 7). Microcirculatory changes and leukocyte adherence were determined by intravital microscopy. Intramuscular pressure was measured, and invasion of granulocytes and macrophages was assessed by immunohistochemistry. Edema and tissue damage was quantified by gravimetry and decreased desmin staining. Closed soft tissue injury significantly decreased functional capillary density (240 +/- 12 cm(-1)); increased microvascular permeability (0.75 +/- 0.03), endothelial leukocyte adherence (995 +/- 77/cm(2)), granulocyte (182.0 +/- 25.5/mm(2)) and macrophage infiltration, edema formation, and myonecrosis (ratio: 2.95 +/- 0.45) within the left extensor digitorum longus muscle. Cryotherapy for 6 hours significantly restored diminished functional capillary density (393 +/- 35), markedly decreased elevated intramuscular pressure, reduced the number of adhering (462 +/- 188/cm(2)) and invading granulocytes (119 +/- 28), and attenuated tissue damage (ratio: 1.7 +/- 0.17). The hypothesis that prolonged cooling reduces posttraumatic microvascular dysfunction, inflammation, and structural impairment was confirmed. These results may have therapeutic implications as cryotherapy after closed soft tissue injury is a valuable therapeutic approach to improve nutritive perfusion and attenuate leukocyte-mediated tissue destruction. The risk for evolving compartment syndrome may be reduced, thereby preventing further irreversible aggravation.

Clinical management of chronic obstructive pulmonary disease patients with muscle dysfunction

PubMed Central

Casadevall, Carme; Pascual, Sergi; Orozco-Levi, Mauricio; Barreiro, Esther

2016-01-01

Muscle dysfunction is frequently observed in chronic obstructive pulmonary disease (COPD) patients, contributing to their exercise limitation and a worsening prognosis. The main factor leading to limb muscle dysfunction is deconditioning, whereas respiratory muscle dysfunction is mostly the result of pulmonary hyperinflation. However, both limb and respiratory muscles are also influenced by other negative factors, including smoking, systemic inflammation, nutritional abnormalities, exacerbations and some drugs. Limb muscle weakness is generally diagnosed through voluntary isometric maneuvers such as handgrip or quadriceps muscle contraction (dynamometry); while respiratory muscle loss of strength is usually recognized through a decrease in maximal static pressures measured at the mouth. Both types of measurements have validated reference values. Respiratory muscle strength can also be evaluated determining esophageal, gastric and transdiaphragmatic maximal pressures although there is a lack of widely accepted reference equations. Non-volitional maneuvers, obtained through electrical or magnetic stimulation, can be employed in patients unable to cooperate. Muscle endurance can also be assessed, generally using repeated submaximal maneuvers until exhaustion, but no validated reference values are available yet. The treatment of muscle dysfunction is multidimensional and includes improvement in lifestyle habits (smoking abstinence, healthy diet and a good level of physical activity, preferably outside), nutritional measures (diet supplements and occasionally, anabolic drugs), and different modalities of general and muscle training. PMID:28066619

Penile histomorphometrical evaluation in hypertensive rats treated with sildenafil or enalapril alone or in combination: a comparison with normotensive and untreated hypertensive rats.

PubMed

Felix-Patrício, Bruno; Medeiros, Jorge L; De Souza, Diogo B; Costa, Waldemar S; Sampaio, Francisco J B

2015-01-01

Erectile dysfunction (ED) is frequently associated to hypertension and antihypertensive drugs; however, the penile morphological aspects on these situations are poorly known. Evaluate the penile morphology of untreated hypertensive rats and rats treated with enalapril or sildenafil alone or in combination to verify the hypothesis that morphological alterations promoted by hypertension on corpus cavernosum could be ameliorated by the use of angiotensin-converting enzyme inhibitors and/or phosphodiesterase type 5 inhibitors. Fifty male rats were assigned into five groups: normotensive rats, untreated spontaneously hypertensive rats (SHRs), and SHR treated with enalapril or sildenafil alone or in combination. Blood pressure was measured weekly. At the conclusion of the study, the rats were euthanized, and their penises were collected for histomorphometrical analysis. The cross-sectional areas of the penis, tunica albuginea, and corpus cavernosum were measured. The density of the corpus cavernosum structures was quantified. Both groups of SHR rats treated with enalapril became normotensive. Untreated SHR showed no difference in penile and cavernosal cross-sectional area compared with normotensive rats; however, those rats treated with enalapril or sildenafil alone demonstrated an increase in these parameters. Rats receiving combination therapy showed no cross-sectional area differences compared with normotensive rats. Cavernosal connective tissue density was increased, while the sinusoidal spaces were diminished in untreated SHR. All treatments were effective in maintaining connective tissue density in comparison with normotensive animals. Cavernosal smooth muscle density was similar in all groups, with the exception of the combination therapy group, which demonstrated a reduction in smooth muscle. Hypertension promoted structural alterations in the corpus cavernosum that may be related to ED. Enalapril- and sildenafil-treated animals had preservation of normal corpus cavernosum structure and an increase in penile and cavernosal cross-sectional area. The combination of these drugs showed less benefit than individual use. © 2014 International Society for Sexual Medicine.

Effects of exercise on obesity-induced mitochondrial dysfunction in skeletal muscle

PubMed Central

Heo, Jun-Won; No, Mi-Hyun; Park, Dong-Ho; Kang, Ju-Hee; Seo, Dae Yun; Han, Jin; Neufer, P. Darrell

2017-01-01

Obesity is known to induce inhibition of glucose uptake, reduction of lipid metabolism, and progressive loss of skeletal muscle function, which are all associated with mitochondrial dysfunction in skeletal muscle. Mitochondria are dynamic organelles that regulate cellular metabolism and bioenergetics, including ATP production via oxidative phosphorylation. Due to these critical roles of mitochondria, mitochondrial dysfunction results in various diseases such as obesity and type 2 diabetes. Obesity is associated with impairment of mitochondrial function (e.g., decrease in O2 respiration and increase in oxidative stress) in skeletal muscle. The balance between mitochondrial fusion and fission is critical to maintain mitochondrial homeostasis in skeletal muscle. Obesity impairs mitochondrial dynamics, leading to an unbalance between fusion and fission by favorably shifting fission or reducing fusion proteins. Mitophagy is the catabolic process of damaged or unnecessary mitochondria. Obesity reduces mitochondrial biogenesis in skeletal muscle and increases accumulation of dysfunctional cellular organelles, suggesting that mitophagy does not work properly in obesity. Mitochondrial dysfunction and oxidative stress are reported to trigger apoptosis, and mitochondrial apoptosis is induced by obesity in skeletal muscle. It is well known that exercise is the most effective intervention to protect against obesity. Although the cellular and molecular mechanisms by which exercise protects against obesity-induced mitochondrial dysfunction in skeletal muscle are not clearly elucidated, exercise training attenuates mitochondrial dysfunction, allows mitochondria to maintain the balance between mitochondrial dynamics and mitophagy, and reduces apoptotic signaling in obese skeletal muscle. PMID:29200899

Topical Combinations to Treat Microvascular Dysfunction of Chronic Postischemia Pain

PubMed Central

Laferrière, André; Abaji, Rachid; Tsai, Cheng-Yu Mark; Ragavendran, J. Vaigunda; Coderre, Terence J.

2015-01-01

Background Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. Methods Mechanical allodynia was induced in the hind paws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (post-occlusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. Results Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared to vehicle in CPIP rats (n = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5 to 10 fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (n = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors, were not reproduced by the same treatment of the contralateral hindpaw (n = 28). Topical combinations produced antiallodynic effects lasting up to 6 h (n = 15), and were significantly enhanced by low dose systemic pregabalin in early, but not late, CPIP rats (n = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed post-occlusive reactive hyperemia in CPIP rats (n = 61), and to increase formazan production in postischemic tissues (skin and muscle) (n = 56). Conclusions The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS. PMID:24651238

In vitro and in vivo aphrodisiac properties of the seed extract from Allium tuberosum on corpus cavernosum smooth muscle relaxation and sexual behavior parameters in male Wistar rats.

PubMed

Tang, Xingli; Olatunji, Opeyemi J; Zhou, Yifeng; Hou, Xilin

2017-12-01

Allium tuberosum is a well-known spice as well as a herb in traditional Chinese medicine, used for increasing libido and treating erectile dysfunction. However, not many studies have been done to evaluate the sexual enhancing properties of A. tuberosum. The aim of this study was to evaluate the aphrodisiac and vasorelaxant properties of A. tuberosum on corpus cavernosum smooth muscle (CCSM) as well as checking the effect on enhancing male rat sexual behavior, libido, potency as well as its spermatogenic properties. The seeds were powdered and sequentially extracted with hexane, ethyl acetate and butanol. Male Wistar rats were administered with graded doses of the n-BuOH extracts (ATB) of A. tuberosum (50, 100, 200 and 400 mg/kg) and Viagra was used as the positive control drug. The extract/drug was administered by gastric probe once daily for 45 days and the sexual behavior was analyzed by exposing the male rats to female rats in the estrus period. ATB relaxed corpus cavernosum smooth muscle (68.9%) at a concentration of 200 μg/ml. The results obtained from the animal studies indicated that ATB significantly increased mount frequency (MF), intromission frequency (IF), ejaculation frequency (EF), ejaculation latency (EL) and markedly reduced post ejaculatory interval (PEI), mount latency (ML), and intromission latency (IL). Furthermore, a remarkable increase in the test for potency was observed as witnessed by marked increase in erections, quick flips, long flips and total reflex. In addition, ATB significantly improved the sperm viability and count as well as increased the concentrations of testosterone, follicle stimulating hormone (FSH), and phosphatases in the treated animals. Thus our results suggest that A. tuberosum could stimulate sexual arousal and enhance sexual execution in male rats, thus providing valuable experimental evidence that A. tuberosum possesses sexual enhancing properties.

Combined Effects of Brain-Derived Neurotrophic Factor Immobilized Poly-Lactic-Co-Glycolic Acid Membrane with Human Adipose-Derived Stem Cells and Basic Fibroblast Growth Factor Hydrogel on Recovery of Erectile Dysfunction

PubMed Central

Lee, Seung Hwan; Kim, In Gul; Jung, Ae Ryang; Shrestha, Kshitiz Raj; Lee, Jin Ho; Park, Ki Dong; Chung, Byung Ha; Kim, Sae Woong; Kim, Ki Hean

2014-01-01

Erectile dysfunction (ED) is the most frequent long-term problem after radical prostatectomy. We aimed to evaluate whether the use of combination therapy with basic fibroblast growth factor (bFGF)-hydrogel on corpus cavernosum and with adipose-derived stem cells (ADSCs) and brain-derived neurotrophic factor (BDNF)-immobilized poly-lactic-co-glycolic acid (PLGA) membrane on the cavernous nerve (CN) could improve erectile function in a rat model of bilateral cavernous nerve crush injury (BCNI). Rats were randomly divided into five groups (n=15 per group): a normal group (N group), a group receiving saline application after bilateral cavernous nerve crush injury (BCNI), a group undergoing bFGF-hydrogel injection in the corpus cavernosum after BCNI (bFGF), a group receiving ADSC application covered with BDNF-membrane after BCNI (ADSC/BDNF), and a group undergoing coadministration of bFGF-hydrogel injection and BDNF-membrane with ADSCs after BDNF (bFGF+ADSC/BDNF). Four weeks postoperatively, the erectile function was assessed by detecting the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP). Smooth muscle and collagen contents were measured using Masson's trichrome staining. Neuronal nitric oxide synthase (nNOS) expression in the dorsal penile nerve was detected by immunostaining. The protein expression of the α-smooth muscle actin (α-SMA) and the cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum were quantified by western blot and cGMP assay, respectively. In the bFGF+ADSC/BDNF group, the erectile function was significantly elevated compared with the BCNI and other treated groups and showed a significantly increased smooth muscle/collagen ratio, nNOS content, α-SMA expression, and cGMP level. In particular, there were no statistical differences in the ICP/MAP ratio, smooth muscle/collagen ratio, and α-SMA and cGMP levels between the bFGF+ADSC/BDNF group and normal group. Application of the BDNF-immobilized PLGA membrane with human ADSC into the CN and bFGF-incorporated hydrogel into the corpus carvernosum improved nearly normal erectile function in a rat model of postprostatectomy ED. This result suggests that a combined application of bFGF+ADSC/BDNF might be a promising treatment for postprostatectomy ED. PMID:24673637

Preventive Effect of Hydrogen Water on the Development of Detrusor Overactivity in a Rat Model of Bladder Outlet Obstruction.

PubMed

Miyazaki, Nozomu; Yamaguchi, Osamu; Nomiya, Masanori; Aikawa, Ken; Kimura, Junko

2016-03-01

Bladder ischemia and oxidative stress contribute to the pathogenesis of bladder dysfunction caused by bladder outlet obstruction. H2 reportedly acts as an effective antioxidant. We investigated whether oral ingestion of H2 water would have a beneficial effect on bladder function in a rat model of bladder outlet obstruction. H2 water was made by dissolving H2 gas in ordinary drinking water using a hydrogen water producing apparatus. The bladder outlet obstruction model was surgically induced in male rats. Rats with obstruction were fed H2 water or ordinary drinking water. On week 4 postoperatively cystometry was performed. Oxidative stress markers and the bladder nerve growth factor level were determined. Bladder tissues were processed for pharmacological studies and histological analysis. The micturition interval and micturition volume significantly decreased in obstructed rats given ordinary drinking water. These decreases were significantly suppressed by oral ingestion of H2 water. Increased post-void residual volume in obstructed rats was significantly reduced by H2 water. Obstruction led to a significant increase in bladder weight, oxidative stress markers and nerve growth factor. H2 water significantly suppressed these increases without affecting bladder weight. There was no significant difference in histological findings between rats with bladder obstruction given H2 water and ordinary drinking water. Decreased responses of detrusor muscle strips from obstructed bladders to KCl, carbachol and electrical field stimulation were reversed by H2 water ingestion. Results suggest that H2 water could ameliorate bladder dysfunction secondary to bladder outlet obstruction by attenuating oxidative stress. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Composition of Muscle Fiber Types in Rat Rotator Cuff Muscles.

PubMed

Rui, Yongjun; Pan, Feng; Mi, Jingyi

2016-10-01

The rat is a suitable model to study human rotator cuff pathology owing to the similarities in morphological anatomy structure. However, few studies have reported the composition muscle fiber types of rotator cuff muscles in the rat. In this study, the myosin heavy chain (MyHC) isoforms were stained by immunofluorescence to show the muscle fiber types composition and distribution in rotator cuff muscles of the rat. It was found that rotator cuff muscles in the rat were of mixed fiber type composition. The majority of rotator cuff fibers labeled positively for MyHCII. Moreover, the rat rotator cuff muscles contained hybrid fibers. So, compared with human rotator cuff muscles composed partly of slow-twitch fibers, the majority of fast-twitch fibers in rat rotator cuff muscles should be considered when the rat model study focus on the pathological process of rotator cuff muscles after injury. Gaining greater insight into muscle fiber types in rotator cuff muscles of the rat may contribute to elucidate the mechanism of pathological change in rotator cuff muscles-related diseases. Anat Rec, 299:1397-1401, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The role of mitochondrial DNA damage at skeletal muscle oxidative stress on the development of type 2 diabetes.

PubMed

Dos Santos, Julia Matzenbacher; de Oliveira, Denise Silva; Moreli, Marcos Lazaro; Benite-Ribeiro, Sandra Aparecida

2018-04-20

Reduced cellular response to insulin in skeletal muscle is one of the major components of the development of type 2 diabetes (T2D). Mitochondrial dysfunction involves in the accumulation of toxic reactive oxygen species (ROS) that leads to insulin resistance. The aim of this study was to verify the involvement of mitochondrial DNA damage at ROS generation in skeletal muscle during development of T2D. Wistar rats were fed a diet containing 60% fat over 8 weeks and at day 14 a single injection of STZ (25 mg/kg) was administered (T2D-induced). Control rats received standard food and an injection of citrate buffer. Blood and soleus muscle were collected. Abdominal fat was quantified as well as glucose, triglyceride, LDL, HDL, and total cholesterol in plasma and mtDNA copy number, cytochrome b (cytb) mRNA, 8-hydroxyguanosine, and 8-isoprostane (a marker of ROS) in soleus muscle. T2D-induced animal presented similar characteristics to humans that develop T2D such as changes in blood glucose, abdominal fat, LDL, HDL and cholesterol total. In soleus muscle 8-isoprostane, mtDNA copy number and 8-hydroxyguanosine were increased, while cytb mRNA was decreased in T2D. Our results suggest that in the development of T2D, when risks factors of T2D are present, intracellular oxidative stress increases in skeletal muscle and is associated with a decrease in cytb transcription. To overcome this process mtDNA increased but due to the proximity of ROS generation, mtDNA remains damaged by oxidation leading to an increase in ROS in a vicious cycle accounting to the development of insulin resistance and further T2D.

Cellular antioxidant effects of atorvastatin in vitro and in vivo.

PubMed

Wassmann, Sven; Laufs, Ulrich; Müller, Kirsten; Konkol, Christian; Ahlbory, Katja; Bäumer, Anselm T; Linz, Wolfgang; Böhm, Michael; Nickenig, Georg

2002-02-01

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 micromol/L atorvastatin. Angiotensin II-induced and epidermal growth factor-induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription-polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by L-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins.

Effect of chronic pre-treatment with angiotensin converting enzyme inhibition on skeletal muscle mitochondrial recovery after ischemia/reperfusion.

PubMed

Thaveau, Fabien; Zoll, Joffrey; Bouitbir, Jamal; N'guessan, Benoît; Plobner, Philippe; Chakfe, Nabil; Kretz, Jean-Georges; Richard, Ruddy; Piquard, François; Geny, Bernard

2010-06-01

Impaired skeletal muscle energetic participates in peripheral arterial disease (PAD) patient's morbidity and mortality. Angiotensin converting enzyme inhibition (ACEi), cornerstone for pharmacologic risk factor management in PAD patients, might also be interesting by protecting skeletal muscle energetic. We therefore determined whether chronic ACEi might reduce ischemia-induced mitochondrial respiratory chain dysfunction in the frequent setting of hindlimb ischemia-reperfusion. Ischemic legs of rats submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hindlimb followed by reperfusion without (IR, n = 11) or after ACEi (n = 14; captopril 40 mg/kg per day during 28 days before surgery) were studied and compared to that of sham-operated animals (n = 11). The effect of ACEi on the non-ischemic contralateral leg was also determined in the ACEi group. Maximal oxidative capacities (V(max)) and complexes I, II and IV activities of the mitochondrial respiratory chain of the gastrocnemius muscle were determined using glutamate-malate, succinate and TMPD-ascorbate substrates. Arterial blood pressure was significantly decreased after ACEi (124 +/- 2.8 vs. 108 +/- 4.19 mmHg; P = 0.01). Ischemia-reperfusion reduced V(max) (4.4 +/- 0.4 vs. 8.7 +/- 0.5 micromol O2/min/g dry weight, -49%, P < 0.001), affecting mitochondrial complexes I, II and IV activities. ACEi failed to modulate ischemia-induced dysfunction (V(max) 5.1 +/- 0.7 micromol O2/min/g dry weight) or the non-ischemic contralateral muscle respiratory rate. Ischemia-reperfusion significantly impaired the mitochondrial respiratory chain I, II and IV complexes of skeletal muscle. Pharmacologic pre-treatment with ACEi did not prevent or increase such alterations. Further studies might be useful to improve the pharmacologic conditioning of PAD patients needing arterial revascularization.

Clomipramine counteracts lipid raft disturbance due to short-term muscle disuse.

PubMed

Bryndina, Irina G; Shalagina, Maria N; Sekunov, Alexey V; Zefirov, Andrei L; Petrov, Alexey M

2018-01-18

Disuse-induced skeletal muscle dysfunction is a serious consequence of long-term spaceflight, numerous diseases and conditions for which treatment possibilities are still strictly limited. We have previously shown that acute hindlimb suspension (HS)-mediated disuse disrupts membrane lipid rafts in the unloaded muscle. Here, we investigated whether pretreatment of rats with the inhibitor of acid sphingomyelinase, clomipramine (1.25mg/g/day, intramuscularly, for 5days before HS), is able to hinder the loss in lipid raft integrity in response to 12h of HS. Clomipramine pretreatment significantly counteracted the decrease in labeling of the plasma membranes with lipid raft markers (fluorescent cholera toxin B subunit and bodipy-GM1-ganglioside) specifically in the junctional regions of the suspended soleus muscle. This was associated with: a) enhancing raft disrupting potential of exogenous sphingomyelinase in the junctional membranes; b) prevention of both ceramide accumulation and cholesterol loss; c) prevention of decline in nicotinic acetylcholine receptor labeling in the unloaded muscle. Our data suggest that sphingomyelinase-mediated raft disturbance serves as one of the earlier events in HS effects. Copyright © 2017 Elsevier B.V. All rights reserved.

In vivo Ca2+ buffering capacity and microvascular oxygen pressures following muscle contractions in diabetic rat skeletal muscles: fiber-type specific effects.

PubMed

Eshima, Hiroaki; Poole, David C; Kano, Yutaka

2015-07-15

In Type 1 diabetes, skeletal muscle resting intracellular Ca(2+) concentration ([Ca(2+)]i) homeostasis is impaired following muscle contractions. It is unclear to what degree this behavior is contingent upon fiber type and muscle oxygenation conditions. We tested the hypotheses that: 1) the rise in resting [Ca(2+)]i evident in diabetic rat slow-twitch (type I) muscle would be exacerbated in fast-twitch (type II) muscle following contraction; and 2) these elevated [Ca(2+)]i levels would relate to derangement of microvascular partial pressure of oxygen (PmvO2 ) rather than sarcoplasmic reticulum dysfunction per se. Adult male Wistar rats were divided randomly into diabetic (DIA: streptozotocin ip) and healthy (CONT) groups. Four weeks later extensor digitorum longus (EDL, predominately type II fibers) and soleus (SOL, predominately type I fibers) muscle contractions were elicited by continuous electrical stimulation (120 s, 100 Hz). Ca(2+) imaging was achieved using fura 2-AM in vivo (i.e., circulation intact). DIA increased fatigability in EDL (P < 0.05) but not SOL. In recovery, SOL [Ca(2+)]i either returned to its resting baseline within 150 s (CONT 1.00 ± 0.02 at 600 s) or was not elevated in recovery at all (DIA 1.03 ± 0.02 at 600 s, P > 0.05). In recovery, EDL CONT [Ca(2+)]i also decreased to values not different from baseline (1.06 ± 0.01, P > 0.05) at 600 s. In marked contrast, EDL DIA [Ca(2+)]i remained elevated for the entire recovery period (i.e., 1.23 ± 0.03 at 600 s, P < 0.05). The inability of [Ca(2+)]i to return to baseline in EDL DIA was not associated with any reduction of SR Ca(2+)-ATPase (SERCA) 1 or SERCA2 protein levels (both increased 30-40%, P < 0.05). However, Pmv(O2) recovery kinetics were markedly slowed in EDL such that mean Pmv(O2) was substantially depressed (CONT 27.9 ± 2.0 vs. DIA 18.4 ± 2.0 Torr, P < 0.05), and this behavior was associated with the elevated [Ca(2+)]i. In contrast, this was not the case for SOL (P > 0.05) in that neither [Ca(2+)]i nor Pmv(O2) were deranged in recovery with DIA. In conclusion, recovery of [Ca(2+)]i homeostasis is impaired in diabetic rat fast-twitch but not slow-twitch muscle in concert with reduced Pmv(O2) pressures. Copyright © 2015 the American Physiological Society.

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.

PubMed

Roy Chowdhury, Subir K; Smith, Darrell R; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A; Fernyhough, Paul

2012-06-01

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway.

Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model.

PubMed

Qiu, Xuefeng; Lin, Guiting; Xin, Zhongcheng; Ferretti, Ludovic; Zhang, Haiyang; Lue, Tom F; Lin, Ching-Shwun

2013-03-01

Introduction.  Low-energy shockwave therapy (LESWT) has been shown to improve erectile function in patients suffering from diabetes mellitus (DM)-associated erectile dysfunction (ED). However, the underlying mechanism remains unknown. Aim.  The aim of this study is to investigate whether LESWT can ameliorate DM-associated ED in a rat model and examine the associated changes in the erectile tissues. Methods.  Newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous mesenchymal stem cells (MSCs). Eight weeks later, eight of these rats were randomly chosen to serve as normal control (N group). The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce DM. Eight of these rats were randomly chosen to serve as DM control (DM group), whereas another eight rats were subject to shockwave (SW) treatment (DM+SW group). Each rat in the DM+SW group received 300 shocks at energy level of 0.1 mJ/mm(2) and frequency of 120/minute. This procedure was repeated three times a week for 2 weeks. Another 2 weeks later, all 24 rats were evaluated for erectile function by intracavernous pressure (ICP) measurement. Afterward, their penile tissues were examined by histology. Main Outcome Measures.  Erectile function was measured by ICP. Neuronal nitric oxide synthase (nNOS)-positive nerves and the endothelium were examined by immunofluorescence staining. Smooth muscle and MSCs were examined by phalloidin and EdU staining, respectively. Results.  STZ treatment caused a significant decrease in erectile function and in the number of nNOS-positive nerves and in endothelial and smooth muscle contents. These DM-associated deficits were all partially but significantly reversed by LESWT. MSCs (EdU-positive cells) were significantly more numerous in DM+SW than in DM rats. Conclusion.  LESWT can partially ameliorate DM-associated ED by promoting regeneration of nNOS-positive nerves, endothelium, and smooth muscle in the penis. These beneficial effects appear to be mediated by recruitment of endogenous MSCs. Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, and Lin C-S. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med 2013;10:738-746. © 2012 International Society for Sexual Medicine.

Myostatin dysfunction impairs force generation in extensor digitorum longus muscle and increases exercise-induced protein efflux from extensor digitorum longus and soleus muscles.

PubMed

Baltusnikas, Juozas; Kilikevicius, Audrius; Venckunas, Tomas; Fokin, Andrej; Bünger, Lutz; Lionikas, Arimantas; Ratkevicius, Aivaras

2015-08-01

Myostatin dysfunction promotes muscle hypertrophy, which can complicate assessment of muscle properties. We examined force generating capacity and creatine kinase (CK) efflux from skeletal muscles of young mice before they reach adult body and muscle size. Isolated soleus (SOL) and extensor digitorum longus (EDL) muscles of Berlin high (BEH) mice with dysfunctional myostatin, i.e., homozygous for inactivating myostatin mutation, and with a wild-type myostatin (BEH+/+) were studied. The muscles of BEH mice showed faster (P < 0.01) twitch and tetanus contraction times compared with BEH+/+ mice, but only EDL displayed lower (P < 0.05) specific force. SOL and EDL of age-matched but not younger BEH mice showed greater exercise-induced CK efflux compared with BEH+/+ mice. In summary, myostatin dysfunction leads to impairment in muscle force generating capacity in EDL and increases susceptibility of SOL and EDL to protein loss after exercise.

Muscle fatigue in the temporal and masseter muscles in patients with temporomandibular dysfunction.

PubMed

Woźniak, Krzysztof; Lipski, Mariusz; Lichota, Damian; Szyszka-Sommerfeld, Liliana

2015-01-01

The aim of this study is to evaluate muscle fatigue in the temporal and masseter muscles in patients with temporomandibular dysfunction (TMD). Two hundred volunteers aged 19.3 to 27.8 years (mean 21.50, SD 0.97) participated in this study. Electromyographical (EMG) recordings were performed using a DAB-Bluetooth Instrument (Zebris Medical GmbH, Germany). Muscle fatigue was evaluated on the basis of a maximum effort test. The test was performed during a 10-second maximum isometric contraction (MVC) of the jaws. An analysis of changes in the mean power frequency of the two pairs of temporal and masseter muscles (MPF%) revealed significant differences in the groups of patients with varying degrees of temporomandibular disorders according to Di (P < 0.0000). The study showed an increase in the muscle fatigue of the temporal and masseter muscles correlated with the intensity of temporomandibular dysfunction symptoms in patients. The use of surface electromyography in assessing muscle fatigue is an excellent diagnostic tool for identifying patients with temporomandibular dysfunction.

Muscle Fatigue in the Temporal and Masseter Muscles in Patients with Temporomandibular Dysfunction

PubMed Central

Woźniak, Krzysztof; Lipski, Mariusz; Lichota, Damian

2015-01-01

The aim of this study is to evaluate muscle fatigue in the temporal and masseter muscles in patients with temporomandibular dysfunction (TMD). Two hundred volunteers aged 19.3 to 27.8 years (mean 21.50, SD 0.97) participated in this study. Electromyographical (EMG) recordings were performed using a DAB-Bluetooth Instrument (Zebris Medical GmbH, Germany). Muscle fatigue was evaluated on the basis of a maximum effort test. The test was performed during a 10-second maximum isometric contraction (MVC) of the jaws. An analysis of changes in the mean power frequency of the two pairs of temporal and masseter muscles (MPF%) revealed significant differences in the groups of patients with varying degrees of temporomandibular disorders according to Di (P < 0.0000). The study showed an increase in the muscle fatigue of the temporal and masseter muscles correlated with the intensity of temporomandibular dysfunction symptoms in patients. The use of surface electromyography in assessing muscle fatigue is an excellent diagnostic tool for identifying patients with temporomandibular dysfunction. PMID:25883949

Reduction-oxidation state and protein degradation in skeletal muscle of fasted and refed rats

NASA Technical Reports Server (NTRS)

Fagan, Julie M.; Tischler, Marc E.

1986-01-01

Redox state and protein degradation were measured in isolated muscles of fasted (up to 10 d) and refed (up to 4 d) 7- to 14-wk-old rats. Protein degradation in the extensor digitorum longus muscle, but not in the soleus muscle, was greater in the fasted rats than in weight-matched muscle from fed rats. The NAD couple was more oxidized in incubated and fresh extensor digitorum longus muscles and in some incubated soleus muscles of fasted rats than in weight-matched muscle from fed rats. In the extensor digitorum longus muscle of refed or prolonged fasted rats, protein degradation was slower and the NAD couple was more reduced than in the fed state. Therefore, oxidation of the NAD couple was associated with increased muscle breakdown during fasting, whereas reduction of the NAD couple was associated with muscle conservation and deposition.

Expression of interleukin-15 and inflammatory cytokines in skeletal muscles of STZ-induced diabetic rats: effect of resistance exercise training.

PubMed

Molanouri Shamsi, M; Hassan, Z H; Gharakhanlou, R; Quinn, L S; Azadmanesh, K; Baghersad, L; Isanejad, A; Mahdavi, M

2014-05-01

Skeletal muscle atrophy is associated with type-1 diabetes. Skeletal muscle is the source of pro- and anti-inflammatory cytokines that can mediate muscle hypertrophy and atrophy, while resistance exercise can modulate both muscle mass and muscle cytokine expression. This study determined the effects of a 5-week resistance exercise training regimen on the expression of muscle cytokines in healthy and streptozotocin-induced diabetic rats, with special emphasis on interleukin-15 (IL-15), a muscle-derived cytokine proposed to be involved in muscle hypertrophy or responses to stress. Induction of diabetes reduced muscle weight in both the fast flexor hallucis longus (FHL) and slow soleus muscles, while resistance training preserved FHL muscle weight in diabetic rats. IL-15 protein content was increased by training in both FHL and soleus muscles, as well as serum, in normal and diabetic rats. With regard to proinflammatory cytokines, muscle IL-6 levels were increased in diabetic rats, while training decreased muscle IL-6 levels in diabetic rats; training had no effect on FHL muscle IL-6 levels in healthy rats. Also, tumor necrosis factor-alpha (TNF-α) and IL-1β levels were increased by diabetes, but not changed by training. In conclusion, we found that in diabetic rats, resistance training increased muscle and serum IL-15 levels, decreased muscle IL-6 levels, and preserved FHL muscle mass.

Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy.

PubMed

Carillion, Aude; Feldman, Sarah; Na, Na; Biais, Matthieu; Carpentier, Wassila; Birenbaum, Aurélie; Cagnard, Nicolas; Loyer, Xavier; Bonnefont-Rousselot, Dominique; Hatem, Stéphane; Riou, Bruno; Amour, Julien

2017-01-01

In the diabetic heart the β-adrenergic response is altered partly by down-regulation of the β1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the β3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their "pleiotropic" effects. The objective of our study was to investigate the role of statin treatment on β-adrenergic dysfunction in diabetic rat cardiomyocytes. β-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline ± SD. Atorvastatin restored the impaired positive inotropic effect of β-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the β-adrenergic pathway and corrected the protein expression of β1-adrenoceptor and β1/β3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the β-adrenoceptor response. Atorvastatin restored the positive inotropic effect of the β-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the β-adrenergic signaling pathway, particularly through the NOS pathway.

Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy

PubMed Central

Carillion, Aude; Feldman, Sarah; Na, Na; Biais, Matthieu; Carpentier, Wassila; Birenbaum, Aurélie; Cagnard, Nicolas; Loyer, Xavier; Bonnefont-Rousselot, Dominique; Hatem, Stéphane; Riou, Bruno

2017-01-01

Background In the diabetic heart the β-adrenergic response is altered partly by down-regulation of the β1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the β3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their “pleiotropic” effects. The objective of our study was to investigate the role of statin treatment on β-adrenergic dysfunction in diabetic rat cardiomyocytes. Methods β-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline ± SD. Results Atorvastatin restored the impaired positive inotropic effect of β-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the β-adrenergic pathway and corrected the protein expression of β1-adrenoceptor and β1/β3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the β-adrenoceptor response. Conclusions Atorvastatin restored the positive inotropic effect of the β-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the β-adrenergic signaling pathway, particularly through the NOS pathway. PMID:28727746

Muscle dysfunction versus wear and tear as a cause of exercise related osteoarthritis: an epidemiological update.

PubMed

Shrier, Ian

2004-10-01

There are two main hypotheses for the cause of exercise related osteoarthritis: wear and tear of the articular cartilage and muscle dysfunction. This is a review of the clinical literature to see which hypothesis has the greatest support. Clinical studies support the muscle dysfunction hypothesis over the wear and tear hypothesis.

Tributyltin chloride induces renal dysfunction by inflammation and oxidative stress in female rats.

PubMed

Coutinho, João V S; Freitas-Lima, Leandro C; Freitas, Frederico F C T; Freitas, Flávia P S; Podratz, Priscila L; Magnago, Rafaella P L; Porto, Marcella L; Meyrelles, Silvana S; Vasquez, Elisardo C; Brandão, Poliane A A; Carneiro, Maria T W D; Paiva-Melo, Francisca D; Miranda-Alves, Leandro; Silva, Ian V; Gava, Agata L; Graceli, Jones B

2016-10-17

Tributyltin chloride (TBT) is an organometallic pollutant that is used as a biocide in antifouling paints. TBT induces several toxic and endocrine-disrupting effects. However, studies evaluating the effects of TBT on renal function are rare. This study demonstrates that TBT exposure is responsible for improper renal function as well as the development of abnormal morphophysiology in mammalian kidneys. Female rats were treated with TBT, and their renal morphophysiology was assessed. Morphophysiological abnormalities such as decreased glomerular filtration rate and increased proteinuria levels were observed in TBT rats. In addition, increases in inflammation, collagen deposition and α-smooth muscle actin (α-SMA) protein expression were observed in TBT kidneys. A disrupted cellular redox balance and apoptosis in kidney tissue were also observed in TBT rats. TBT rats demonstrated reduced serum estrogen levels and estrogen receptor-α (ERα) protein expression in renal cortex. Together, these data provide in vivo evidence that TBT is toxic to normal renal function and that these effects may be associated with renal histopathology complications, such as inflammation and fibrosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A role of pancreatic stellate cells in islet fibrosis and β-cell dysfunction in type 2 diabetes mellitus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Esder; Ryu, Gyeong Ryul; Ko, Seung-Hyun

Objectives: To investigate whether the activation of pancreatic stellate cells (PSCs) leads to pancreatic β-cell dysfunction in type 2 diabetes mellitus (T2DM). Methods: The pancreases of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of T2DM, and patient with T2DM were analyzed. And the in vitro and in vivo effects of pirfenidone, an antifibrotic agent, on PSC activation, islet fibrosis, and β-cells were studied. Results: The extent of islet fibrosis and the percentage of activated PSCs, positive for α-smooth muscle actin, in the islets were significantly greater in OLETF rats compared with non-diabetic rats. Also, the extent of islet fibrosis inmore » patients with T2DM was slightly greater compared with age- and BMI-matched non-diabetic patients. In rat PSCs cultured with high glucose for 72 h, pirfenidone produced decreases in cell proliferation, release of collagen, and the expression of fibronectin and connective tissue growth factor. Treatment of OLETF rats with pirfenidone for 16 weeks decreased the activation of PSCs and the extent of islet fibrosis, but did not enhance glucose tolerance, pancreatic insulin content, or β-cell mass. Conclusions: Activated PSCs in islets might lead to islet fibrosis in T2DM. However, PSC activation itself might not contribute significantly to progressive β-cell failure in T2DM. - Highlights: • Islet fibrosis developed progressively in OLETF rats, a model of type 2 diabetes. • PSCs in the islets became activated in OLETF rats. • Islet fibrosis was increased in patients with type 2 diabetes. • Pirfenidone attenuated the activation of PSCs and islet fibrosis in OLETF rats. • Pirfenidonet had no effects on glucose tolerance or on β-cells in OLETF rats.« less

Myogenic regulatory factors during regeneration of skeletal muscle in young, adult, and old rats

NASA Technical Reports Server (NTRS)

Marsh, D. R.; Criswell, D. S.; Carson, J. A.; Booth, F. W.

1997-01-01

Myogenic factor mRNA expression was examined during muscle regeneration after bupivacaine injection in Fischer 344/Brown Norway F1 rats aged 3, 18, and 31 mo of age (young, adult, and old, respectively). Mass of the tibialis anterior muscle in the young rats had recovered to control values by 21 days postbupivacaine injection but in adult and old rats remained 40% less than that of contralateral controls at 21 and 28 days of recovery. During muscle regeneration, myogenin mRNA was significantly increased in muscles of young, adult, and old rats 5 days after bupivacaine injection. Subsequently, myogenin mRNA levels in young rat muscle decreased to postinjection control values by day 21 but did not return to control values in 28-day regenerating muscles of adult and old rats. The expression of MyoD mRNA was also increased in muscles at day 5 of regeneration in young, adult, and old rats, decreased to control levels by day 14 in young and adult rats, and remained elevated in the old rats for 28 days. In summary, either a diminished ability to downregulate myogenin and MyoD mRNAs in regenerating muscle occurs in old rat muscles, or the continuing myogenic effort includes elevated expression of these mRNAs.

Hyperglycemia inhibits recovery from disuse-induced skeletal muscle atrophy in rats.

PubMed

Kataoka, H; Nakano, J; Morimoto, Y; Honda, Y; Sakamoto, J; Origuchi, T; Okita, M; Yoshimura, T

2014-01-01

The purpose of this study was to evaluate the effects of hyperglycemia on skeletal muscle recovery following disuse-induced muscle atrophy in rats. Wistar rats were grouped as streptozotocin-induced diabetic rats and non-diabetic rats. Both ankle joints of each rat were immobilized to induce atrophy of the gastrocnemius muscles. After two weeks of immobilization and an additional two weeks of recovery, tail blood and gastrocnemius muscles were isolated. Serial cross sections of muscles were stained for myosin ATPase (pH 4.5) and alkaline phosphatase activity. Serum insulin and muscle insulin-like growth factor-1 (IGF-1) levels were also measured. Serum insulin levels were significantly reduced in the diabetic rats compared to the non-diabetic controls. The diameters of type I, IIa, and IIb myofibers and capillary-to-myofiber ratio in the isolated muscle tissue were decreased after immobilization in both treatments. During the recovery period, these parameters were restored in the non-diabetic rats, but not in the diabetic rats. In addition, muscle IGF-1 levels after recovery increased significantly in the non-diabetic rats, but not in the diabetic rats. We conclude that decreased levels of insulin and IGF-1 and impairment of angiogenesis associated with diabetes might be partly responsible for the inhibition of regrowth in diabetic muscle.

Resistance to Aerobic Exercise Training Causes Metabolic Dysfunction and Reveals Novel Exercise-Regulated Signaling Networks

PubMed Central

Lessard, Sarah J.; Rivas, Donato A.; Alves-Wagner, Ana B.; Hirshman, Michael F.; Gallagher, Iain J.; Constantin-Teodosiu, Dumitru; Atkins, Ryan; Greenhaff, Paul L.; Qi, Nathan R.; Gustafsson, Thomas; Fielding, Roger A.; Timmons, James A.; Britton, Steven L.; Koch, Lauren G.; Goodyear, Laurie J.

2013-01-01

Low aerobic exercise capacity is a risk factor for diabetes and a strong predictor of mortality, yet some individuals are “exercise-resistant” and unable to improve exercise capacity through exercise training. To test the hypothesis that resistance to aerobic exercise training underlies metabolic disease risk, we used selective breeding for 15 generations to develop rat models of low and high aerobic response to training. Before exercise training, rats selected as low and high responders had similar exercise capacities. However, after 8 weeks of treadmill training, low responders failed to improve their exercise capacity, whereas high responders improved by 54%. Remarkably, low responders to aerobic training exhibited pronounced metabolic dysfunction characterized by insulin resistance and increased adiposity, demonstrating that the exercise-resistant phenotype segregates with disease risk. Low responders had impaired exercise-induced angiogenesis in muscle; however, mitochondrial capacity was intact and increased normally with exercise training, demonstrating that mitochondria are not limiting for aerobic adaptation or responsible for metabolic dysfunction in low responders. Low responders had increased stress/inflammatory signaling and altered transforming growth factor-β signaling, characterized by hyperphosphorylation of a novel exercise-regulated phosphorylation site on SMAD2. Using this powerful biological model system, we have discovered key pathways for low exercise training response that may represent novel targets for the treatment of metabolic disease. PMID:23610057

Muscle regeneration during hindlimb unloading results in a reduction in muscle size after reloading

NASA Technical Reports Server (NTRS)

Mozdziak, P. E.; Pulvermacher, P. M.; Schultz, E.

2001-01-01

The hindlimb-unloading model was used to study the ability of muscle injured in a weightless environment to recover after reloading. Satellite cell mitotic activity and DNA unit size were determined in injured and intact soleus muscles from hindlimb-unloaded and age-matched weight-bearing rats at the conclusion of 28 days of hindlimb unloading, 2 wk after reloading, and 9 wk after reloading. The body weights of hindlimb-unloaded rats were significantly (P < 0.05) less than those of weight-bearing rats at the conclusion of hindlimb unloading, but they were the same (P > 0.05) as those of weight-bearing rats 2 and 9 wk after reloading. The soleus muscle weight, soleus muscle weight-to-body weight ratio, myofiber diameter, number of nuclei per millimeter, and DNA unit size were significantly (P < 0.05) smaller for the injured soleus muscles from hindlimb-unloaded rats than for the soleus muscles from weight-bearing rats at each recovery time. Satellite cell mitotic activity was significantly (P < 0.05) higher in the injured soleus muscles from hindlimb-unloaded rats than from weight-bearing rats 2 wk after reloading, but it was the same (P > 0.05) as in the injured soleus muscles from weight-bearing rats 9 wk after reloading. The injured soleus muscles from hindlimb-unloaded rats failed to achieve weight-bearing muscle size 9 wk after reloading, because incomplete compensation for the decrease in myonuclear accretion and DNA unit size expansion occurred during the unloading period.

Quantitative Biology of Exercise-Induced Signal Transduction Pathways.

PubMed

Liu, Timon Cheng-Yi; Liu, Gang; Hu, Shao-Juan; Zhu, Ling; Yang, Xiang-Bo; Zhang, Quan-Guang

2017-01-01

Exercise is essential in regulating energy metabolism. Exercise activates cellular, molecular, and biochemical pathways with regulatory roles in training response adaptation. Among them, endurance/strength training of an individual has been shown to activate its respective signal transduction pathways in skeletal muscle. This was further studied from the viewpoint of quantitative difference (QD). For the mean values, [Formula: see text], of two sets of data, their QD is defined as [Formula: see text] ([Formula: see text]). The function-specific homeostasis (FSH) of a function of a biosystem is a negative-feedback response of the biosystem to maintain the function-specific conditions inside the biosystem so that the function is perfectly performed. A function in/far from its FSH is called a normal/dysfunctional function. A cellular normal function can resist the activation of other signal transduction pathways so that there are normal function-specific signal transduction pathways which full activation maintains the normal function. An acute endurance/strength training may be dysfunctional, but its regular training may be normal. The normal endurance/strength training of an individual may resist the activation of other signal transduction pathways in skeletal muscle so that there may be normal endurance/strength training-specific signal transduction pathways (NEPs/NSPs) in skeletal muscle. The endurance/strength training may activate NSPs/NEPs, but the QD from the control is smaller than 0.80. The simultaneous activation of both NSPs and NEPs may enhance their respective activation, and the QD from the control is larger than 0.80. The low level laser irradiation pretreatment of rats may promote the activation of NSPs in endurance training skeletal muscle. There may be NEPs/NSPs in skeletal muscle trained by normal endurance/strength training.

Jaw Dysfunction Is Associated with Neck Disability and Muscle Tenderness in Subjects with and without Chronic Temporomandibular Disorders

PubMed Central

Silveira, A.; Gadotti, I. C.; Armijo-Olivo, S.; Biasotto-Gonzalez, D. A.; Magee, D.

2015-01-01

Purpose. Tender points in the neck are common in patients with temporomandibular disorders (TMD). However, the correlation among neck disability, jaw dysfunction, and muscle tenderness in subjects with TMD still needs further investigation. This study investigated the correlation among neck disability, jaw dysfunction, and muscle tenderness in subjects with and without chronic TMD. Participants. Forty females between 19 and 49 years old were included in this study. There were 20 healthy controls and 20 subjects who had chronic TMD and neck disability. Methods. Subjects completed the neck disability index and the limitations of daily functions in TMD questionnaires. Tenderness of the masticatory and cervical muscles was measured using an algometer. Results. The correlation between jaw disability and neck disability was significantly high (r = 0.915, P < 0.05). The correlation between level of muscle tenderness in the masticatory and cervical muscles with jaw dysfunction and neck disability showed fair to moderate correlations (r = 0.32–0.65). Conclusion. High levels of muscle tenderness in upper trapezius and temporalis muscles correlated with high levels of jaw and neck dysfunction. Moreover, high levels of neck disability correlated with high levels of jaw disability. These findings emphasize the importance of considering the neck and its structures when evaluating and treating patients with TMD. PMID:25883963

Jaw dysfunction is associated with neck disability and muscle tenderness in subjects with and without chronic temporomandibular disorders.

PubMed

Silveira, A; Gadotti, I C; Armijo-Olivo, S; Biasotto-Gonzalez, D A; Magee, D

2015-01-01

Tender points in the neck are common in patients with temporomandibular disorders (TMD). However, the correlation among neck disability, jaw dysfunction, and muscle tenderness in subjects with TMD still needs further investigation. This study investigated the correlation among neck disability, jaw dysfunction, and muscle tenderness in subjects with and without chronic TMD. Participants. Forty females between 19 and 49 years old were included in this study. There were 20 healthy controls and 20 subjects who had chronic TMD and neck disability. Subjects completed the neck disability index and the limitations of daily functions in TMD questionnaires. Tenderness of the masticatory and cervical muscles was measured using an algometer. The correlation between jaw disability and neck disability was significantly high (r = 0.915, P < 0.05). The correlation between level of muscle tenderness in the masticatory and cervical muscles with jaw dysfunction and neck disability showed fair to moderate correlations (r = 0.32-0.65). High levels of muscle tenderness in upper trapezius and temporalis muscles correlated with high levels of jaw and neck dysfunction. Moreover, high levels of neck disability correlated with high levels of jaw disability. These findings emphasize the importance of considering the neck and its structures when evaluating and treating patients with TMD.

Antifibrogenic role of valproic acid in streptozotocin induced diabetic rat penis.

PubMed

Kutlu, O; Karaguzel, E; Gurgen, S G; Okatan, A E; Kutlu, S; Bayraktar, C; Kazaz, I O; Eren, H

2016-05-01

We investigated the therapeutic effects of valproic acid (VPA) on erectile dysfunction and reducing penile fibrosis in streptozocin (STZ)-induced diabetic rats. Eighteen male rats were divided into three experimental groups (Control, STZ-DM, STZ-DM plus VPA) and diabetes was induced by transperitoneal single dose STZ. Eight weeks after, VPA and placebo treatments were given according to groups for 15 days. All rats were anesthetised for the measurement of in vivo erectile response to cavernous nerve stimulation. Afterward penes were evaluated histologically in terms of immune labelling scores of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). Slides were also evaluated in terms of collagen/smooth muscle ratio and penile apoptosis. After the treatment with VPA, erectile responses were found as improved when compared with STZ-DM rats but not statistically meaningful. eNOS and VEGF immune expressions diminished in penile corpora of STZ-DM rats and improved with VPA treatment. VPA led to decrease in TGF-β1 expression and collagen content of diabetic rats' penes. Penile apoptosis was not diminished with VPA. In conclusion, VPA treatment seems to be effective for reducing penile fibrosis in diabetic rats and more prolonged treatment period may enhance erectile functions. © 2015 Blackwell Verlag GmbH.

An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease.

PubMed

Maltais, François; Decramer, Marc; Casaburi, Richard; Barreiro, Esther; Burelle, Yan; Debigaré, Richard; Dekhuijzen, P N Richard; Franssen, Frits; Gayan-Ramirez, Ghislaine; Gea, Joaquim; Gosker, Harry R; Gosselink, Rik; Hayot, Maurice; Hussain, Sabah N A; Janssens, Wim; Polkey, Micheal I; Roca, Josep; Saey, Didier; Schols, Annemie M W J; Spruit, Martijn A; Steiner, Michael; Taivassalo, Tanja; Troosters, Thierry; Vogiatzis, Ioannis; Wagner, Peter D

2014-05-01

Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

PubMed Central

Maltais, François; Decramer, Marc; Casaburi, Richard; Barreiro, Esther; Burelle, Yan; Debigaré, Richard; Dekhuijzen, P. N. Richard; Franssen, Frits; Gayan-Ramirez, Ghislaine; Gea, Joaquim; Gosker, Harry R.; Gosselink, Rik; Hayot, Maurice; Hussain, Sabah N. A.; Janssens, Wim; Polkey, Micheal I.; Roca, Josep; Saey, Didier; Schols, Annemie M. W. J.; Spruit, Martijn A.; Steiner, Michael; Taivassalo, Tanja; Troosters, Thierry; Vogiatzis, Ioannis; Wagner, Peter D.

2014-01-01

Background: Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. Purpose: The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. Methods: An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. Results: We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. Conclusions: Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed. PMID:24787074

Long-term obesity promotes alterations in diastolic function induced by reduction of phospholamban phosphorylation at serine-16 without affecting calcium handling.

PubMed

Lima-Leopoldo, Ana Paula; Leopoldo, André S; da Silva, Danielle C T; do Nascimento, André F; de Campos, Dijon H S; Luvizotto, Renata A M; de Deus, Adriana F; Freire, Paula P; Medeiros, Alessandra; Okoshi, Katashi; Cicogna, Antonio C

2014-09-15

Few studies have evaluated the relationship between the duration of obesity, cardiac function, and the proteins involved in myocardial calcium (Ca(2+)) handling. We hypothesized that long-term obesity promotes cardiac dysfunction due to a reduction of expression and/or phosphorylation of myocardial Ca(2+)-handling proteins. Thirty-day-old male Wistar rats were distributed into two groups (n = 10 each): control (C; standard diet) and obese (Ob; high-fat diet) for 30 wk. Morphological and histological analyses were assessed. Left ventricular cardiac function was assessed in vivo by echocardiographic evaluation and in vitro by papillary muscle. Cardiac protein expression of sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), calsequestrin, L-type Ca(2+) channel, and phospholamban (PLB), as well as PLB serine-16 phosphorylation (pPLB Ser(16)) and PLB threonine-17 phosphorylation (pPLB Thr(17)) were determined by Western blot. The adiposity index was higher (82%) in Ob rats than in C rats. Obesity promoted cardiac hypertrophy without alterations in interstitial collagen levels. Ob rats had increased endocardial and midwall fractional shortening, posterior wall shortening velocity, and A-wave compared with C rats. Cardiac index, early-to-late diastolic mitral inflow ratio, and isovolumetric relaxation time were lower in Ob than in C. The Ob muscles developed similar baseline data and myocardial responsiveness to increased extracellular Ca(2+). Obesity caused a reduction in cardiac pPLB Ser(16) and the pPLB Ser(16)/PLB ratio in Ob rats. Long-term obesity promotes alterations in diastolic function, most likely due to the reduction of pPLB Ser(16), but does not impair the myocardial Ca(2+) entry and recapture to SR. Copyright © 2014 the American Physiological Society.

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction

PubMed Central

Zizola, Cynthia; Kennel, Peter J.; Akashi, Hirokazu; Ji, Ruiping; Castillero, Estibaliz; George, Isaac; Homma, Shunichi

2015-01-01

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. PMID:25713305

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.

PubMed

Zizola, Cynthia; Kennel, Peter J; Akashi, Hirokazu; Ji, Ruiping; Castillero, Estibaliz; George, Isaac; Homma, Shunichi; Schulze, P Christian

2015-05-01

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. Copyright © 2015 the American Physiological Society.

Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma

NASA Technical Reports Server (NTRS)

Baracos, V. E.; DeVivo, C.; Hoyle, D. H.; Goldberg, A. L.

1995-01-01

Rats implanted with Yoshida ascites hepatoma (YAH) show a rapid and selective loss of muscle protein due mainly to a marked increase (63-95%) in the rate of protein degradation (compared with rates in muscles of pair-fed controls). To define which proteolytic pathways contribute to this increase, epitrochlearis muscles from YAH-bearing and control rats were incubated under conditions that modify different proteolytic systems. Overall proteolysis in either group of rats was not affected by removal of Ca2+ or by blocking the Ca(2+)-dependent proteolytic system. Inhibition of lysosomal function with methylamine reduced proteolysis (-12%) in muscles from YAH-bearing rats, but not in muscles of pair-fed rats. When ATP production was also inhibited, the remaining accelerated proteolysis in muscles of tumor-bearing rats fell to control levels. Muscles of YAH-bearing rats showed increased levels of ubiquitin-conjugated proteins and a 27-kDa proteasome subunit in Western blot analysis. Levels of mRNA encoding components of proteolytic systems were quantitated using Northern hybridization analysis. Although their total RNA content decreased 20-38%, pale muscles of YAH-bearing rats showed increased levels of ubiquitin mRNA (590-880%) and mRNA for multiple subunits of the proteasome (100-215%). Liver, kidney, heart, and brain showed no weight loss and no change in these mRNA species. Muscles of YAH-bearing rats also showed small increases (30-40%) in mRNA for cathepsins B and D, but not for calpain I or heat shock protein 70. Our findings suggest that accelerated muscle proteolysis and muscle wasting in tumor-bearing rats result primarily from activation of the ATP-dependent pathway involving ubiquitin and the proteasome.

Botulinum neurotoxin effects on masseter muscle fibre in WNIN obese rats-Scanning electron microscope analysis.

PubMed

Nemani, Shivaram; Putchha, Uday K; Periketi, Madhusudhanachary; Pothana, Sailaja; Nappanveettil, Giridharan; Nemani, Harishankar

2016-09-01

WNIN/Ob obese mutant rats are unique in comparison to similar rodent models of obesity established in the West. The present study is aimed to evaluate the masticatory function and histological changes in masseter muscle fibres treated with botulinum toxin type A (BoNT/A) in WNIN/Ob rats. Twelve WNIN/Ob obese rats and 12 lean rats at 35 days of age were taken and divided into four groups (6 rats in each group): Group-I (WNIN/Ob) and Group-II (lean) rats were injected with BoNT/A (1 unit) into right side of masseter muscle. For control left masseter of both phenotypes was injected with saline. Group-III (WNIN/Ob) and Group-IV (lean) rats were without any treatment. Growth and food intake was monitored daily for 45 days. Rats were euthanized and gross necropsy was carried out to check any abnormalities. Masseter muscles were dissected and mean muscle mass was recorded. Small portion of muscle was stored in 10% formalin for hematoxylin-eosin (H&E) staining and remaining tissue stored in gluteraldehyde for scanning electron microscopy (SEM). There is a significant decrease in the body weights and food intake of BoNT/A treated obese rats. The H&E staining of the masseter muscle in both groups showed normal morphology and orientation. The SEM analysis showed that, fibre size in BoNT/A treated masseter muscle of obese rats increased more than the saline treated side and in control rats. The increase in the muscle fibre size and transition of muscle fibre subtypes may be due to the reduced masticatory function of the masseter muscle. SCANNING 38:396-402, 2016. © 2015 Wiley Periodicals, Inc. © Wiley Periodicals, Inc.

Active and passive characteristics of muscle tone and their relationship to models of subluxation/joint dysfunction

PubMed Central

Knutson, Gary A.; Owens, Edward F.

2003-01-01

The relationship of muscles to the causes and effects of the pathophysiologic entity referred to as chiropractic subluxation or joint dysfunction is critical. Part I of this paper reviewed the complexities of skeletal muscle in regards to anatomy, active and passive tone, detection of muscle tone, neurophysiology, and how muscle function fits into a variety of subluxation/joint dysfunction models. The concluding part of the review culminates in a hypothesis to describe and explain varying degrees of muscle tone that may be encountered clinically. It is hoped that knowledge of the differing levels of muscle tone and their causes will help the clinician to better determine the underlying cause of a neuromusculoskeletal problem allowing application of necessary and proper intervention.

The Use of Trace Eyeblink Classical Conditioning to Assess Hippocampal Dysfunction in a Rat Model of Fetal Alcohol Spectrum Disorders

PubMed Central

Tran, Tuan D.; Amin, Aenia; Jones, Keith G.; Sheffer, Ellen M.; Ortega, Lidia; Dolman, Keith

2017-01-01

Neonatal rats were administered a relatively high concentration of ethyl alcohol (11.9% v/v) during postnatal days 4-9, a time when the fetal brain undergoes rapid organizational change and is similar to accelerated brain changes that occur during the third trimester in humans. This model of fetal alcohol spectrum disorders (FASDs) produces severe brain damage, mimicking the amount and pattern of binge-drinking that occurs in some pregnant alcoholic mothers. We describe the use of trace eyeblink classical conditioning (ECC), a higher-order variant of associative learning, to assess long-term hippocampal dysfunction that is typically seen in alcohol-exposed adult offspring. At 90 days of age, rodents were surgically prepared with recording and stimulating electrodes, which measured electromyographic (EMG) blink activity from the left eyelid muscle and delivered mild shock posterior to the left eye, respectively. After a 5 day recovery period, they underwent 6 sessions of trace ECC to determine associative learning differences between alcohol-exposed and control rats. Trace ECC is one of many possible ECC procedures that can be easily modified using the same equipment and software, so that different neural systems can be assessed. ECC procedures in general, can be used as diagnostic tools for detecting neural pathology in different brain systems and different conditions that insult the brain. PMID:28809846

Saturated high-fat diet-induced obesity increases adenylate cyclase of myocardial β-adrenergic system and does not compromise cardiac function.

PubMed

Vileigas, Danielle F; de Deus, Adriana F; da Silva, Danielle C T; de Tomasi, Loreta C; de Campos, Dijon H S; Adorni, Caroline S; de Oliveira, Scarlet M; Sant'Ana, Paula G; Okoshi, Katashi; Padovani, Carlos R; Cicogna, Antonio C

2016-09-01

Obesity is a worldwide pandemic associated with high incidence of cardiovascular disease. The mechanisms by which the obesity leads cardiac dysfunction are not fully elucidated and few studies have evaluated the relationship between obesity and proteins involved in myocardial β-adrenergic (βA) system. The purpose of this study was to evaluate the cardiac function and βA pathway components in myocardium of obese rats. Male Wistar rats were distributed into two groups: control (n = 17; standard diet) and obese (n = 17; saturated high-fat diet) fed for 33 weeks. Nutritional profile and comorbidities were assessed. Cardiac structure and function was evaluated by macroscopic postmortem, echocardiographic and isolated papillary muscle analyzes. Myocardial protein expression of β1- and β2-adrenergic receptors, Gαs protein, adenylate cyclase (AC) and protein kinase A (PKA) was performed by Western blot. Cardiac cyclic adenosine monophosphate (cAMP) levels and PKA activity were assessed by ELISA Obese rats showed increased adiposity index (P < 0.001) and several comorbidities as hypertension, glucose intolerance, insulin resistance, and dyslipidemia compared with control rats. Echocardiographic assessment revealed increased left atrium diameter (C: 4.98 ± 0.38 vs. Ob: 5.47 ± 0.53, P = 0.024) and posterior wall shortening velocity (C: 37.1 ± 3.6 vs. Ob: 41.8 ± 3.8, P = 0.007) in obese group. Papillary muscle evaluation indicated that baseline data and myocardial responsiveness to isoproterenol stimulation were similar between the groups. Protein expression of myocardial AC was higher in obese group than in the control (C: 1.00 ± 0.21 vs. Ob: 1.25 ± 0.10, P = 0.025), whereas the other components were unchanged. These results suggest that saturated high-fat diet-induced obesity was not effective in triggering cardiac dysfunction and impair the beta-adrenergic signaling. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis.

PubMed

Maestraggi, Quentin; Lebas, Benjamin; Clere-Jehl, Raphaël; Ludes, Pierre-Olivier; Chamaraux-Tran, Thiên-Nga; Schneider, Francis; Diemunsch, Pierre; Geny, Bernard; Pottecher, Julien

2017-01-01

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

Negative pressure ventilation and positive pressure ventilation promote comparable levels of ventilator-induced diaphragmatic dysfunction in rats.

PubMed

Bruells, Christian S; Smuder, Ashley J; Reiss, Lucy K; Hudson, Matthew B; Nelson, William Bradley; Wiggs, Michael P; Sollanek, Kurt J; Rossaint, Rolf; Uhlig, Stefan; Powers, Scott K

2013-09-01

Mechanical ventilation is a life-saving intervention for patients with respiratory failure. Unfortunately, a major complication associated with prolonged mechanical ventilation is ventilator-induced diaphragmatic atrophy and contractile dysfunction, termed ventilator-induced diaphragmatic dysfunction (VIDD). Emerging evidence suggests that positive pressure ventilation (PPV) promotes lung damage (ventilator-induced lung injury [VILI]), resulting in the release of signaling molecules that foster atrophic signaling in the diaphragm and the resultant VIDD. Although a recent report suggests that negative pressure ventilation (NPV) results in less VILI than PPV, it is unknown whether NPV can protect against VIDD. Therefore, the authors tested the hypothesis that compared with PPV, NPV will result in a lower level of VIDD. Adult rats were randomly assigned to one of three experimental groups (n = 8 each): (1) acutely anesthetized control (CON), (2) 12 h of PPV, and (3) 12 h of NPV. Dependent measures included indices of VILI, diaphragmatic muscle fiber cross-sectional area, diaphragm contractile properties, and the activity of key proteases in the diaphragm. Our results reveal that no differences existed in the degree of VILI between PPV and NPV animals as evidenced by VILI histological scores (CON = 0.082 ± 0.001; PPV = 0.22 ± 0.04; NPV = 0.25 ± 0.02; mean ± SEM). Both PPV and NPV resulted in VIDD. Importantly, no differences existed between PPV and NPV animals in diaphragmatic fiber cross-sectional area, contractile properties, and the activation of proteases. These results demonstrate that NPV and PPV result in similar levels of VILI and that NPV and PPV promote comparable levels of VIDD in rats.

Structural and functional abnormalities of hepatic tissues in male Wistar rats fed hyperwhey and super amino anabolic protein.

PubMed

Ali, Doaa A; El-Sayyad, Hassan I H; Moftah, Osama A; Chilibeck, Phil D

2016-01-01

Athletes and bodybuilders consume high-protein supplements to obtain energy and enhance the development and strength of their muscles. Over time, different investigations have revealed dysfunctions of their body organs. There are contradictions among scientists concerning the benefits and the alarm of developing body dysfunction. The aim of this study was to illustrate the effects on consumption of two anabolic protein supplements on body weight and structure and function of hepatocytes in male albino Wistar rats. We assigned male Wistar albino rats into three groups (n = 10 each): control, hyperwhey protein (Nutrabolics, Richmond, Canada) (2.5 g/kg body weight), and super amino 2500 (SA) (APN, Ft. Launderale, FL, USA) (2.5 g/kg body weight). The applied dose was orally administered daily in tap water for 14 wk. Body weight was regularly measured. At 14 wk, animals were sacrificed and dissected. Blood was collected from a puncture of the heart and the liver was removed and weighed. Biochemical analysis of liver function tests, lipidogram, hematology, histopathology, transmission electron microscopy, immunohistochemistry of proliferating cell nuclear antigen, B-cell lymphoma 2 and 70 kd heat shock proteins, and flow-cytometry of hepatocyte cell cycle were performed. Hyperwhey- and SA-supplemented rats had lower body weight gain compared with the control group and developed hepatic dysfunction manifested by apparent congestion of blood vessel, increased apoptosis, and breakdown of hepatocytes. The SA group had thickening of the liver capsule and more drastic damage of hepatocytes. The level of transaminases was markedly increased. Insulin level was also markedly decreased in parallel with increase cholesterol, low-density lipoprotein, and triacylglycerols. Hyperwhey and SA protein formula administration dramatically altered the liver function and increased hepatic damage similar to the development of suspected diabetes. Copyright © 2016 Elsevier Inc. All rights reserved.

Prophylactic effects of swimming exercise on autophagy-induced muscle atrophy in diabetic rats

PubMed Central

Lee, Youngjeon; Kim, Joo-Heon; Hong, Yunkyung; Lee, Sang-Rae; Chang, Kyu-Tae

2012-01-01

Diabetes decreases skeletal muscle mass and induces atrophy. However, the mechanisms by which hyperglycemia and insulin deficiency modify muscle mass are not well defined. In this study, we evaluated the effects of swimming exercise on muscle mass and intracellular protein degradation in diabetic rats, and proposed that autophagy inhibition induced by swimming exercise serves as a hypercatabolic mechanism in the skeletal muscles of diabetic rats, supporting a notion that swimming exercise could efficiently reverse the reduced skeletal muscle mass caused by diabetes. Adult male Sprague-Dawley rats were injected intraperitoneally with streptozotocin (60 mg/kg body weight) to induce diabetes and then submitted to 1 hr per day of forced swimming exercise, 5 days per week for 4 weeks. We conducted an intraperitoneal glucose tolerance test on the animals and measured body weight, skeletal muscle mass, and protein degradation and examined the level of autophagy in the isolated extensor digitorum longus, plantaris, and soleus muscles. Body weight and muscle tissue mass were higher in the exercising diabetic rats than in control diabetic rats that remained sedentary. Compared to control rats, exercising diabetic rats had lower blood glucose levels, increased intracellular contractile protein expression, and decreased autophagic protein expression. We conclude that swimming exercise improves muscle mass in diabetes-induced skeletal muscle atrophy, suggesting the activation of autophagy in diabetes contributes to muscle atrophy through hypercatabolic metabolism and that aerobic exercise, by suppressing autophagy, may modify or reverse skeletal muscle wasting in diabetic patients. PMID:23091517

Remodeling of Aorta Extracellular Matrix as a Result of Transient High Oxygen Exposure in Newborn Rats: Implication for Arterial Rigidity and Hypertension Risk

PubMed Central

Castro, Michele M.; Cloutier, Anik; Bertagnolli, Mariane; Sartelet, Hervé; Germain, Nathalie; Comte, Blandine; Schulz, Richard; DeBlois, Denis; Nuyt, Anne Monique

2014-01-01

Neonatal high-oxygen exposure leads to elevated blood pressure, microvascular rarefaction, vascular dysfunction and arterial (aorta) rigidity in adult rats. Whether structural changes are present in the matrix of aorta wall is unknown. Considering that elastin synthesis peaks in late fetal life in humans, and early postnatal life in rodents, we postulated that transient neonatal high-oxygen exposure can trigger premature vascular remodelling. Sprague Dawley rat pups were exposed from days 3 to 10 after birth to 80% oxygen (vs. room air control) and were studied at 4 weeks. Blood pressure and vasomotor response of the aorta to angiotensin II and to the acetylcholine analogue carbachol were not different between groups. Vascular superoxide anion production was similar between groups. There was no difference between groups in aortic cross sectional area, smooth muscle cell number or media/lumen ratio. In oxygen-exposed rats, aorta elastin/collagen content ratio was significantly decreased, the expression of elastinolytic cathepsin S was increased whereas collagenolytic cathepsin K was decreased. By immunofluorescence we observed an increase in MMP-2 and TIMP-1 staining in aortas of oxygen-exposed rats whereas TIMP-2 staining was reduced, indicating a shift in the balance towards degradation of the extra-cellular matrix and increased deposition of collagen. There was no significant difference in MMP-2 activity between groups as determined by gelatin zymography. Overall, these findings indicate that transient neonatal high oxygen exposure leads to vascular wall alterations (decreased elastin/collagen ratio and a shift in the balance towards increased deposition of collagen) which are associated with increased rigidity. Importantly, these changes are present prior to the elevation of blood pressure and vascular dysfunction in this model, and may therefore be contributory. PMID:24743169

Implication of altered ubiquitin-proteasome system and ER stress in the muscle atrophy of diabetic rats.

PubMed

Reddy, S Sreenivasa; Shruthi, Karnam; Prabhakar, Y Konda; Sailaja, Gummadi; Reddy, G Bhanuprakash

2018-02-01

Skeletal muscle is adversely affected in type-1 diabetes, and excessively stimulated ubiquitin-proteasome system (UPS) was found to be a leading cause of muscle wasting or atrophy. The role of endoplasmic reticulum (ER) stress in muscle atrophy of type-1 diabetes is not known. Hence, we investigated the role of UPS and ER stress in the muscle atrophy of chronic diabetes rat model. Diabetes was induced with streptozotocin (STZ) in male Sprague-Dawley rats and were sacrificed 2- and 4-months thereafter to collect gastrocnemius muscle. In another experiment, 2-months post-STZ-injection diabetic rats were treated with MG132, a proteasome inhibitor, for the next 2-months and gastrocnemius muscle was collected. The muscle fiber cross-sectional area was diminished in diabetic rats. The expression of UPS components: E1, MURF1, TRIM72, UCHL1, UCHL5, ubiquitinated proteins, and proteasome activity were elevated in the diabetic rats indicating activated UPS. Altered expression of ER-associated degradation (ERAD) components and increased ER stress markers were detected in 4-months diabetic rats. Proteasome inhibition by MG132 alleviated alterations in the UPS and ER stress in diabetic rat muscle. Increased UPS activity and ER stress were implicated in the muscle atrophy of diabetic rats and proteasome inhibition exhibited beneficiary outcome. Copyright © 2017 Elsevier Inc. All rights reserved.

Preventive Effects of the Dietary Intake of Medium-chain Triacylglycerols on Immobilization-induced Muscle Atrophy in Rats.

PubMed

Nishimura, Shuhei; Inai, Makoto; Takagi, Tetsuo; Nonaka, Yudai; Urashima, Shogo; Honda, Kazumitsu; Aoyama, Toshiaki; Terada, Shin

2017-08-01

Previous studies have shown that medium-chain triacylglycerols (MCTs) exert favorable effects on protein metabolism. This study evaluated the effects of the dietary intake of MCTs on rat skeletal muscle mass and total protein content during casting-induced hindlimb immobilization, which causes substantial protein degradation and muscle atrophy. Rats were fed a standard diet containing long-chain triacylglycerols (LCTs) or MCTs for 3 days and then a unilateral hindlimb was immobilized while they received the same diet. After immobilization for 3, 7, and 14 days, muscle mass and total protein content in immobilized soleus muscle in the LCT-fed rats had markedly decreased compared to the contralateral muscle; however, these losses were partially suppressed in MCT-fed rats. Autophagosomal membrane proteins (LC-I and -II), which are biomarkers of autophagy-lysosome activity, did not differ significantly between the LCT- and MCT-fed rats. In contrast, the immobilization-induced increase in muscle-specific E3 ubiquitin ligase MuRF-1 protein expression in immobilized soleus muscle relative to contralateral muscle was completely blocked in the MCT-fed rats and was significantly lower than that observed in the LCT-fed rats. Collectively, these results indicate that the dietary intake of MCTs at least partly alleviates immobilization-induced muscle atrophy by inhibiting the ubiquitin-proteasome pathway.

Effects of voluntary wheel running on satellite cells in the rat plantaris muscle.

PubMed

Kurosaka, Mitsutoshi; Naito, Hisashi; Ogura, Yuji; Kojima, Atsushi; Goto, Katsumasa; Katamoto, Shizuo

2009-01-01

This study investigated the effects of voluntary wheel running on satellite cells in the rat plantaris muscle. Seventeen 5-week-old male Wistar rats were assigned to a control (n = 5) or training (n = 12) group. Each rat in the training group ran voluntarily in a running-wheel cage for 8 weeks. After the training period, the animals were anesthetized, and the plantaris muscles were removed, weighed, and analyzed immunohistochemically and biochemically. Although there were no significant differences in muscle weight or fiber area between the groups, the numbers of satellite cells and myonuclei per muscle fiber, percentage of satellite cells, and citrate synthase activity were significantly higher in the training group compared with the control group (p < 0.05). The percentage of satellite cells was also positively correlated with distance run in the training group (r = 0.61, p < 0.05). Voluntary running can induce an increase in the number of satellite cells without changing the mean fiber area in the rat plantaris muscle; this increase in satellite cell content is a function of distance run. Key pointsThere is no study about the effect of voluntary running on satellite cells in the rat plantaris muscle.Voluntary running training causes an increase of citrate synthase activity in the rat plantaris muscle but does not affect muscle weight and mean fiber area in the rat plantaris muscle.Voluntary running can induce an increase in the number of satellite cells without hypertrophy of the rat plantaris muscle.

Postoperative respiratory muscle dysfunction: pathophysiology and preventive strategies.

PubMed

Sasaki, Nobuo; Meyer, Matthew J; Eikermann, Matthias

2013-04-01

Postoperative pulmonary complications are responsible for significant increases in hospital cost as well as patient morbidity and mortality; respiratory muscle dysfunction represents a contributing factor. Upper airway dilator muscles functionally resist the upper airway collapsing forces created by the respiratory pump muscles. Standard perioperative medications (anesthetics, sedatives, opioids, and neuromuscular blocking agents), interventions (patient positioning, mechanical ventilation, and surgical trauma), and diseases (lung hyperinflation, obesity, and obstructive sleep apnea) have differential effects on the respiratory muscle subgroups. These effects on the upper airway dilators and respiratory pump muscles impair their coordination and function and can result in respiratory failure. Perioperative management strategies can help decrease the incidence of postoperative respiratory muscle dysfunction. Such strategies include minimally invasive procedures rather than open surgery, early and optimal mobilizing of respiratory muscles while on mechanical ventilation, judicious use of respiratory depressant anesthetics and neuromuscular blocking agents, and noninvasive ventilation when possible.

Sonic Hedgehog Protein Is Decreased and Penile Morphology Is Altered in Prostatectomy and Diabetic Patients

PubMed Central

Angeloni, Nicholas L.; Bond, Christopher W.; McVary, Kevin T.; Podlasek, Carol A.

2013-01-01

Erectile dysfunction (ED) is a debilitating medical condition and current treatments are ineffective in patients with cavernous nerve (CN) injury, due to penile remodeling and apoptosis. A critical regulator of penile smooth muscle and apoptosis is the secreted protein sonic hedgehog (SHH). SHH protein is decreased in rat prostatectomy and diabetic ED models, SHH inhibition in the penis induces apoptosis and ED, and SHH treatment at the time of CN injury suppresses smooth muscle apoptosis and promotes regeneration of erectile function. Thus SHH treatment has significant translational potential as an ED therapy if similar mechanisms underlie ED development in patients. In this study we quantify SHH protein and morphological changes in corpora cavernosal tissue of control, prostatectomy and diabetic patients and hypothesize that decreased SHH protein is an underlying cause of ED development in prostatectomy and diabetic patients. Our results show significantly decreased SHH protein in prostatectomy and diabetic penis. Morphological remodelling of the penis, including significantly increased apoptotic index and decreased smooth muscle/collagen ratio, accompanies declining SHH. SHH signaling is active in human penis and is altered in a parallel manner to previous observations in the rat. These results suggest that SHH has significant potential to be developed as an ED therapy in prostatectomy and diabetic patients. The increased apoptotic index long after initial injury is suggestive of ongoing remodeling that may be clinically manipulatable. PMID:23967143

NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension.

PubMed

Dumas, Sébastien J; Bru-Mercier, Gilles; Courboulin, Audrey; Quatredeniers, Marceau; Rücker-Martin, Catherine; Antigny, Fabrice; Nakhleh, Morad K; Ranchoux, Benoit; Gouadon, Elodie; Vinhas, Maria-Candida; Vocelle, Matthieu; Raymond, Nicolas; Dorfmüller, Peter; Fadel, Elie; Perros, Frédéric; Humbert, Marc; Cohen-Kaminsky, Sylvia

2018-05-29

Excessive proliferation and apoptosis resistance in pulmonary vascular cells underlie vascular remodeling in pulmonary arterial hypertension (PAH). Specific treatments for PAH exist, mostly targeting endothelial dysfunction, but high pulmonary arterial pressure still causes heart failure and death. Pulmonary vascular remodeling may be driven by metabolic reprogramming of vascular cells to increase glutaminolysis and glutamate production. The N -methyl-d-aspartate receptor (NMDAR), a major neuronal glutamate receptor, is also expressed on vascular cells, but its role in PAH is unknown. We assessed the status of the glutamate-NMDAR axis in the pulmonary arteries of patients with PAH and controls through mass spectrometry imaging, Western blotting, and immunohistochemistry. We measured the glutamate release from cultured pulmonary vascular cells using enzymatic assays and analyzed NMDAR regulation/phosphorylation through Western blot experiments. The effect of NMDAR blockade on human pulmonary arterial smooth muscle cell proliferation was determined using a BrdU incorporation assay. We assessed the role of NMDARs in vascular remodeling associated to pulmonary hypertension, in both smooth muscle-specific NMDAR knockout mice exposed to chronic hypoxia and the monocrotaline rat model of pulmonary hypertension using NMDAR blockers. We report glutamate accumulation, upregulation of the NMDAR, and NMDAR engagement reflected by increases in GluN1-subunit phosphorylation in the pulmonary arteries of human patients with PAH. K v channel inhibition and type A-selective endothelin receptor activation amplified calcium-dependent glutamate release from human pulmonary arterial smooth muscle cell, and type A-selective endothelin receptor and platelet-derived growth factor receptor activation led to NMDAR engagement, highlighting crosstalk between the glutamate-NMDAR axis and major PAH-associated pathways. The platelet-derived growth factor-BB-induced proliferation of human pulmonary arterial smooth muscle cells involved NMDAR activation and phosphorylated GluN1 subunit localization to cell-cell contacts, consistent with glutamatergic communication between proliferating human pulmonary arterial smooth muscle cells via NMDARs. Smooth-muscle NMDAR deficiency in mice attenuated the vascular remodeling triggered by chronic hypoxia, highlighting the role of vascular NMDARs in pulmonary hypertension. Pharmacological NMDAR blockade in the monocrotaline rat model of pulmonary hypertension had beneficial effects on cardiac and vascular remodeling, decreasing endothelial dysfunction, cell proliferation, and apoptosis resistance while disrupting the glutamate-NMDAR pathway in pulmonary arteries. These results reveal a dysregulation of the glutamate-NMDAR axis in the pulmonary arteries of patients with PAH and identify vascular NMDARs as targets for antiremodeling treatments in PAH. © 2018 American Heart Association, Inc.

Management of cricopharyngeus muscle dysfunction.

PubMed

Kuhn, Maggie A; Belafsky, Peter C

2013-12-01

The cricopharyngeus muscle (CPM) is a key component of the upper esophageal sphincter (UES). In dysphagia, cricopharyngeus muscle dysfunction (CPD) refers to the muscle's failure to appropriately and completely relax or expand during deglutition. A variety of disease processes may cause CPD, and the resultant clinical manifestation is solid food or solid and liquid dysphagia. Several diagnostic tools are available for dysphagia clinicians to distinguish CPD from other causes of UES dysfunction. For CPD, accurate diagnosis is paramount for the recommendation of appropriate treatment. In appropriately selected patients, intervention at the CPM may yield significant improvement in dysphagia. Copyright © 2013 Elsevier Inc. All rights reserved.

Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies - potential role of ER stress pathways.

PubMed

Lightfoot, Adam P; Nagaraju, Kanneboyina; McArdle, Anne; Cooper, Robert G

2015-11-01

Discussion of endoplasmic reticulum (ER) stress pathway activation in idiopathic inflammatory myopathies (IIM), and downstream mechanisms causative of muscle weakness. In IIM, ER stress is an important pathogenic process, but how it causes muscle dysfunction is unknown. We discuss relevant pathways modified in response to ER stress in IIM: reactive oxygen species (ROS) generation and mitochondrial dysfunction, and muscle cytokine (myokine) generation. First, ER stress pathway activation can induce changes in mitochondrial bioenergetics and ROS production. ROS can oxidize cellular components, causing muscle contractile dysfunction and energy deficits. Novel compounds targeting ROS generation and/or mitochondrial dysfunction can improve muscle function in several myopathologies. Second, recent research has demonstrated that skeletal muscle produces multiple myokines. It is suggested that these play a role in causing muscle weakness. Myokines are capable of immune cell recruitment, thus contributing to perturbed muscle function. A characterization of myokines in IIM would clarify their pathogenic role, and so identify new therapeutic targets. ER stress pathway activation is clearly of etiological relevance in IIM. Research to better understand mechanisms of weakness downstream of ER stress is now required, and which may discover new therapeutic targets for nonimmune cell-mediated weakness.

Recombinant Factor XIII Mitigates Hemorrhagic Shock-Induced Organ Dysfunction

PubMed Central

Zaets, Sergey B.; Xu, Da-Zhong; Lu, Qi; Feketova, Eleonora; Berezina, Tamara L.; Malinina, Inga V.; Deitch, Edwin A.; Olsen, Eva H.

2012-01-01

Background Plasma factor XIII (FXIII) is responsible for stabilization of fibrin clot at the final stage of blood coagulation. Since FXIII has also been shown to modulate inflammation, endothelial permeability, as well as diminish multiple organ dysfunction (MOD) after gut ischemia-reperfusion injury, we hypothesized that FXIII would reduce MOD caused by trauma-hemorrhagic shock (THS). Materials and methods Rats were subjected to a 90 min THS or trauma sham shock (TSS) and treated with either recombinant human FXIII A2 subunit (rFXIII) or placebo immediately after resuscitation with shed blood or at the end of the TSS period. Lung permeability, lung and gut myeloperoxidase (MPO) activity, gut histology, neutrophil respiratory burst, microvascular blood flow in the liver and muscles, and cytokine levels were measured 3 h after the THS or TSS. FXIII levels were measured before THS or TSS and after the 3-h post-shock period. Results THS-induced lung permeability as well as lung and gut MPO activity was significantly lower in rFXIII-treated than in placebo-treated animals. Similarly, rFXIII-treated rats had lower neutrophil respiratory burst activity and less ileal mucosal injury. rFXIII-treated rats also had a higher liver microvascular blood flow compared with the placebo group. Cytokine response was more favorable in rFXIII-treated animals. Trauma-hemorrhagic shock did not cause a drop in FXIII activity during the study period. Conclusions Administration of rFXIII diminishes THS-induced MOD in rats, presumably by preservation of the gut barrier function, limitation of polymorphonuclear leukocyte (PMN) activation, and modulation of the cytokine response. PMID:21276979

Muscle Dysfunction in Androgen Deprivation: Role of Ryanodine Receptor

DTIC Science & Technology

2016-11-01

undergoing ORX have reduced muscle specific force due to calcium leak through RyR1, which is caused by high levels of TGFβ released from the bone during... leak could be causing long-term effects, such as decreased muscle mass, body weight and forelimb grip strength. 15. SUBJECT TERMS Prostate Cancer...calcium leak and contractile dysfunction in chronic muscle fatigue, heart failure and muscular dystrophy (13-16). RyR1 is the skeletal muscle

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes

PubMed Central

Smith, Darrell R.; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A.; Fernyhough, Paul

2012-01-01

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3–5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway. PMID:22561641

Management of craniomandibular disorders. Part 1: A craniocervical dysfunction index.

PubMed

Wallace, C; Klineberg, I J

1993-01-01

A craniocervical dysfunction index has been developed (based on the Helkimo Dysfunction Index) to comprehensively assess craniocervical dysfunction and to objectively monitor the management of patients who present with these clinical problems. The close functional interrelationship of temporomandibular joints, jaw muscles, and cervical joints and muscles is reviewed, and a mechanism is proposed to explain dysfunctional relationships between these structures. This is the first of three papers stemming from a clinical study that investigated craniomandibular disorders and assessed the effect of routine dental management on craniomandibular and craniocervical dysfunction.

Role of medullary astroglial glutamine synthesis in tooth pulp hypersensitivity associated with frequent masseter muscle contraction.

PubMed

Watase, Tetsuro; Shimizu, Kohei; Ohara, Kinuyo; Komiya, Hiroki; Kanno, Kohei; Hatori, Keisuke; Noma, Noboru; Honda, Kuniya; Tsuboi, Yoshiyuki; Katagiri, Ayano; Shinoda, Masamichi; Ogiso, Bunnai; Iwata, Koichi

2018-01-01

Background The mechanisms underlying tooth pulp hypersensitivity associated with masseter muscle hyperalgesia remain largely underinvestigated. In the present study, we aimed to determine whether masseter muscle contraction induced by daily electrical stimulation influences the mechanical head-withdrawal threshold and genioglossus electromyography activity caused by the application of capsaicin to the upper first molar tooth pulp. We further investigated whether astroglial glutamine synthesis is involved in first molar tooth pulp hypersensitivity associated with masseter muscle contraction. Methods The first molar tooth pulp was treated with capsaicin or vehicle in masseter muscle contraction or sham rats, following which the astroglial glutamine synthetase inhibitor methionine sulfoximine or Phosphate buffered saline (PBS) was applied. Astroglial activation was assessed via immunohistochemistry. Results The mechanical head-withdrawal threshold of the ipsilateral masseter muscle was significantly decreased in masseter muscle contraction rats than in sham rats. Genioglossus electromyography activity was significantly higher in masseter muscle contraction rats than sham rats. Glial fibrillary acidic protein-immunoreactive cell density was significantly higher in masseter muscle contraction rats than in sham rats. Administration of methionine sulfoximine induced no significant changes in the density of glial fibrillary acidic protein-immunoreactive cells relative to PBS treatment. However, mechanical head-withdrawal threshold was significantly higher in masseter muscle contraction rats than PBS-treated rats after methionine sulfoximine administration. Genioglossus electromyography activity following first molar tooth pulp capsaicin treatment was significantly lower in methionine sulfoximine-treated rats than in PBS-treated rats. In the ipsilateral region, the total number of phosphorylated extracellular signal-regulated protein kinase immunoreactive cells in the medullary dorsal horn was significantly smaller upon first molar tooth pulp capsaicin application in methionine sulfoximine-treated rats than in PBS-treated rats. Conclusions Our results suggest that masseter muscle contraction induces astroglial activation, and that this activation spreads from caudal to the obex in the medullary dorsal horn, resulting in enhanced neuronal excitability associated with astroglial glutamine synthesis in medullary dorsal horn neurons receiving inputs from the tooth pulp. These findings provide significant insight into the mechanisms underlying tooth pulp hypersensitivity associated with masseter muscle contraction.

Oxidative stress exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation in rats with hypertension induced by angiotensin II.

PubMed

Koba, Satoshi; Watanabe, Ryosuke; Kano, Naoko; Watanabe, Tatsuo

2013-01-01

Muscle contraction stimulates thin fiber muscle afferents and evokes reflex sympathoexcitation. In hypertension, this reflex is exaggerated. ANG II, which is elevated in hypertension, has been reported to trigger the production of superoxide and other reactive oxygen species. In the present study, we tested the hypothesis that increased ANG II in hypertension exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation by inducing oxidative stress in the muscle. In rats, subcutaneous infusion of ANG II at 450 ng·kg(-1)·min(-1) for 14 days significantly (P < 0.05) elevated blood pressure compared with sham-operated (sham) rats. Electrically induced 30-s hindlimb muscle contraction in decerebrate rats with hypertension evoked larger renal sympathoexcitatory and pressor responses [+1,173 ± 212 arbitrary units (AU) and +35 ± 5 mmHg, n = 10] compared with sham normotensive rats (+419 ± 103 AU and +13 ± 2 mmHg, n = 11). Tempol, a SOD mimetic, injected intra-arterially into the hindlimb circulation significantly reduced responses in hypertensive rats, whereas this compound had no effect on responses in sham rats. Tiron, another SOD mimetic, also significantly reduced reflex renal sympathetic and pressor responses in a subset of hypertensive rats (n = 10). Generation of muscle superoxide, as evaluated by dihydroethidium staining, was increased in hypertensive rats. RT-PCR and immunoblot experiments showed that mRNA and protein for gp91(phox), a NADPH oxidase subunit, in skeletal muscle tissue were upregulated in hypertensive rats. Taken together, hese results suggest that increased ANG II in hypertension induces oxidative stress in skeletal muscle, thereby exaggerating the muscle reflex.

Reinvestigation of the dysfunction in neck and shoulder girdle muscles as the reason of cervicogenic headache among office workers.

PubMed

Huber, Juliusz; Lisiński, Przemysław; Polowczyk, Agnieszka

2013-05-01

Dysfunction of cervical and shoulder girdle muscles as reason of cervicogenic headache (CEH) was reinvestigated with clinical and neurophysiological studies. Forty office workers were randomized into two groups to verify efficiency of supervised kinesiotherapy (N = 20) aimed with improvement of muscle's activity and headache symptoms releasing. Headache intensity was evaluated with visual analog scale (VAS), range of cervical movement (ROM) with goniometer, trigger points (TrPs) incidence with palpation and muscle's strength with Lovett's scale. Reaction of patients for muscle's elongation was also evaluated. Surface electromyographical recordings were bilaterally analyzed at rest (rEMG) and during maximal contraction (mcEMG). Deficits of cervical flexion and muscles strength were found in all patients. TrPs occurred predominantly in painful trapezius muscle. Incidence of trigger points coexisted with intensity of CEH. Results indicated on muscles dysfunction which improved only after supervised therapy. Positive correlations between increase in rEMG amplitudes and high VAS scores, high-amplitude rEMG recordings incidence and increased number of TrPs were found. Negative correlation was detected between amplitude in mcEMG and amplitude of rEMG recordings. Dysfunction of trapezius muscle was most responsible for CEH etiology. Proposed algorithm of kinesiotherapy was effective as complementary method of the CEH patients treatment.

Effect of obesity and exercise on the expression of the novel myokines, Myonectin and Fibronectin type III domain containing 5

PubMed Central

Mart, Ryan; Bond, Cherie E.

2014-01-01

Metabolic dysfunction in skeletal muscle is a major contributor to the development of type 2 diabetes. Endurance exercise training has long been established as an effective means to directly restore skeletal muscle glucose and lipid uptake and metabolism. However, in addition to the direct effects of skeletal muscle on glucose and lipids, there is renewed interest in the ability of skeletal muscle to coordinate metabolic activity of other tissues, such as adipose tissue and liver. The purpose of this study was to examine the effects of endurance exercise on the expression level of two novel muscle-derived secreted factors, or myokines, Myonectin and Fibronectin type III domain containing 5 (FNDC5), the precursor for Irisin. Methods. We performed immunoblot analysis and quantitative real-time PCR analysis of Myonectin and FNDC5 in the diaphragm muscles of obese Zucker rat (OZR) and lean Zucker rat (LZR) with 9 weeks of aerobic training on a motorized treadmill. Results. We show that myonectin gene expression is increased in the OZR model of obesity and decreases with exercise in both lean and obese Zucker rats. Conversely, myonectin protein concentration was elevated with exercise. Similarly, FNDC5 mRNA levels are significantly higher in the OZR, however exercise training had no effect on the expression level of FNDC5 in either the LZR or OZR. We did not observe any difference in muscle protein content of Irisin with obesity or exercise. Conclusion. Our data shows that exercise training does not increase either FNDC5 or myonectin gene expression, indicating that increased transcriptional regulation of these myokines is not induced by exercise. However, our data also indicates a yet to be explored disconnect between myonectin gene expression and protein content. Further, this report highlights the importance of verifying reference genes when completing gene expression analysis. We found that many commonly used reference genes varied significantly by obesity and/or exercise and would have skewed the results of this study if used to normalize gene expression data. The unstable reference genes include: beta-Actin, beta-2-microglobulin, Non-POU domain containing, octamer-binding, Peptidylprolyl isomerase H, 18S ribosomal RNA, TATA box binding protein and Transferrin receptor. PMID:25289190

Microvascular oxygen partial pressure during hyperbaric oxygen in diabetic rat skeletal muscle.

PubMed

Yamakoshi, Kohei; Yagishita, Kazuyoshi; Tsuchimochi, Hirotsugu; Inagaki, Tadakatsu; Shirai, Mikiyasu; Poole, David C; Kano, Yutaka

2015-12-15

Hyperbaric oxygen (HBO) is a major therapeutic treatment for ischemic ulcerations that perforate skin and underlying muscle in diabetic patients. These lesions do not heal effectively, in part, because of the hypoxic microvascular O2 partial pressures (PmvO2 ) resulting from diabetes-induced cardiovascular dysfunction, which alters the dynamic balance between O2 delivery (Q̇o2) and utilization (V̇o2) rates. We tested the hypothesis that HBO in diabetic muscle would exacerbate the hyperoxic PmvO2 dynamics due, in part, to a reduction or slowing of the cardiovascular, sympathetic nervous, and respiratory system responses to acute HBO exposure. Adult male Wistar rats were divided randomly into diabetic (DIA: streptozotocin ip) and healthy (control) groups. A small animal hyperbaric chamber was pressurized with oxygen (100% O2) to 3.0 atmospheres absolute (ATA) at 0.2 ATA/min. Phosphorescence quenching techniques were used to measure PmvO2 in tibialis anterior muscle of anesthetized rats during HBO. Lumbar sympathetic nerve activity (LSNA), heart rate (HR), and respiratory rate (RR) were measured electrophysiologically. During the normobaric hyperoxia and HBO, DIA tibialis anterior PmvO2 increased faster (mean response time, CONT 78 ± 8, DIA 55 ± 8 s, P < 0.05) than CONT. Subsequently, PmvO2 remained elevated at similar levels in CONT and DIA muscles until normobaric normoxic recovery where the DIA PmvO2 retained its hyperoxic level longer than CONT. Sympathetic nervous system and cardiac and respiratory responses to HBO were slower in DIA vs. CONT. Specifically the mean response times for RR (CONT: 6 ± 1 s, DIA: 29 ± 4 s, P < 0.05), HR (CONT: 16 ± 1 s, DIA: 45 ± 5 s, P < 0.05), and LSNA (CONT: 140 ± 16 s, DIA: 247 ± 34 s, P < 0.05) were greater following HBO onset in DIA than CONT. HBO treatment increases tibialis anterior muscle PmvO2 more rapidly and for a longer duration in DIA than CONT, but not to a greater level. Whereas respiratory, cardiovascular, and LSNA responses to HBO are profoundly slowed in DIA, only the cardiovascular arm (via HR) may contribute to the muscle vascular incompetence and these faster PmvO2 kinetics. Copyright © 2015 the American Physiological Society.

Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export.

PubMed

White, Phillip J; Lapworth, Amanda L; An, Jie; Wang, Liping; McGarrah, Robert W; Stevens, Robert D; Ilkayeva, Olga; George, Tabitha; Muehlbauer, Michael J; Bain, James R; Trimmer, Jeff K; Brosnan, M Julia; Rolph, Timothy P; Newgard, Christopher B

2016-07-01

A branched-chain amino acid (BCAA)-related metabolic signature is strongly associated with insulin resistance and predictive of incident diabetes and intervention outcomes. To better understand the role that this metabolite cluster plays in obesity-related metabolic dysfunction, we studied the impact of BCAA restriction in a rodent model of obesity in which BCAA metabolism is perturbed in ways that mirror the human condition. Zucker-lean rats (ZLR) and Zucker-fatty rats (ZFR) were fed either a custom control, low fat (LF) diet, or an isonitrogenous, isocaloric LF diet in which all three BCAA (Leu, Ile, Val) were reduced by 45% (LF-RES). We performed comprehensive metabolic and physiologic profiling to characterize the effects of BCAA restriction on energy balance, insulin sensitivity, and glucose, lipid and amino acid metabolism. LF-fed ZFR had higher levels of circulating BCAA and lower levels of glycine compared to LF-fed ZLR. Feeding ZFR with the LF-RES diet lowered circulating BCAA to levels found in LF-fed ZLR. Activity of the rate limiting enzyme in the BCAA catabolic pathway, branched chain keto acid dehydrogenase (BCKDH), was lower in liver but higher in skeletal muscle of ZFR compared to ZLR and was not responsive to diet in either tissue. BCAA restriction had very little impact on metabolites studied in liver of ZFR where BCAA content was low, and BCKDH activity was suppressed. However, in skeletal muscle of LF-fed ZFR compared to LF-fed ZLR, where BCAA content and BCKDH activity were increased, accumulation of fatty acyl CoAs was completely normalized by dietary BCAA restriction. BCAA restriction also normalized skeletal muscle glycine content and increased urinary acetyl glycine excretion in ZFR. These effects were accompanied by lower RER and improved skeletal muscle insulin sensitivity in LF-RES fed ZFR as measured by hyperinsulinemic-isoglycemic clamp. Our data are consistent with a model wherein elevated circulating BCAA contribute to development of obesity-related insulin resistance by interfering with lipid oxidation in skeletal muscle. BCAA-dependent lowering of the skeletal muscle glycine pool appears to contribute to this effect by slowing acyl-glycine export to the urine.

Hindlimb suspension reduces muscle regeneration

NASA Technical Reports Server (NTRS)

Mozdziak, P. E.; Truong, Q.; Macius, A.; Schultz, E.

1998-01-01

Exposure of juvenile skeletal muscle to a weightless environment reduces growth and satellite cell mitotic activity. However, the effect of a weightless environment on the satellite cell population during muscle repair remains unknown. Muscle injury was induced in rat soleus muscles using the myotoxic snake venom, notexin. Rats were placed into hindlimb-suspended or weightbearing groups for 10 days following injury. Cellular proliferation during regeneration was evaluated using 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and image analysis. Hindlimb suspension reduced (P < 0.05) regenerated muscle mass, regenerated myofiber diameter, uninjured muscle mass, and uninjured myofiber diameter compared to weightbearing rats. Hindlimb suspension reduced (P < 0.05) BrdU labeling in uninjured soleus muscles compared to weight-bearing muscles. However, hindlimb suspension did not abolish muscle regeneration because myofibers formed in the injured soleus muscles of hindlimb-suspended rats, and BrdU labeling was equivalent (P > 0.10) on myofiber segments isolated from the soleus muscles of hindlimb-suspended and weightbearing rats following injury. Thus, hindlimb suspension (weightlessness) does not suppress satellite cell mitotic activity in regenerating muscles before myofiber formation, but reduces growth of the newly formed myofibers.

The lumbrical muscle: a novel in situ system to evaluate adult skeletal muscle proteolysis and anticatabolic drugs for therapeutic purposes.

PubMed

Bergantin, Leandro Bueno; Figueiredo, Leonardo Bruno; Godinho, Rosely Oliveira

2011-12-01

The molecular regulation of skeletal muscle proteolysis and the pharmacological screening of anticatabolic drugs have been addressed by measuring tyrosine release from prepubertal rat skeletal muscles, which are thin enough to allow adequate in vitro diffusion of oxygen and substrates. However, the use of muscle at accelerated prepubertal growth has limited the analysis of adult muscle proteolysis or that associated with aging and neurodegenerative diseases. Here we established the adult rat lumbrical muscle (4/hindpaw; 8/rat) as a new in situ experimental model for dynamic measurement of skeletal muscle proteolysis. By incubating lumbrical muscles attached to their individual metatarsal bones in Tyrode solution, we showed that the muscle proteolysis rate of adult and aged rats (3-4 to 24 mo old) is 45-25% of that in prepubertal animals (1 mo old), which makes questionable the usual extrapolation of proteolysis from prepubertal to adult/senile muscles. While acute mechanical injury or 1- to 7-day denervation increased tyrosine release from adult lumbrical muscle by up to 60%, it was reduced by 20-28% after 2-h incubation with β-adrenoceptor agonists, forskolin or phosphodiesterase inhibitor IBMX. Using inhibitors of 26S-proteasome (MG132), lysosome (methylamine), or calpain (E64/leupeptin) systems, we showed that ubiquitin-proteasome is accountable for 40-50% of total lumbrical proteolysis of adult, middle-aged, and aged rats. In conclusion, the lumbrical model allows the analysis of muscle proteolysis rate from prepubertal to senile rats. By permitting eight simultaneous matched measurements per rat, the new model improves similar protocols performed in paired extensor digitorum longus (EDL) muscles from prepubertal rats, optimizing the pharmacological screening of drugs for anticatabolic purposes.

Vardenafil inhibiting parasympathetic function of tracheal smooth muscle.

PubMed

Lee, Fei-Peng; Chao, Pin-Zhir; Wang, Hsing-Won

2018-07-01

Levitra, a phosphodiesterase-5 (PDE5) inhibitor, is the trade name of vardenafil. Nowadays, it is applied to treatment of erectile dysfunction. PDE5 inhibitors are employed to induce dilatation of the vascular smooth muscle. The effect of Levitra on impotency is well known; however, its effect on the tracheal smooth muscle has rarely been explored. When administered for sexual symptoms via oral intake or inhalation, Levitra might affect the trachea. This study assessed the effects of Levitra on isolated rat tracheal smooth muscle by examining its effect on resting tension of tracheal smooth muscle, contraction caused by 10 -6  M methacholine as a parasympathetic mimetic, and electrically induced tracheal smooth muscle contractions. The results showed that adding methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of Levitra at doses of 10 -5  M or above elicited a significant relaxation response to 10 -6  M methacholine-induced contraction. Levitra could inhibit electrical field stimulation-induced spike contraction. It alone had minimal effect on the basal tension of the trachea as the concentration increased. High concentrations of Levitra could inhibit parasympathetic function of the trachea. Levitra when administered via oral intake might reduce asthma attacks in impotent patients because it might inhibit parasympathetic function and reduce methacholine-induced contraction of the tracheal smooth muscle. Copyright © 2018. Published by Elsevier Taiwan LLC.

Differential Adaptations of the Musculoskeletal System after Spinal Cord Contusion and Transection in Rats.

PubMed

Lin, Ching-Yi; Androjna, Charlie; Rozic, Richard; Nguyen, Bichtram; Parsons, Brett; Midura, Ronald J; Lee, Yu-Shang

2018-04-05

Spinal cord injury (SCI) causes impaired neuronal function with associated deficits in the musculoskeletal system, which can lead to permanent disability. Here, the impact of SCI on in vivo musculoskeletal adaptation was determined by studying deficits in locomotor function and analyzing changes that occur in the muscle and bone compartments within the rat hindlimb after contusion or transection SCI. Analyses of locomotor patterns, as assessed via the Basso, Beattie, and Bresnahan (BBB) rating scale, revealed that transection animals showed significant deficits, while the contusion group had moderate deficits, compared with naïve groups. Muscle myofiber cross-sectional areas (CSA) of both the soleus and tibialis anterior muscles were significantly decreased three months after contusion SCI. Such decreases in CSA were even more dramatic in the transection SCI group, suggesting a dependence on muscle activity, which is further validated by the correlation analyses between BBB score and myofiber CSA. Bone compartment analyses, however, revealed that transection animals showed the most significant deficits, while contusion animals showed no significant differences in the trabecular bone content within the proximal tibia compartment. In general, values of bone volume per total bone volume (BV/TV) were similar across the SCI groups. Significant decreases were observed, however, in the transection animals for bone mineral content, bone mineral density, and three-dimensional trabecular structure parameters (trabecular number, thickness, and spacing) compared with the naïve and contusion groups. Together, these findings suggest an altered musculoskeletal system can be correlated directly to motor dysfunctions seen after SCI.

Vagal sensory innervation of the gastric sling muscle and antral wall: implications for gastro-esophageal reflux disease?

PubMed

Powley, T L; Gilbert, J M; Baronowsky, E A; Billingsley, C N; Martin, F N; Phillips, R J

2012-10-01

The gastric sling muscle has not been investigated for possible sensory innervation, in spite of the key roles the structure plays in lower esophageal sphincter (LES) function and gastric physiology. Thus, the present experiment used tracing techniques to label vagal afferents and survey their projections in the lesser curvature. Sprague-Dawley rats received injections of dextran biotin into the nodose ganglia. Fourteen days postinjection, animals were euthanized and their stomachs were processed to visualize the vagal afferent innervation. In different cases, neurons, muscle cells, or interstitial cells of Cajal (ICC) were counterstained. The sling muscle is innervated throughout its length by vagal afferent intramuscular arrays (IMAs) associated with ICC. In addition, the distal antral attachment site of the sling muscle is innervated by a novel vagal afferent terminal specialization, an antral web ending. The muscle wall of the distal antrum is also innervated by conventional IMAs and intraganglionic laminar endings, the two types of mechanoreceptors found throughout stomach smooth muscle. The innervation of sling muscle by IMAs, putative stretch receptors, suggests that sling sensory feedback may generate vago-vagal or other reflexes with vagal afferent limbs. The restricted distribution of afferent web endings near the antral attachments of sling fibers suggests the possibility of specialized mechanoreceptor functions linking antral and pyloric activity to the operation of the LES. Dysfunctional sling afferents could generate LES motor disturbances, or normative compensatory sensory feedback from the muscle could compromise therapies targeting only effectors. © 2012 Blackwell Publishing Ltd.

Muscle fiber types composition and type identified endplate morphology of forepaw intrinsic muscles in the rat.

PubMed

Pan, Feng; Mi, Jing-Yi; Zhang, Yan; Pan, Xiao-Yun; Rui, Yong-Jun

2016-06-01

The failure to accept reinnervation is considered to be one of the reasons for the poor motor functional recovery of intrinsic hand muscles (IHMs) after nerve injury. Rat could be a suitable model to be used in simulating motor function recovery of the IHMs after nerve injury as to the similarities in function and anatomy of the muscles between human and rat. However, few studies have reported the muscle fiber types composition and endplate morphologic characteristics of intrinsic forepaw muscles (IFMs) in the rat. In this study, the myosin heavy chain isoforms and acetylcholine receptors were stained by immunofluorescence to show the muscle fiber types composition and endplates on type-identified fibers of the lumbrical muscles (LMs), interosseus muscles (IMs), abductor digiti minimi (AM) and flexor pollicis brevis (FM) in rat forepaw. The majority of IFMs fibers were labeled positively for fast-switch fiber. However, the IMs were composed of only slow-switch fiber. With the exception of the IMs, the other IFMs had a part of hybrid fibers. Two-dimensional morphological characteristics of endplates on I and IIa muscle fiber had no significant differences among the IFMs. The LMs is the most suitable IFMs of rat to stimulate reinnervation of the IHMs after nerve injury. Gaining greater insight into the muscle fiber types composition and endplate morphology in the IFMs of rat may help understand the pathological and functional changes of IFMs in rat model stimulating reinnervation of IHMs after peripheral nerve injury.

Tongue muscle plasticity following hypoglossal nerve stimulation in aged rats

PubMed Central

Connor, Nadine P.; Russell, John A.; Jackson, Michelle A.; Kletzien, Heidi; Wang, Hao; Schaser, Allison J.; Leverson, Glen E.; Zealear, David L.

2012-01-01

Introduction Age-related decreases in tongue muscle mass and strength have been reported. It may be possible to prevent age-related tongue muscle changes using neuromuscular electrical stimulation (NMES). Our hypothesis was that alterations in muscle contractile properties and myosin heavy chain composition would be found following NMES. Methods Fifty-four young, middle-aged and old Fischer 344/Brown Norway rats were included. Twenty-four rats underwent bilateral electrical stimulation of the hypoglossal nerves for 8 weeks and were compared with control or sham rats. Muscle contractile properties and myosin heavy chain (MHC) in the genioglossus (GG), styloglossus (SG) and hyoglossus (HG) muscles were examined. Results In comparison with unstimulated control rats, we found reduced muscle fatigue, increased contraction and half decay times and increased twitch and tetanic tension. Increased Type I MHC was found, except for GG in old and middle-aged rats. Discussion Transitions in tongue muscle contractile properties and phenotype were found following NMES. PMID:23169566

Mangiferin protects against adverse skeletal muscle changes and enhances muscle oxidative capacity in obese rats

PubMed Central

Acevedo, Luz M.; Raya, Ana I.; Martínez-Moreno, Julio M.

2017-01-01

Obesity-related skeletal muscle changes include muscle atrophy, slow-to-fast fiber-type transformation, and impaired mitochondrial oxidative capacity. These changes relate with increased risk of insulin resistance. Mangiferin, the major component of the plant Mangifera indica, is a well-known anti-inflammatory, anti-diabetic, and antihyperlipidemic agent. This study tested the hypothesis that mangiferin treatment counteracts obesity-induced fiber atrophy and slow-to-fast fiber transition, and favors an oxidative phenotype in skeletal muscle of obese rats. Obese Zucker rats were fed gelatin pellets with (15 mg/kg BW/day) or without (placebo group) mangiferin for 8 weeks. Lean Zucker rats received the same gelatin pellets without mangiferin and served as non-obese and non-diabetic controls. Lesser diameter, fiber composition, and histochemical succinic dehydrogenase activity (an oxidative marker) of myosin-based fiber-types were assessed in soleus and tibialis cranialis muscles. A multivariate discriminant analysis encompassing all fiber-type features indicated that obese rats treated with mangiferin displayed skeletal muscle phenotypes significantly different compared with both lean and obese control rats. Mangiferin significantly decreased inflammatory cytokines, preserved skeletal muscle mass, fiber cross-sectional size, and fiber-type composition, and enhanced muscle fiber oxidative capacity. These data demonstrate that mangiferin attenuated adverse skeletal muscle changes in obese rats. PMID:28253314

Mangiferin protects against adverse skeletal muscle changes and enhances muscle oxidative capacity in obese rats.

PubMed

Acevedo, Luz M; Raya, Ana I; Martínez-Moreno, Julio M; Aguilera-Tejero, Escolástico; Rivero, José-Luis L

2017-01-01

Obesity-related skeletal muscle changes include muscle atrophy, slow-to-fast fiber-type transformation, and impaired mitochondrial oxidative capacity. These changes relate with increased risk of insulin resistance. Mangiferin, the major component of the plant Mangifera indica, is a well-known anti-inflammatory, anti-diabetic, and antihyperlipidemic agent. This study tested the hypothesis that mangiferin treatment counteracts obesity-induced fiber atrophy and slow-to-fast fiber transition, and favors an oxidative phenotype in skeletal muscle of obese rats. Obese Zucker rats were fed gelatin pellets with (15 mg/kg BW/day) or without (placebo group) mangiferin for 8 weeks. Lean Zucker rats received the same gelatin pellets without mangiferin and served as non-obese and non-diabetic controls. Lesser diameter, fiber composition, and histochemical succinic dehydrogenase activity (an oxidative marker) of myosin-based fiber-types were assessed in soleus and tibialis cranialis muscles. A multivariate discriminant analysis encompassing all fiber-type features indicated that obese rats treated with mangiferin displayed skeletal muscle phenotypes significantly different compared with both lean and obese control rats. Mangiferin significantly decreased inflammatory cytokines, preserved skeletal muscle mass, fiber cross-sectional size, and fiber-type composition, and enhanced muscle fiber oxidative capacity. These data demonstrate that mangiferin attenuated adverse skeletal muscle changes in obese rats.

Perianal implantation of bioengineered human internal anal sphincter constructs intrinsically innervated with human neural progenitor cells.

PubMed

Raghavan, Shreya; Miyasaka, Eiichi A; Gilmont, Robert R; Somara, Sita; Teitelbaum, Daniel H; Bitar, Khalil N

2014-04-01

The internal anal sphincter (IAS) is a major contributing factor to pressure within the anal canal and is required for maintenance of rectoanal continence. IAS damage or weakening results in fecal incontinence. We have demonstrated that bioengineered, intrinsically innervated, human IAS tissue replacements possess key aspects of IAS physiology, such as the generation of spontaneous basal tone and contraction/relaxation in response to neurotransmitters. The objective of this study is to demonstrate the feasibility of implantation of bioengineered IAS constructs in the perianal region of athymic rats. Human IAS tissue constructs were bioengineered from isolated human IAS circular smooth muscle cells and human enteric neuronal progenitor cells. After maturation of the bioengineered constructs in culture, they were implanted operatively into the perianal region of athymic rats. Platelet-derived growth factor was delivered to the implanted constructs through a microosmotic pump. Implanted constructs were retrieved from the animals 4 weeks postimplantation. Animals tolerated the implantation well, and there were no early postoperative complications. Normal stooling was observed during the implantation period. At harvest, implanted constructs were adherent to the perirectal rat tissue and appeared healthy and pink. Immunohistochemical analysis revealed neovascularization. Implanted smooth muscle cells maintained contractile phenotype. Bioengineered constructs responded in vitro in a tissue chamber to neuronally evoked relaxation in response to electrical field stimulation and vasoactive intestinal peptide, indicating the preservation of neuronal networks. Our results indicate that bioengineered innervated IAS constructs can be used to augment IAS function in an animal model. This is a regenerative medicine based therapy for fecal incontinence that would directly address the dysfunction of the IAS muscle. Copyright © 2014 Mosby, Inc. All rights reserved.

The Role of Rac1 on Carbachol-induced Contractile Activity in Detrusor Smooth Muscle from Streptozotocin-induced Diabetic Rats.

PubMed

Evcim, Atiye Sinem; Micili, Serap Cilaker; Karaman, Meral; Erbil, Guven; Guneli, Ensari; Gidener, Sedef; Gumustekin, Mukaddes

2015-06-01

This study was designed to determine the role of the small GTPase Rac1 on carbachol-induced contractile activity in detrusor smooth muscle using small inhibitor NSC 23766 in diabetic rats. Rac1 expression in bladder tissue was also evaluated. In the streptozotocin (STZ)-induced diabetic rat model, three study groups were composed of control, diabetic and insulin-treated diabetic subjects. The detrusor muscle strips were suspended in organ baths at the end of 8-12 weeks after STZ injection. Carbachol (CCh) (10(-9) -10(-4) M) concentration-response curves were obtained both in the absence and in the presence of Rac1 inhibitor NSC 23766 (0.1, 1 and 10 μM). Diabetes-related histopathological changes and Rac1 expressions were assessed by haematoxylin and eosin staining and immunohistochemical staining, respectively. CCh caused dose-dependent contractile responses in all the study groups. Rac1 inhibitor NSC 23766 inhibited CCh-induced contractile responses in all groups, but this inhibition seen in both diabetes groups was greater than in the control group. Histological examination revealed an increased bladder wall thickness both in the diabetes and in the insulin-treated diabetes groups compared to the control group. In immunohistochemical staining, expression of Rac1 was observed to be increased in all layers of bladder in both diabetic groups compared to the control group. In the diabetic bladders, increased expression of Rac1 and considerable inhibition of CCh-induced responses in the presence of NSC 23766 compared to those of the control group may indicate a specific role of Rac1 in diabetes-related bladder dysfunction, especially associated with cholinergic mediated detrusor overactivity. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

[Amino acid composition of the rat quadriceps femoris muscle after a flight on the Kosmos-936 biosatellite].

PubMed

Vlasova, T F; Miroshnikova, E B; Poliakov, V V; Murugova, T P

1982-01-01

The amino acid composition of the quadriceps muscle of rats flown onboard the biosatellite Cosmos-936 and exposed to the ground-based synchronous control experiment was studied. The weightless rats showed changes in the amino acid concentration in the quadriceps muscle. The centrifuged flight and synchronous rats displayed an accumulation of free amino acids in the above muscle.

Metabolomic Profiling Reveals Mitochondrial-Derived Lipid Biomarkers That Drive Obesity-Associated Inflammation

PubMed Central

Sampey, Brante P.; Freemerman, Alex J.; Zhang, Jimmy; Kuan, Pei-Fen; Galanko, Joseph A.; O'Connell, Thomas M.; Ilkayeva, Olga R.; Muehlbauer, Michael J.; Stevens, Robert D.; Newgard, Christopher B.; Brauer, Heather A.; Troester, Melissa A.; Makowski, Liza

2012-01-01

Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to “Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome. PMID:22701716

Orthodontic treatment of a patient with unilateral orofacial muscle dysfunction: The efficacy of myofunctional therapy on the treatment outcome.

PubMed

Sugawara, Yasuyo; Ishihara, Yoshihito; Takano-Yamamoto, Teruko; Yamashiro, Takashi; Kamioka, Hiroshi

2016-07-01

The orofacial muscle is an important factor in the harmony of the occlusion, and its dysfunction significantly influences a patient's occlusion after craniofacial growth and development. In this case report, we describe the successful orthodontic treatment of a patient with unilateral orofacial muscle dysfunction. A boy, 10 years 0 months of age, with a chief complaint of anterior open bite, was diagnosed with a Class III malocclusion with facial musculoskeletal asymmetry. His maxillomandibular relationships were unstable, and he was unable to lift the right corner of his mouth upon smiling because of weak right orofacial muscles. A satisfactory occlusion and a balanced smile were achieved after orthodontic treatment combined with orofacial myofunctional therapy, including muscle exercises. An acceptable occlusion and facial proportion were maintained after a 2-year retention period. These results suggest that orthodontic treatment with orofacial myofunctional therapy is an effective option for a patient with orofacial muscle dysfunction. Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet.

PubMed

Sohrabipour, Shahla; Sharifi, Mohammad Reza; Talebi, Ardeshir; Sharifi, Mohammadreza; Soltani, Nepton

2018-05-05

Skeletal muscle, hepatic insulin resistance, and beta cell dysfunction are the characteristic pathophysiological features of type 2 diabetes mellitus. GABA has an important role in pancreatic islet cells. The present study attempted to clarify the possible mechanism of GABA to improve glucose tolerance in a model of type 2 diabetes mellitus in rats. Fifty Wistar rats were divided into five groups: NDC that was fed the normal diet, CD which received a high-fat diet with streptozotocin, CD-GABA animals that received GABA via intraperitoneal injection, plus CD-Ins1 and CD-Ins2 groups which were treated with low and high doses of insulin, respectively. Body weight and blood glucose were measured weekly. Intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), urine volume, amount of water drinking, and food intake assessments were performed monthly. The hyperinsulinemic euglycemic clamp was done for assessing insulin resistance. Plasma insulin and glucagon were measured. Abdominal fat was measured. Glucagon receptor, Glucose 6 phosphatase, Phosphoenolpyruvate carboxykinase genes expression were evaluated in liver and Glucose transporter 4 (GLUT4) genes expression and protein translocation were evaluated in the muscle. GABA or insulin therapy improved blood glucose, insulin level, IPGTT, ITT, gluconeogenesis pathway, Glucagon receptor, body weight and body fat in diabetic rats. GLUT4 gene and protein expression increased. GABA whose beneficial effect was comparable to that of insulin, also increased glucose infusion rate during an euglycemic clamp. GABA could improve insulin resistance via rising GLUT4 and also decreasing the gluconeogenesis pathway and Glucagon receptor gene expression. Copyright © 2018. Published by Elsevier B.V.

Skeletal muscle metabolism in hypokinetic rats

NASA Technical Reports Server (NTRS)

Tischler, M. E.

1984-01-01

Muscle growth, protein metabolism, and amino acid metabolism were studied in various groups of rats. Certain groups were adrenaliectomized; some rats were suspended while others (the controls) were weight bearing. Results show that: (1) metabolic changes in the extensor digitorum longus muscle of suspended rats are due primarily to increased circulating glucocorticoids; (2) metabolic changes in the soleus muscle due to higher steroid levels are probably potentiated by greater numbers of steroid receptors; and (3) not all metabolic responses of the soleus muscle to unloading are due to the elevated levels of glucocorticoids or the increased sensitivity of this muscle to these hormones.

Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings

PubMed Central

Pascual, Sergi; Casadevall, Carme; Orozco-Levi, Mauricio; Barreiro, Esther

2015-01-01

Respiratory and/or limb muscle dysfunction, which are frequently observed in chronic obstructive pulmonary disease (COPD) patients, contribute to their disease prognosis irrespective of the lung function. Muscle dysfunction is caused by the interaction of local and systemic factors. The key deleterious etiologic factors are pulmonary hyperinflation for the respiratory muscles and deconditioning secondary to reduced physical activity for limb muscles. Nonetheless, cigarette smoke, systemic inflammation, nutritional abnormalities, exercise, exacerbations, anabolic insufficiency, drugs and comorbidities also seem to play a relevant role. All these factors modify the phenotype of the muscles, through the induction of several biological phenomena in patients with COPD. While respiratory muscles improve their aerobic phenotype (percentage of oxidative fibers, capillarization, mitochondrial density, enzyme activity in the aerobic pathways, etc.), limb muscles exhibit the opposite phenotype. In addition, both muscle groups show oxidative stress, signs of damage and epigenetic changes. However, fiber atrophy, increased number of inflammatory cells, altered regenerative capacity; signs of apoptosis and autophagy, and an imbalance between protein synthesis and breakdown are rather characteristic features of the limb muscles, mostly in patients with reduced body weight. Despite that significant progress has been achieved in the last decades, full elucidation of the specific roles of the target biological mechanisms involved in COPD muscle dysfunction is still required. Such an achievement will be crucial to adequately tackle with this relevant clinical problem of COPD patients in the near-future. PMID:26623119

[The effects of hippophae juice on free radical metabolism of rat skeletal muscle and the content of Hb, Ck, T in blood].

PubMed

Qiao, Xiu-Fang; Pan, Hong-Ying

2010-08-01

To explore the effects of hippophae juice on free radical metabolism of rat skeletal muscle and partial biomarkers in blood. Randomly dividing the 30 SD rats into 3 groups (n = 10): sedentary group, training group and hippophae training group. Measuring related indices of skeletal muscle and blood in rat after 6 week training and hippophae juice supplement. Compared with training group, hippophae training group showed obviously longer exhaustive time, significantly increased antioxidant enzyme in skeletal muscle, remarkably decreased malonaldehyde (MDA) content in skeletal muscle, obviously increased testosterone (T) and hemoglobin (Hb) content in blood, significantly decreased creatine kinase (CK). Hippophae juice can impove the antioxidant ability of rat skeletal muscle, the level of T and Hb in blood, delay fatigue, therefore effectively enhance the aerobic stamina of rat.

Diaphragm Plasticity in Aging and Disease: Therapies for Muscle Weakness go from Strength to Strength.

PubMed

Greising, Sarah M; Ottenheijm, Coen A C; O'Halloran, Ken D; Barreiro, Esther

2018-04-19

The diaphragm is the main inspiratory muscle and is required to be highly active throughout the lifespan. The diaphragm muscle must be able to produce and sustain various behaviors that range from ventilatory to non-ventilatory such as those required for airway maintenance and clearance. Throughout the lifespan various circumstances and conditions may affect the ability of the diaphragm muscle to generate requisite forces and in turn the diaphragm muscle may undergo significant weakness and dysfunction. For example, hypoxic stress, critical illness, cancer cachexia, chronic obstructive pulmonary disorder (COPD), and age-related sarcopenia all represent conditions in which significant diaphragm muscle dysfunction exits. This perspective review article presents several interesting topics involving diaphragm plasticity in aging and disease that were presented at the International Union of Physiological Sciences (IUPS) Conference in 2017.This review seeks to maximize the broad and collective research impact on diaphragm muscle dysfunction in the search for transformative treatment approaches to improve the diaphragm muscle health during aging and disease.

Interleukin-6 (IL-6) mediated the increased contraction of distal colon in streptozotocin-induced diabetes in rats via IL-6 receptor pathway

PubMed Central

Chang, Xin-Wen; Qin, Ying; Jin, Zhi; Xi, Tao-Fang; Yang, Xiao; Lu, Ze-Hao; Tang, Yu-Ping; Cai, Wen-Ting; Chen, Shao-Jun; Xie, Dong-Ping

2015-01-01

Colonic dysmotility occurs in diabetes and blood plasma interleukin (IL)-6 levels are significantly elevated in type 1 diabetes mellitus. The aim of this study was to investigate whether IL-6 and the IL-6 receptor pathway mediates colonic dysfunction in type 1 diabetes mellitus. Male SD rats were treated with a single intraperitoneally injected dose of streptozotocin (STZ), and those displaying sustained high blood glucose were selected as diabetes mellitus models. Longitudinal muscle strips of colon were prepared to monitor colonic contraction in vitro. Contractile responses of strips of colon were recorded following treatment with IL-6 in control animals, and following anti IL-6 antibody treatment in STZ-induced diabetes in rats. Concentration of IL-6 in plasma and colon were determined by ELISA. Expressions of IL-6 α-receptor and IL-6 β-receptor in colon tissues were determined by immunohistochemistry or Western blot analysis. The non-diabetes rats treated with IL-6 and the untreated diabetes rats showed increased contraction of distal colon, whereas the diabetes rats treated with anti-IL-6 antibody showed decreased contraction of distal colon compared with the untreated diabetes rats. The IL-6 levels of plasma but not colon increased in diabetes rats. The expression of IL-6 α-receptor increased in diabetes rats. These results indicate that diabetes rats show an increase in the contractions of distal colon partly via the IL-6-IL-6 receptor pathway. PMID:26191141

Treatment with Riluzole Restores Normal Control of Soleus and Extensor Digitorum Longus Muscles during Locomotion in Adult Rats after Sciatic Nerve Crush at Birth

PubMed Central

Cabaj, Anna M.; Sławińska, Urszula

2017-01-01

The effects of sciatic nerve crush (SNC) and treatment with Riluzole on muscle activity during unrestrained locomotion were identified in an animal model by analysis of the EMG activity recorded from soleus (Sol) and extensor digitorum longus (EDL) muscles of both hindlimbs; in intact rats (IN) and in groups of rats treated for 14 days with saline (S) or Riluzole (R) after right limb nerve crush at the 1st (1S and 1R) or 2nd (2S and 2R) day after birth. Changes in the locomotor pattern of EMG activity were correlated with the numbers of survived motor units (MUs) identified in investigated muscles. S rats with 2–8 and 10–28 MUs that survived in Sol and EDL muscles respectively showed increases in the duration and duty factor of muscle EMG activity and a loss of correlation between the duty factors of muscle activity, and abnormal flexor-extensor co-activation 3 months after SNC. R rats with 5, 6 (Sol) and 15–29 MUs (EDL) developed almost normal EMG activity of both Sol and control EDL muscles, whereas EDL muscles with SNC showed a lack of recovery. R rats with 8 (Sol) and 23–33 (EDL) MUs developed almost normal EMG activities of all four muscles. A subgroup of S rats with a lack of recovery and R rats with almost complete recovery that had similar number of MUs (8 and 24–28 vs 8 and 23–26), showed that the number of MUs was not the only determinant of treatment effectiveness. The results demonstrated that rats with SNC failed to develop normal muscle activity due to malfunction of neuronal circuits attenuating EDL muscle activity during the stance phase, whereas treatment with Riluzole enabled almost normal EMG activity of Sol and EDL muscles during locomotor movement. PMID:28095499

Treatment with Riluzole Restores Normal Control of Soleus and Extensor Digitorum Longus Muscles during Locomotion in Adult Rats after Sciatic Nerve Crush at Birth.

PubMed

Zmysłowski, Wojciech; Cabaj, Anna M; Sławińska, Urszula

2017-01-01

The effects of sciatic nerve crush (SNC) and treatment with Riluzole on muscle activity during unrestrained locomotion were identified in an animal model by analysis of the EMG activity recorded from soleus (Sol) and extensor digitorum longus (EDL) muscles of both hindlimbs; in intact rats (IN) and in groups of rats treated for 14 days with saline (S) or Riluzole (R) after right limb nerve crush at the 1st (1S and 1R) or 2nd (2S and 2R) day after birth. Changes in the locomotor pattern of EMG activity were correlated with the numbers of survived motor units (MUs) identified in investigated muscles. S rats with 2-8 and 10-28 MUs that survived in Sol and EDL muscles respectively showed increases in the duration and duty factor of muscle EMG activity and a loss of correlation between the duty factors of muscle activity, and abnormal flexor-extensor co-activation 3 months after SNC. R rats with 5, 6 (Sol) and 15-29 MUs (EDL) developed almost normal EMG activity of both Sol and control EDL muscles, whereas EDL muscles with SNC showed a lack of recovery. R rats with 8 (Sol) and 23-33 (EDL) MUs developed almost normal EMG activities of all four muscles. A subgroup of S rats with a lack of recovery and R rats with almost complete recovery that had similar number of MUs (8 and 24-28 vs 8 and 23-26), showed that the number of MUs was not the only determinant of treatment effectiveness. The results demonstrated that rats with SNC failed to develop normal muscle activity due to malfunction of neuronal circuits attenuating EDL muscle activity during the stance phase, whereas treatment with Riluzole enabled almost normal EMG activity of Sol and EDL muscles during locomotor movement.

Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

PubMed

Sabharwal, Rasna; Chapleau, Mark W

2014-04-01

New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of LV dysfunction and higher mortality in Sgcd-/- mice. Treatment of Sgcd-/- mice with the angiotensin type 1 receptor blocker losartan for 8-9 weeks, beginning at 3 weeks of age, decreased fibrosis and oxidative stress in skeletal muscle, increased locomotor activity and prevented autonomic dysfunction. Chronic infusion of the counter-regulatory peptide angiotensin-(1-7) resulted in similar protection. We conclude that activation of the renin-angiotensin system, at a young age, contributes to skeletal muscle and autonomic dysfunction in muscular dystrophy. We speculate that the latter is mediated via abnormal sensory nerve and/or cytokine signalling from dystrophic skeletal muscle to the brain and contributes to age-related LV dysfunction, dilated cardiomyopathy, arrhythmias and premature death. Therefore, correcting the early autonomic dysregulation and renin-angiotensin system activation may provide a novel therapeutic approach in muscular dystrophy.

Beta2-adrenoceptor agonist fenoterol enhances functional repair of regenerating rat skeletal muscle after injury.

PubMed

Beitzel, Felice; Gregorevic, Paul; Ryall, James G; Plant, David R; Sillence, Martin N; Lynch, Gordon S

2004-04-01

Beta(2)-adrenoceptor agonists such as fenoterol are anabolic in skeletal muscle, and because they promote hypertrophy and improve force-producing capacity, they have potential application for enhancing muscle repair after injury. No previous studies have measured the beta(2)-adrenoceptor population in regenerating skeletal muscle or determined whether fenoterol can improve functional recovery in regenerating muscle after myotoxic injury. In the present study, the extensor digitorum longus (EDL) muscle of the right hindlimb of deeply anesthetized rats was injected with bupivacaine hydrochloride, which caused complete degeneration of all muscle fibers. The EDL muscle of the left hindlimb served as the uninjured control. Rats received either fenoterol (1.4 mg x kg(-1) x day(-1)) or an equal volume of saline for 2, 7, 14, or 21 days. Radioligand binding assays identified a approximately 3.5-fold increase in beta(2)-adrenoceptor density in regenerating muscle at 2 days postinjury. Isometric contractile properties of rat EDL muscles were measured in vitro. At 14 and 21 days postinjury, maximum force production (P(o)) of injured muscles from fenoterol-treated rats was 19 and 18% greater than from saline-treated rats, respectively, indicating more rapid restoration of function after injury. The increase in P(o) in fenoterol-treated rats was due to increases in muscle mass, fiber cross-sectional area, and protein content. These findings suggest a physiological role for beta(2)-adrenoceptor-mediated mechanisms in muscle regeneration and show clearly that fenoterol hastens recovery after injury, indicating its potential therapeutic application.

Effects provoked by chronic undernourishment on the fibre type composition and contractility of fast muscles in male and female developing rats.

PubMed

Pereyra-Venegas, J; Segura-Alegría, B; Guadarrama-Olmos, J C; Mariscal-Tovar, S; Quiróz-González, S; Jiménez-Estrada, I

2015-10-01

In this study, we compare the effects of pre- and post-natal food deprivation on the relative proportion of fibre types and contractile responses in the extensor digitorum longus (EDL) muscle of female and male rats at different post-natal ages. EDL muscles from undernourished male (UM) rats showed a higher proportion of Type IIB than IIA fibres and larger normalized twitch responses (with respect to muscle weight) than those of controls (CM). In contrast, EDL muscles from control (CF) and undernourished female rats (UF) showed no significant differences in their fibre type composition and normalized twitch forces at most of the ages analysed. Our data are indicative that the EDL muscles from undernourished males are more susceptible to the effects exerted by low food income than the EDL muscles from female rats. It is proposed that changes in the reactive oxygen species (ROS) concentration and hormonal factors, due to undernutrition, are involved in the alterations observed in the fibre type composition and force production of EDL muscles in undernourished male rats and that estrogens may have an antioxidant protective role on the undernourished EDL muscles in female rats. Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH.

Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction.

PubMed

Hotta, Yuji; Hattori, Mayuko; Kataoka, Tomoya; Ohno, Risa; Mikumo, Mayumi; Maeda, Yasuhiro; Kimura, Kazunori

2011-03-01

Chronic phosphodiesterase type 5 inhibitor treatment may be useful in reversing erectile dysfunction (ED). However, the mechanisms of this improvement remain unknown. The aim of this article was to determine the mechanisms of the improvement by chronic vardenafil treatment for acute arteriogenic ED in rats. Eight-week-old male Wistar-ST rats were divided into four groups: sham-operated rats (Control group) and rats with acute arteriogenic ED induced by ligating bilateral internal iliac arteries (Ligation group), subsequently treated with low-dose (0.4 mg/kg/day; VL group) or high-dose (4.0 mg/kg/day; VH group) vardenafil for 20 days from 1 week after ligature. Erectile function was assessed based on changes of intracavernous pressure (ICP) followed by electrostimulation of the cavernous nerves and was evaluated by the area under the curve of ICP/area under the curve of mean arterial pressure (area of ICP/MAP). Transforming growth factor (TGF)-β(1), vascular endothelial growth factor-A, endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS mRNA expression levels in penile corpus cavernosum were determined by real-time PCR. Western blotting for TGF-β(1) protein levels and Masson trichrome staining of penile tissues were performed in each at group 4 weeks after surgery. In the VH group, area of ICP/MAP was significantly improved when compared with the Ligation group (P < 0.01). The smooth muscle (SM)/collagen ratio in the VH group was significantly higher than in the Ligation group (P < 0.05), and was comparable with that in the Control group. TGF-β(1) mRNA and protein levels in the VH group were significantly lower when compared with the Ligation group (P < 0.05). Chronic vardenafil administration ameliorates impairment of penile hemodynamics and maintains normal SM to collagen ratio in cavernous tissues after acute arterial injury in rats. © 2010 International Society for Sexual Medicine.

SMAD signaling drives heart and muscle dysfunction in a Drosophila model of muscular dystrophy.

PubMed

Goldstein, Jeffery A; Kelly, Sean M; LoPresti, Peter P; Heydemann, Ahlke; Earley, Judy U; Ferguson, Edwin L; Wolf, Matthew J; McNally, Elizabeth M

2011-03-01

Loss-of-function mutations in the genes encoding dystrophin and the associated membrane proteins, the sarcoglycans, produce muscular dystrophy and cardiomyopathy. The dystrophin complex provides stability to the plasma membrane of striated muscle during muscle contraction. Increased SMAD signaling due to activation of the transforming growth factor-β (TGFβ) pathway has been described in muscular dystrophy; however, it is not known whether this canonical TGFβ signaling is pathogenic in the muscle itself. Drosophila deleted for the γ/δ-sarcoglycan gene (Sgcd) develop progressive muscle and heart dysfunction and serve as a model for the human disorder. We used dad-lacZ flies to demonstrate the signature of TGFβ activation in response to exercise-induced injury in Sgcd null flies, finding that those muscle nuclei immediately adjacent to muscle injury demonstrate high-level TGFβ signaling. To determine the pathogenic nature of this signaling, we found that partial reduction of the co-SMAD Medea, homologous to SMAD4, or the r-SMAD, Smox, corrected both heart and muscle dysfunction in Sgcd mutants. Reduction in the r-SMAD, MAD, restored muscle function but interestingly not heart function in Sgcd mutants, consistent with a role for activin but not bone morphogenic protein signaling in cardiac dysfunction. Mammalian sarcoglycan null muscle was also found to exhibit exercise-induced SMAD signaling. These data demonstrate that hyperactivation of SMAD signaling occurs in response to repetitive injury in muscle and heart. Reduction of this pathway is sufficient to restore cardiac and muscle function and is therefore a target for therapeutic reduction.

SMAD signaling drives heart and muscle dysfunction in a Drosophila model of muscular dystrophy

PubMed Central

Goldstein, Jeffery A.; Kelly, Sean M.; LoPresti, Peter P.; Heydemann, Ahlke; Earley, Judy U.; Ferguson, Edwin L.; Wolf, Matthew J.; McNally, Elizabeth M.

2011-01-01

Loss-of-function mutations in the genes encoding dystrophin and the associated membrane proteins, the sarcoglycans, produce muscular dystrophy and cardiomyopathy. The dystrophin complex provides stability to the plasma membrane of striated muscle during muscle contraction. Increased SMAD signaling due to activation of the transforming growth factor-β (TGFβ) pathway has been described in muscular dystrophy; however, it is not known whether this canonical TGFβ signaling is pathogenic in the muscle itself. Drosophila deleted for the γ/δ-sarcoglycan gene (Sgcd) develop progressive muscle and heart dysfunction and serve as a model for the human disorder. We used dad-lacZ flies to demonstrate the signature of TGFβ activation in response to exercise-induced injury in Sgcd null flies, finding that those muscle nuclei immediately adjacent to muscle injury demonstrate high-level TGFβ signaling. To determine the pathogenic nature of this signaling, we found that partial reduction of the co-SMAD Medea, homologous to SMAD4, or the r-SMAD, Smox, corrected both heart and muscle dysfunction in Sgcd mutants. Reduction in the r-SMAD, MAD, restored muscle function but interestingly not heart function in Sgcd mutants, consistent with a role for activin but not bone morphogenic protein signaling in cardiac dysfunction. Mammalian sarcoglycan null muscle was also found to exhibit exercise-induced SMAD signaling. These data demonstrate that hyperactivation of SMAD signaling occurs in response to repetitive injury in muscle and heart. Reduction of this pathway is sufficient to restore cardiac and muscle function and is therefore a target for therapeutic reduction. PMID:21138941

Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy

PubMed Central

Røe, Åsmund T.; Aronsen, Jan Magnus; Skårdal, Kristine; Hamdani, Nazha; Linke, Wolfgang A.; Danielsen, Håvard E.; Sejersted, Ole M.; Sjaastad, Ivar; Louch, William E.

2017-01-01

Abstract Aims Concentric hypertrophy following pressure-overload is linked to preserved systolic function but impaired diastolic function, and is an important substrate for heart failure with preserved ejection fraction. While increased passive stiffness of the myocardium is a suggested mechanism underlying diastolic dysfunction in these hearts, the contribution of active diastolic Ca2+ cycling in cardiomyocytes remains unclear. In this study, we sought to dissect contributions of passive and active mechanisms to diastolic dysfunction in the concentrically hypertrophied heart following pressure-overload. Methods and results Rats were subjected to aortic banding (AB), and experiments were performed 6 weeks after surgery using sham-operated rats as controls. In vivo ejection fraction and fractional shortening were normal, confirming preservation of systolic function. Left ventricular concentric hypertrophy and diastolic dysfunction following AB were indicated by thickening of the ventricular wall, reduced peak early diastolic tissue velocity, and higher E/e’ values. Slowed relaxation was also observed in left ventricular muscle strips isolated from AB hearts, during both isometric and isotonic stimulation, and accompanied by increases in passive tension, viscosity, and extracellular collagen. An altered titin phosphorylation profile was observed with hypophosphorylation of the phosphosites S4080 and S3991 sites within the N2Bus, and S12884 within the PEVK region. Increased titin-based stiffness was confirmed by salt-extraction experiments. In contrast, isolated, unloaded cardiomyocytes exhibited accelerated relaxation in AB compared to sham, and less contracture at high pacing frequencies. Parallel enhancement of diastolic Ca2+ handling was observed, with augmented NCX and SERCA2 activity and lowered resting cytosolic [Ca2+]. Conclusion In the hypertrophied heart with preserved systolic function, in vivo diastolic dysfunction develops as cardiac fibrosis and alterations in titin phosphorylation compromise left ventricular compliance, and despite compensatory changes in cardiomyocyte Ca2+ homeostasis. PMID:28472418

Psychological Stress Alters Ultrastructure and Energy Metabolism of Masticatory Muscle in Rats

PubMed Central

Chen, Yong-Jin; Huang, Fei; Zhang, Min; Shang, Hai-Yan

2010-01-01

To investigate the effects of psychological stress on the masticatory muscles of rats, a communication box was applied to induce the psychological stress (PS) in rats. The successful establishment of psychological stimulation was confirmed by elevated serum levels of adrenocorticotropic hormone (ACTH) and changed behaviors in the elevated plusmaze apparatus. The energy metabolism of the bilateral masseter muscles was tested via chemocolorimetric analysis, whereas muscle ultrastructure was assessed by electron microscopy. In comparison to the control group, the PS group showed evidence of swollen mitochondria with cristae loss and reduced matrix density in the masticatory muscles after three weeks of stimulation; after five weeks of stimulation, severe vacuolar changes to the mitochondria were observed. Increased vascular permeability of the masticatory muscle capillaries was found in the five-week PS rats. In addition, there was decreased activity of Na+-K+ATPase and Ca2+-ATPase and a simultaneous increase in the activity of lactate dehydrogenase and lactic acid in the masticatory muscles of PS rats. Together, these results indicate that psychological stress induces alterations in the ultrastructure and energy metabolism of masticatory muscles in rats. PMID:21052548

Age-dependent increase in oxidative stress in gastrocnemius muscle with unloading

PubMed Central

Siu, Parco M.; Pistilli, Emidio E.; Alway, Stephen E.

2008-01-01

Oxidative stress increases during unloading in muscle from young adult rats. The present study examined the markers of oxidative stress and antioxidant enzyme gene and protein expressions in medial gastrocnemius muscles of aged and young adult (30 and 6 mo of age) Fischer 344 × Brown Norway rats after 14 days of hindlimb suspension. Medial gastrocnemius muscle weight was decreased by ∼30% in young adult and aged rats following suspension. When muscle weight was normalized to animal body weight, it was reduced by 12% and 22% in young adult and aged rats, respectively, after suspension. Comparisons between young adult and aged control animals demonstrated a 25% and 51% decline in muscle mass when expressed as absolute muscle weight and muscle weight normalized to the animal body weight, respectively. H2O2 content was elevated by 43% while Mn superoxide dismutase (MnSOD) protein content was reduced by 28% in suspended muscles compared with control muscles exclusively in the aged animals. Suspended muscles had greater content of malondialdehyde (MDA)/4-hydroxyalkenals (4-HAE) (29% and 58% increase in young adult and aged rats, respectively), nitrotyrosine (76% and 65% increase in young adult and aged rats, respectively), and catalase activity (69% and 43% increase in young adult and aged rats, respectively) relative to control muscles. Changes in oxidative stress markers MDA/4-HAE, H2O2, and MnSOD protein contents in response to hindlimb unloading occurred in an age-dependent manner. These findings are consistent with the hypotheses that oxidative stress has a role in mediating disuse-induced and sarcopenia-associated muscle losses. Our data suggest that aging may predispose skeletal muscle to increased levels of oxidative stress both at rest and during unloading. PMID:18801960

Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats.

PubMed

Alvarez, Pedro; Green, Paul G; Levine, Jon D

2018-06-01

Neonatal handling (NH) of male rat pups strongly attenuates stress response and stress-induced persistent muscle hyperalgesia in adults. Because female sex is a well established risk factor for stress-induced chronic muscle pain, we explored whether NH provides resilience to stress-induced hyperalgesia in adult female rats. Rat pups underwent NH, or standard (control) care. Muscle mechanical nociceptive threshold was assessed before and after water avoidance (WA) stress, when they were adults. In contrast to male rats, NH produced only a modest protection against WA stress-induced muscle hyperalgesia in female rats. Gonadectomy completely abolished NH-induced resilience in male rats but produced only a small increase in this protective effect in female rats. The administration of the antiestrogen drug fulvestrant, in addition to gonadectomy, did not enhance the protective effect of NH in female rats. Finally, knockdown of the androgen receptor by intrathecal antisense treatment attenuated the protective effect of NH in intact male rats. Together, these data indicate that androgens play a key role in NH-induced resilience to WA stress-induced muscle hyperalgesia. NH induces androgen-dependent resilience to stress-induced muscle pain. Therefore, androgens may contribute to sex differences observed in chronic musculoskeletal pain and its enhancement by stress. Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.

Role of insulin on exercise-induced GLUT-4 protein expression and glycogen supercompensation in rat skeletal muscle.

PubMed

Kuo, Chia-Hua; Hwang, Hyonson; Lee, Man-Cheong; Castle, Arthur L; Ivy, John L

2004-02-01

The purpose of this study was to investigate the role of insulin on skeletal muscle GLUT-4 protein expression and glycogen storage after postexercise carbohydrate supplementation. Male Sprague-Dawley rats were randomly assigned to one of six treatment groups: sedentary control (Con), Con with streptozocin (Stz/C), immediately postexercise (Ex0), Ex0 with Stz (Stz/Ex0), 5-h postexercise (Ex5), and Ex5 with Stz (Stz/Ex5). Rats were exercised by swimming (2 bouts of 3 h) and carbohydrate supplemented immediately after each exercise session by glucose intubation (1 ml of a 50% wt/vol). Stz was administered 72-h before exercise, which resulted in hyperglycemia and elimination of the insulin response to the carbohydrate supplement. GLUT-4 protein of Ex0 rats was 30% above Con in fast-twitch (FT) red and 21% above Con in FT white muscle. In Ex5, GLUT-4 protein was 52% above Con in FT red and 47% above Con in FT white muscle. Muscle glycogen in FT red and white muscle was also increased above Con in Ex5 rats. Neither GLUT-4 protein nor muscle glycogen was increased above Con in Stz/Ex0 or Stz/Ex5 rats. GLUT-4 mRNA in FT red muscle of Ex0 rats was 61% above Con but only 33% above Con in Ex5 rats. GLUT-4 mRNA in FT red muscle of Stz/C and Stz/Ex0 rats was similar but significantly elevated in Ex5/Stz rats. These results suggest that insulin is essential for the increase in GLUT-4 protein expression following postexercise carbohydrate supplementation.

Effects of insulin and exercise on rat hindlimb muscles after simulated microgravity

NASA Technical Reports Server (NTRS)

Stump, Craig S.; Balon, Thomas W.; Tipton, Charles M.

1992-01-01

The effect of simulated microgravity on the insulin- and exercise-stimulated glucose uptake and metabolism in the hindlimb muscles of rats was investigated using three groups of rats suspended at 45 head-down tilt (SUS) for 14 days: (1) cage control, (2) exercising (treadmill running) control, and (3) rats subjected to suspension followed by exercise (SUS-E). It was found that the suspension of rats with hindlimbs non-weight bearing led to enhanced muscle responses to insulin and exercise, when these stimuli were applied separately. However, the insulin affect appeared to be impaired after exercise for the SUS-E rats, especially for the soleus muscle.

Recovery of skeletal muscle mass after extensive injury: positive effects of increased contractile activity.

PubMed

Richard-Bulteau, Hélène; Serrurier, Bernard; Crassous, Brigitte; Banzet, Sébastien; Peinnequin, André; Bigard, Xavier; Koulmann, Nathalie

2008-02-01

The present study was designed to test the hypothesis that increasing physical activity by running exercise could favor the recovery of muscle mass after extensive injury and to determine the main molecular mechanisms involved. Left soleus muscles of female Wistar rats were degenerated by notexin injection before animals were assigned to either a sedentary group or an exercised group. Both regenerating and contralateral intact muscles from active and sedentary rats were removed 5, 7, 14, 21, 28 and 42 days after injury (n = 8 rats/group). Increasing contractile activity through running exercise during muscle regeneration ensured the full recovery of muscle mass and muscle cross-sectional area as soon as 21 days after injury, whereas muscle weight remained lower even 42 days postinjury in sedentary rats. Proliferator cell nuclear antigen and MyoD protein expression went on longer in active rats than in sedentary rats. Myogenin protein expression was higher in active animals than in sedentary animals 21 days postinjury. The Akt-mammalian target of rapamycin (mTOR) pathway was activated early during the regeneration process, with further increases of mTOR phosphorylation and its downstream effectors, eukaryotic initiation factor-4E-binding protein-1 and p70(s6k), in active rats compared with sedentary rats (days 7-14). The exercise-induced increase in mTOR phosphorylation, independently of Akt, was associated with decreased levels of phosphorylated AMP-activated protein kinase. Taken together, these results provided evidence that increasing contractile activity during muscle regeneration ensured early and full recovery of muscle mass and suggested that these beneficial effects may be due to a longer proliferative step of myogenic cells and activation of mTOR signaling, independently of Akt, during the maturation step of muscle regeneration.

Alterations in Skeletal Muscle Microcirculation of Head-Down Tilted Rats

NASA Technical Reports Server (NTRS)

Musacchia, X. J.; Stepke, Bernhard; Fleming, John T.; Joshua, Irving G.

1992-01-01

In this study we assessed the function of microscopic blood vessels in skeletal muscle (cremaster muscle) for alterations which may contribute to the observed elevation of blood pressure associated with head-down tilted whole body suspension (HDT/WBS), a model of weightlessness. Arteriolar baseline diameters, vasoconstrictor responses to norepinephrine (NE) and vasodilation to nitroprusside (NP) were assessed in control rats, rats suspended for 7 or 14 day HDT/WBS rats, and rats allowed to recover for 1 day after 7 days HDT/WBS. Neither baseline diameters nor ability to dilate were influenced by HDT/WBS. Maximum vasoconstriction to norepinephrine was significantly greater in arterioles of hypertensive 14 day HDT/WBS rats. This first study of the intact microvasculature in skeletal muscle indicates that an elevated contractility of arterioles to norepinephrine in suspended rats, and suggests an elevated peripheral resistance in striated muscle may contribute to the increase in blood pressures among animals subjected to HDT/WBS.

The influence of rat suspension-hypokinesia on the gastrocnemius muscle

NASA Technical Reports Server (NTRS)

Templeton, G. H.; Padalino, M.; Manton, J.; Leconey, T.; Hagler, H.; Glasberg, M.

1984-01-01

Hind-limb hypokinesia was induced in rats by the Morey method to characterize the response of the gastrocnemius muscle. A comparison of rats suspended for 2 weeks with weight, sex, and litter-matched control rats indicate no difference in gastrocnemius wet weight, contraction, or one-half relaxation times, but less contractile function as indicated by lowered dP/dt. Myosin ATPase staining identified uniform Type I (slow-twitch) and II (fast-twitch) atrophy in the muscles from 4 of 10 rats suspended for 2 weeks and 1 of 12 rats suspended for 4 weeks; muscles from three other rats of the 4-week group displayed greater Type I atrophy. Other histochemical changes were characteristic of a neuropathy. These data together with recently acquired soleus data (29) indicate the Morey model, like space flight, evokes greater changes in the Type I or slow twitch fibers of the gastrocnemius and soleus muscles.

Divergent skeletal muscle respiratory capacities in rats artificially selected for high and low running ability: a role for Nor1?

PubMed Central

Stephenson, Erin J.; Stepto, Nigel K.; Koch, Lauren G.; Britton, Steven L.

2012-01-01

Inactivity-related diseases are becoming a huge burden on Western society. While there is a major environmental contribution to metabolic health, the intrinsic properties that predispose or protect against particular health traits are harder to define. We used rat models of inborn high running capacity (HCR) and low running capacity (LCR) to determine inherent differences in mitochondrial volume and function, hypothesizing that HCR rats would have greater skeletal muscle respiratory capacity due to an increase in mitochondrial number. Additionally, we sought to determine if there was a link between the expression of the orphan nuclear receptor neuron-derived orphan receptor (Nor)1, a regulator of oxidative metabolism, and inherent skeletal muscle respiratory capacity. LCR rats were 28% heavier (P < 0.0001), and fasting serum insulin concentrations were 62% greater than in HCR rats (P = 0.02). In contrast, HCR rats had better glucose tolerance and reduced adiposity. In the primarily oxidative soleus muscle, maximal respiratory capacity was 21% greater in HCR rats (P = 0.001), for which the relative contribution of fat oxidation was 20% higher than in LCR rats (P = 0.02). This was associated with increased citrate synthase (CS; 33%, P = 0.009) and β-hydroxyacyl-CoA (β-HAD; 33%, P = 0.0003) activities. In the primarily glycolytic extensor digitum longus muscle, CS activity was 29% greater (P = 0.01) and β-HAD activity was 41% (P = 0.0004) greater in HCR rats compared with LCR rats. Mitochondrial DNA copy numbers were also elevated in the extensor digitum longus muscles of HCR rats (35%, P = 0.049) and in soleus muscles (44%, P = 0.16). Additionally, HCR rats had increased protein expression of individual mitochondrial respiratory complexes, CS, and uncoupling protein 3 in both muscle types (all P < 0.05). In both muscles, Nor1 protein was greater in HCR rats compared with LCR rats (P < 0.05). We propose that the differential expression of Nor1 may contribute to the differences in metabolic regulation between LCR and HCR phenotypes. PMID:22936731

L-arginine fails to prevent ventricular remodeling and heart failure in the spontaneously hypertensive rat.

PubMed

Brooks, Wesley W; Conrad, Chester H; Robinson, Kathleen G; Colucci, Wilson S; Bing, Oscar H L

2009-02-01

The effects of long-term oral administration of L-arginine, a substrate for nitric oxide (NO) production, on left ventricular (LV) remodeling, myocardial function and the prevention of heart failure (HF) was compared to the angiotensin-converting enzyme (ACE) inhibitor captopril in a rat model of hypertensive HF (aged spontaneously hypertensive rat (SHR)). SHRs and age-matched normotensive Wistar-Kyoto (WKY) rats were assigned to either no treatment, treatment with L-arginine (7.5 g/l in drinking water) or captopril (1 g/l in drinking water) beginning at 14 months of age, a time when SHRs exhibit stable compensated hypertrophy with no hemodynamic impairment; animals were studied at 23 months of age or at the time of HF. In untreated SHR, relative to WKY, there was significant LV hypertrophy, myocardial fibrosis, and isolated LV muscle performance and response to isoproterenol (ISO) were depressed; and, 7 of 10 SHRs developed HF. Captopril administration to six SHRs attenuated hypertrophy and prevented impaired inotropic responsiveness to ISO, contractile dysfunction, fibrosis, increased passive stiffness, and HF. In contrast, L-arginine administration to SHR increased LV hypertrophy and myocardial fibrosis while cardiac performance was depressed; and 7 of 9 SHRs developed HF. In WKY, L-arginine treatment but not captopril resulted in increased LV weight and the contractile response to ISO was blunted. Neither L-arginine nor captopril treatment of WKY changed fibrosis and HF did not occur. These data demonstrate that in contrast to captopril, long-term treatment with L-arginine exacerbates age-related cardiac hypertrophy, fibrosis, and did not prevent contractile dysfunction or the development of HF in aging SHR.

Respiratory muscle function and exercise limitation in patients with chronic obstructive pulmonary disease: a review.

PubMed

Charususin, Noppawan; Dacha, Sauwaluk; Gosselink, Rik; Decramer, Marc; Von Leupoldt, Andreas; Reijnders, Thomas; Louvaris, Zafeiris; Langer, Daniel

2018-01-01

Respiratory muscle dysfunction is common and contributes to dyspnea and exercise limitation in patients with chronic obstructive pulmonary disease (COPD). Improving dynamic function of respiratory muscles during exercise might help to reduce symptoms and improve exercise capacity. Areas covered: The aims of this review are to 1) summarize physiological mechanisms linking respiratory muscle dysfunction to dyspnea and exercise limitation; 2) provide an overview of available therapeutic approaches to better maintain load-capacity balance of respiratory muscles during exercise; and 3) to summarize current knowledge on potential mechanisms explaining effects of interventions aimed at optimizing dynamic respiratory muscle function with a special focus on inspiratory muscle training. Expert commentary: Several mechanisms which are potentially linking improvements in dynamic respiratory muscle function to symptomatic and functional benefits have not been studied so far in COPD patients. Examples of underexplored areas include the study of neural processes related to the relief of acute dyspnea and the competition between respiratory and peripheral muscles for limited energy supplies during exercise. Novel methodologies are available to non-invasively study these mechanisms. Better insights into the consequences of dynamic respiratory muscle dysfunction will hopefully contribute to further refine and individualize therapeutic approaches in patients with COPD.

The changes in beta-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac beta3-adrenoceptors.

PubMed

Arioglu, E; Guner, S; Ozakca, I; Altan, V M; Ozcelikay, A T

2010-02-01

Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

Understanding Muscle Dysfunction in Chronic Fatigue Syndrome

PubMed Central

Rutherford, Gina; Manning, Philip; Newton, Julia L.

2016-01-01

Introduction. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown aetiology, characterised by severe disabling fatigue in the absence of alternative diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue; however, this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial, and neuronal pathways. For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examined the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level. Methods. Literature was examined following searches of PUB MED, MEDLINE, and Google Scholar, using key words such as CFS/ME, immune, autoimmune, mitochondria, muscle, and acidosis. Results. Studies show evidence for skeletal muscle biochemical abnormality in CFS/ME patients, particularly in relation to bioenergetic dysfunction. Discussion. Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise. Potentially, these abnormalities may lead to the perception of severe fatigue in CFS/ME. PMID:26998359

The Effects of Phrenic Nerve Degeneration by Axotomy and Crush on the Electrical Activities of Diaphragm Muscles of Rats.

PubMed

Alkiş, Mehmet Eşref; Kavak, Servet; Sayır, Fuat; Him, Aydin

2016-03-01

The aim of this study was to investigate the effect of axotomy and crush-related degeneration on the electrical activities of diaphragm muscle strips of experimental rats. In the present study, twenty-one male Wistar-albino rats were used and divided into three groups. The animals in the first group were not crushed or axotomized and served as controls. Phrenic nerves of the rats in the second and third groups were crushed or axotomized in the diaphragm muscle. Resting membrane potential (RMP) was decreased significantly in both crush and axotomy of diaphragm muscle strips of experimental rats (p < 0.05). Depolarization time (T DEP) and half-repolarization (1/2 RT) time were significantly prolonged in crush and axotomy rats (p < 0.05). Crushing or axotomizing the phrenic nerves may produce electrical activities in the diaphragm muscle of the rat by depolarization time and half-repolarization time prolonged in crush and axotomy rats.

Bariatric surgery improves the cavernosal neuronal, vasorelaxation, and contraction mechanisms for erectile dysfunction as result of amelioration of glucose homeostasis in a diabetic rat model.

PubMed

Choi, Yong Sun; Lee, Sang Kuon; Bae, Woong Jin; Kim, Su Jin; Cho, Hyuk Jin; Hong, Sung-Hoo; Lee, Ji Youl; Hwang, Tae-Kon; Kim, Sae Woong

2014-01-01

Bariatric surgery is an effective treatment option for both obesity and obesity-related type 2 diabetes mellitus (T2DM). However, little is known regarding the effects of bariatric surgery on erectile dysfunction among patients with T2DM. Therefore, we investigated whether bariatric surgery would lead to structural and biochemical changes in the corpus cavernosum. Twenty-five male Otsuka Long-Evans Tokushima Fatty rats were assigned to either a control group (sham operation, n = 10) or a bariatric surgery group (gastric bypass surgery, n = 15). Four weeks after the operation, each group of rats was evaluated with an oral glucose tolerance test (OGTT). The penile intracavernous pressure was measured for erectile functional analysis. Histologic evaluation of the tissue was performed with Masson's trichrome staining. Endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), Rho kinase, and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels in the corpus cavernosum were assayed by using western blot and ELISA. The mean body weight of the bariatric surgery group was lower than the control group (p = 0.002). The postoperative OGTT result was lower in the bariatric surgery group than in the control group (p = 0.014), and this was lower than the preoperative value (p = 0.037). The intracavernous pressure/mean arterial pressure ratio was higher in the bariatric surgery group compared to the control group (p = 0.021), and a higher cavernosum smooth muscle/collagen ratio was observed in the bariatric surgery group compared to the control group (p = 0.025). Likewise, the expression of eNOS and nNOS was higher in bariatric surgery group than in the control group (p = 0.027 and p = 0.008, respectively). Decreased expression of Rho kinase and levels of 8-OHdG were observed in the bariatric surgery group (p = 0.032). In this animal model, bariatric surgery appears to ameliorate T2DM-related metabolic dysfunction leading to structural and biochemical changes in the corpus cavernosum, and thus, results in improvement of erectile dysfunction associated with T2DM.

A specific amino acid formula prevents alcoholic liver disease in rodents.

PubMed

Tedesco, Laura; Corsetti, Giovanni; Ruocco, Chiara; Ragni, Maurizio; Rossi, Fabio; Carruba, Michele O; Valerio, Alessandra; Nisoli, Enzo

2018-05-01

Chronic alcohol consumption promotes mitochondrial dysfunction, oxidative stress, defective protein metabolism, and fat accumulation in hepatocytes (liver steatosis). Inadequate amino acid metabolism is worsened by protein malnutrition, frequently present in alcohol-consuming patients, with reduced circulating branched-chain amino acids (BCAAs). Here we asked whether dietary supplementation with a specific amino acid mixture, enriched in BCAAs (BCAAem) and able to promote mitochondrial function in muscle of middle-aged rodents, would prevent mitochondrial dysfunction and liver steatosis in Wistar rats fed on a Lieber-DeCarli ethanol (EtOH)-containing liquid diet. Supplementation of BCAAem, unlike a mixture based on the amino acid profile of casein, abrogated the EtOH-induced fat accumulation, mitochondrial impairment, and oxidative stress in liver. These effects of BCAAem were accompanied by normalization of leucine, arginine, and tryptophan levels, which were reduced in liver of EtOH-consuming rats. Moreover, although the EtOH exposure of HepG2 cells reduced mitochondrial DNA, mitochondrial transcription factors, and respiratory chain proteins, the BCAAem but not casein-derived amino acid supplementation halted this mitochondrial toxicity. Nicotinamide adenine dinucleotide levels and sirtuin 1 (Sirt1) expression, as well as endothelial nitric oxide (eNOS) and mammalian/mechanistic target of rapamycin (mTOR) signaling pathways, were downregulated in the EtOH-exposed HepG2 cells. BCAAem reverted these molecular defects and the mitochondrial dysfunction, suggesting that the mitochondrial integrity obtained with the amino acid supplementation could be mediated through a Sirt1-eNOS-mTOR pathway. Thus a dietary activation of the mitochondrial biogenesis and function by a specific amino acid supplement protects against the EtOH toxicity and preserves the liver integrity in mammals. NEW & NOTEWORTHY Dietary supplementation of a specific amino acid formula prevents both fat accumulation and mitochondrial dysfunction in hepatocytes of alcohol-consuming rats. These effects are accompanied also by increased expression of anti-reactive oxygen species genes. The amino acid-protective effects likely reflect activation of sirtuin 1-endothelial nitric oxide synthase-mammalian target of rapamycin pathway able to regulate the cellular energy balance of hepatocytes exposed to chronic, alcoholic damage.

BIOCHEMISTRY OF THE ANTERIOR, MEDIAL, AND POSTERIOR GENIOGLOSSUS IN THE AGED RAT

PubMed Central

Schaser, Allison J.; Wang, Hao; Volz, Lana M.; Connor, Nadine P.

2010-01-01

Age-related tongue weakness may contribute to swallowing deficits in the elderly. One contributing factor may be an alteration in muscle fiber type properties with aging. However, it is not clear how muscle fiber types within the aged tongue may vary from those found in young adults, or how fiber types may vary across the anteroposterior axis of the extrinsic tongue muscles. We examined myosin heavy chain (MHC) composition of anterior, medial, and posterior sections of the genioglossus muscle (GG) in 10 old male Fischer 344/Brown Norway rats and compared findings to previously reported data from young adult male rats. Significant differences (p< .01) between young adult and old rats were found in the distribution of MHC isoforms along the anteroposterior axis of the muscle. In the anterior, medial, and posterior regions, there was a significantly smaller proportion of type IIb MHC in the old rat GG muscles, while the proportion of type IIx MHC was significantly greater. In the medial region, the proportion of type I MHC was found to be significantly greater in the old rats. Thus, we found a shift to more slowly contracting muscle fibers in the aged rat tongue. PMID:20809174

Cytochrome c oxidase rather than cytochrome c is a major determinant of mitochondrial respiratory capacity in skeletal muscle of aged rats: role of carnitine and lipoic acid.

PubMed

Tamilselvan, Jayavelu; Sivarajan, Kumarasamy; Anusuyadevi, Muthuswamy; Panneerselvam, Chinnakkannu

2007-09-01

The release of mitochondrial cytochrome c followed by activation of caspase cascade has been reported with aging in various tissues, whereas little is known about the caspase-independent pathway involved in mitochondrial dysfunction. To determine the functional impact of cytochrome c loss on mitochondrial respiratory capacity, we monitored NADH redox transitions and oxygen consumption in isolated skeletal muscle mitochondria of 4- and 24-month-old rats in the presence and absence of exogenous cytochrome c; and assessed the efficacy of cosupplementation of carnitine and lipoic acid on age-related alteration in mitochondrial respiration. The loss of mitochondrial cytochrome c with age was accompanied with alteration in respiratory transition, which in turn was not rescued by exogenous addition of cytochrome c to isolated mitochondria. The analysis of mitochondrial and nuclear-encoded cytochrome c oxidase subunits suggests that the decreased levels of cytochrome c oxidase may be attributed for the irresponsiveness to exogenously added cytochrome c on mitochondrial respiratory transitions, possibly through reduction of upstream electron carriers. Oral supplementation of carnitine and lipoic acid to aged rats help to maintaining the mitochondrial oxidative capacity by regulating the release of cytochrome c and improves cytochrome c oxidase transcript levels. Thus, carnitine and lipoic acid supplementation prevents the loss of cytochrome c and their associated decline in cytochrome c oxidase activity; thereby, effectively attenuating any putative decrease in cellular energy and redox status with age.

The effects of Creatine Long-Term Supplementation on Muscle Morphology and Swimming Performance in Rats

PubMed Central

Yildiz, Ahmet; Ozdemir, Ercan; Gulturk, Sefa; Erdal, Sena

2009-01-01

Creatine (Cr) has been shown to increase the total muscle mass. The purpose of this study was to investigate the effect of Cr supplementation on muscle morphology and swimming performance, using an animal model. Each rat was subjected to exercise 15-minute period daily for the 12 weeks. The rats were randomly divided into four groups: no Cr supplementation (CON), no Cr supplementation and incomplete food intake (lacking lysine and methionine in diet for rats) (INCO), Cr supplementation 1 g·kg-1·day-1 (CREAT-I) and Cr supplementation 2 g·kg-1·day-1 (CREAT-II). Three months later, all groups adult rats exercised in swimming pool chambers. Swimming time was recorded as minute for each rat. Following swimming performance period, the animals were killed by cervical dislocation and the gastrocnemius and diaphragm muscles were dissected. Serial slices of 5-7 μm were allocated paraffin wax and histochemical staining procedure of cross-sections was carried out with heamatoxylin-eosin technics. All groups gained body weight at the end of 12 weeks but there was no statistical difference among them. Swimming time values were statistical difference between CREAT-II and CON group as well as between CREAT-I and CON group (p < 0.05). In the INCO group was determined increased connective tissue cell of the muscle sample. In contrast, in the CREAT-I and CREAT-II group, the basic histological changes were large-scale muscle fibers and hypertrophic muscle cells. These results suggest that long-term creatine supplementation increased the number of muscle fibers and enhanced endurance swimming performance in rats. Key points There is no study about the effects of creatine long-term supplementation on muscle morphology and swimming performance in rats. Long-term creatine supplementation increase muscle hypertrophy (but not body weight) and enhance endurance swimming performance in rats. The quantitative analysis indicated that the number of muscle fibers per defined area increased in creatine supplementation groups. PMID:24149591

Vagal Sensory Innervation of the Gastric Sling Muscle and Antral Wall: Implications for GERD?

PubMed Central

Powley, Terry L.; Gilbert, Jared M.; Baronowsky, Elizabeth A.; Billingsley, Cherie N.; Martin, Felecia N.; Phillips, Robert J.

2012-01-01

Background The gastric sling muscle has not been investigated for possible sensory innervation, in spite of the key roles the structure plays in lower esophageal sphincter (LES) function and gastric physiology. Thus, the present experiment used tracing techniques to label vagal afferents and survey their projections in the lesser curvature. Methods Sprague Dawley rats received injections of dextran biotin into the nodose ganglia. Fourteen days post-injection, animals were euthanized and their stomachs were processed to visualize the vagal afferent innervation. In different cases, neurons, muscle cells, or interstitial cells of Cajal were counterstained. Key Results The sling muscle is innervated throughout its length by vagal afferent intramuscular arrays (IMAs) associated with interstitial cells of Cajal. In addition, the distal antral attachment site of the sling muscle is innervated by a novel vagal afferent terminal specialization, an antral web ending. The muscle wall of the distal antrum is also innervated by conventional IMAs and intraganglionic laminar endings (IGLEs), the two types of mechanoreceptors found throughout stomach smooth muscle. Conclusions & Inferences The innervation of sling muscle by IMAs, putative stretch receptors, suggests that sling sensory feedback may generate vago-vagal or other reflexes with vagal afferent limbs. The restricted distribution of afferent web endings near the antral attachments of sling fibers suggests the possibility of specialized mechanoreceptor functions linking antral and pyloric activity to the operation of the LES. Dysfunctional sling afferents could generate LES motor disturbances, or normative compensatory sensory feedback from the muscle could compromise therapies targeting only effectors. PMID:22925069

Calorie restriction enhances insulin-stimulated glucose uptake and Akt phosphorylation in both fast-twitch and slow-twitch skeletal muscle of 24-month-old rats.

PubMed

Sequea, Donel A; Sharma, Naveen; Arias, Edward B; Cartee, Gregory D

2012-12-01

Calorie restriction (CR) induces enhanced insulin-stimulated glucose uptake in fast-twitch (type II) muscle from old rats, but the effect of CR on slow-twitch (type I) muscle from old rats is unknown. The purpose of this study was to assess insulin-stimulated glucose uptake and phosphorylation of key insulin signaling proteins in isolated epitrochlearis (fast-twitch) and soleus (slow-twitch) muscles from 24-month-old ad libitum fed and CR (consuming 65% of ad libitum, intake) rats. Muscles were incubated with and without 1.2 nM insulin. CR versus ad libitum rats had greater insulin-stimulated glucose uptake and Akt phosphorylation (pAkt) on T308 and S473 for both muscles incubated with insulin. GLUT4 protein abundance and phosphorylation of the insulin receptor (Y1162/1163) and AS160 (T642) were unaltered by CR in both muscles. These results implicate enhanced pAkt as a potential mechanism for the CR-induced increase in insulin-stimulated glucose uptake by the fast-twitch epitrochlearis and slow-twitch soleus of old rats.

Vagal Afferent Innervation of the Lower Esophageal Sphincter

PubMed Central

Powley, Terry L.; Baronowsky, Elizabeth A.; Gilbert, Jared M.; Hudson, Cherie N.; Martin, Felecia N.; Mason, Jacqueline K.; McAdams, Jennifer L.; Phillips, Robert J.

2013-01-01

To supply a fuller morphological characterization of the vagal afferents innervating the lower esophageal sphincter (LES), specifically to label vagal terminals in the tissues forming the LES in the gastroesophageal junction, the present experiment employed injections of dextran biotin into the nodose ganglia of rats. Four types of vagal afferents innervated the LES. Clasp and sling muscle fibers were directly and prominently innervated by intramuscular arrays (IMAs). Individual IMA terminals subtended about 16° of arc of the esophageal circumference, and, collectively, the terminal fields were distributed within the muscle ring to establish a 360° annulus of mechanoreceptors in the sphincter wall. 3D morphometry of the terminals established that, compared to sling muscle IMAs, clasp muscle IMAs had more extensive arbors and larger receptive fields. In addition, at the cardia, local myenteric ganglia between smooth muscle sheets and striated muscle bundles were innervated by intraganglionic laminar endings (IGLEs), in a pattern similar to the innervation of the myenteric plexus throughout the stomach and esophagus. Finally, as previously described, the principle bundle of sling muscle fibers that links LES sphincter tissue to the antropyloric region of the lesser curvature was innervated by exceptionally long IMAs as well as by unique web ending specializations at the distal attachment of the bundle. Overall, the specialized varieties of densely distributed vagal afferents innervating the LES underscore the conclusion that these sensory projections are critically involved in generating LES reflexes and may be promising targets for managing esophageal dysfunctions. PMID:23583280

Effect of seven days of spaceflight on hindlimb muscle protein, RNA and DNA in adult rats

NASA Technical Reports Server (NTRS)

Steffen, J. M.; Musacchia, X. J.

1985-01-01

Effects of seven days of spaceflight on skeletal muscle (soleus, gastrocnemius, EDL) content of protein, RNA and DNA were determined in adult rats. Whereas total protein contents were reduced in parallel with muscle weights, myofibrillar protein appeared to be more affected. There were no significant changes in absolute DNA contents, but a significant (P less than 0.05) increase in DNA concentration (microgram/milligram) in soleus muscles from flight rats. Absolute RNA contents were significantly (P less than 0.025) decreased in the soleus and gastrocnemius muscles of flight rats, with RNA concentrations reduced 15-30 percent. These results agree with previous ground-based observations on the suspended rat with unloaded hindlimbs and support continued use of this model.

[The effect of 18beta-glycyrrhetinic acid on gap junction among cerebral arteriolar smooth muscle cells in Wistar rat and spontaneously hypertensive rat].

PubMed

Chen, Xin-Yan; Si, Jun-Qiang; Li, Li; Zhao, Lei; Wei, Li-Li; Jiang, Xue-Wei; Ma, Ke-Tao

2013-05-01

This study compared Wistar rat with spontaneously hypertensive rat (SHR) on the electrophysiology and coupling force of the smooth muscle cells in the cerebral arteriolar segments and observe the influence of 18beta-glycyrrhetinic acid(18beta-GA) on the gap junctions between the arterial smooth muscle cells. The outer layer's connective tissue of the cerebral arteriolar segments was removed. Whole-cell patch clamp recordings were used to observe the 18beta-GA's impaction on the arteriolar segment membrane's input capacitance (C(input)), input conductance (G(input)) and input resistance (R(input)) of the smooth muscle cells. (1) The C(input) and G(input) of the SHR arteriolar segment smooth muscle cells was much higher than the Wistar rats, there was significant difference (P < 0.05). (2) 18beta-GA concentration-dependently reduced C(input) and G(input) (or increase R(input)) on smooth muscle cells in arteriolar segment. IC50 of 18beta-GA suppression's G(input) of the Wistar rat and SHR were 1.7 and 2.0 micromol/L respectively, there was not significant difference (P > 0.05). After application of 18beta-GA concentration > or = 100 micrmol/L, the C(input), G(input) and R(input) of the single smooth muscle cells was very close. Gap junctional coupling is enhanced in the SHR cerebral arterial smooth muscle cells. 18beta-GA concentration-dependent inhibits Wistar rat's and SHR cerebral arteriolar gap junctions between arterial smooth muscle cells. The inhibitory potency is similar between the two different rats. When 18beta-GA concentration is > or = 100 micromol/L, it can completely block gap junctions between arteriolar smooth muscle cells.

A grape polyphenol extract modulates muscle membrane fatty acid composition and lipid metabolism in high-fat--high-sucrose diet-fed rats.

PubMed

Aoun, Manar; Michel, Francoise; Fouret, Gilles; Schlernitzauer, Audrey; Ollendorff, Vincent; Wrutniak-Cabello, Chantal; Cristol, Jean-Paul; Carbonneau, Marie-Annette; Coudray, Charles; Feillet-Coudray, Christine

2011-08-01

Accumulation of muscle TAG content and modification of muscle phospholipid fatty acid pattern may have an impact on lipid metabolism, increasing the risk of developing diabetes. Some polyphenols have been reported to modulate lipid metabolism, in particular those issued from red grapes. The present study was designed to determine whether a grape polyphenol extract (PPE) modulates skeletal muscle TAG content and phospholipid fatty acid composition in high-fat-high-sucrose (HFHS) diet-fed rats. Muscle plasmalemmal and mitochondrial fatty acid transporters, GLUT4 and lipid metabolism pathways were also explored. The PPE decreased muscle TAG content in HFHS/PPE diet-fed rats compared with HFHS diet-fed rats and induced higher proportions of n-3 PUFA in phospholipids. The PPE significantly up-regulated GLUT4 mRNA expression. Gene and protein expression of muscle fatty acid transporter cluster of differentiation 36 (CD36) was increased in HFHS diet-fed rats but returned to control values in HFHS/PPE diet-fed rats. Carnitine palmitoyltransferase 1 protein expression was decreased with the PPE. Mitochondrial β-hydroxyacyl CoA dehydrogenase was increased in HFHS diet-fed rats and returned to control values with PPE supplementation. Lipogenesis, mitochondrial biogenesis and mitochondrial activity were not affected by the PPE. In conclusion, the PPE modulated membrane phospholipid fatty acid composition and decreased muscle TAG content in HFHS diet-fed rats. The PPE lowered CD36 gene and protein expression, probably decreasing fatty acid transport and lipid accumulation within skeletal muscle, and increased muscle GLUT4 expression. These effects of the PPE are in favour of a better insulin sensibility.

A novel mode-of-action mediated by the fetal muscle nicotinic acetylcholine receptor resulting in developmental toxicity in rats.

PubMed

Rasoulpour, Reza J; Ellis-Hutchings, Robert G; Terry, Claire; Millar, Neil S; Zablotny, Carol L; Gibb, Alasdair; Marshall, Valerie; Collins, Toby; Carney, Edward W; Billington, Richard

2012-06-01

Sulfoxaflor (X11422208), a novel agricultural molecule, induced fetal effects (forelimb flexure, hindlimb rotation, and bent clavicle) and neonatal death in rats at high doses (≥ 400 ppm in diet); however, no such effects occurred in rabbit dietary studies despite achieving similar maternal and fetal plasma exposure levels. Mode-of-action (MoA) studies were conducted to test the hypothesis that the effects in rats had a single MoA induced by sulfoxaflor agonism on the fetal rat muscle nicotinic acetylcholine receptor (nAChR). The studies included cross-fostering and critical windows of exposure studies in rats, fetal ((α1)(2)β1γδ) and adult ((α1)(2)β1δε) rat and human muscle nAChR in vitro agonism experiments, and neonatal rat phrenic nerve-hemidiaphragm contracture studies. The weight of evidence from these studies supported a novel MoA where sulfoxaflor is an agonist to the fetal, but not adult, rat muscle nAChR and that prolonged agonism on this receptor in fetal/neonatal rats causes sustained striated muscle contracture resulting in concomitant reduction in muscle responsiveness to physiological nerve stimulation. Fetal effects were inducible with as little as 1 day of exposure at the end of gestation, but were rapidly reversible after birth, consistent with a pharmacological MoA. With respect to human relevance, sulfoxaflor was shown to have no agonism on human fetal or adult muscle nAChRs. Taken together, the data support the hypothesis that the developmental effects of sulfoxaflor in rats are mediated via sustained agonism on the fetal muscle nAChR during late fetal development and are considered not relevant to humans.

Transgenic animal model for studying the mechanism of obesity-associated stress urinary incontinence.

PubMed

Wang, Lin; Lin, Guiting; Lee, Yung-Chin; Reed-Maldonado, Amanda B; Sanford, Melissa T; Wang, Guifang; Li, Huixi; Banie, Lia; Xin, Zhengcheng; Lue, Tom F

2017-02-01

To study and compare the function and structure of the urethral sphincter in female Zucker lean (ZL) and Zucker fatty (ZF) rats and to assess the viability of ZF fats as a model for female obesity-associated stress urinary incontinence (SUI). Two study arms were created: a ZL arm including 16-week-old female ZL rats (ZUC-Lepr fa 186; n = 12) and a ZF arm including 16-week-old female ZF rats (ZUC-Lepr fa 185; n = 12). I.p. insulin tolerance testing was carried out before functional study. Metabolic cages, conscious cystometry and leak point pressure (LPP) assessments were conducted. Urethral tissues were harvested for immunofluorescence staining to check intramyocellular lipid (IMCL) and sphincter muscle (smooth muscle and striated muscle) composition. The ZF rats had insulin resistance, a greater voiding frequency and lower LPP compared with ZL rats (P < 0.05), with more IMCL deposition localized in the urethral striated muscle fibres of the ZF rats (P < 0.05). The thickness of the striated muscle layer and the ratio of striated muscle to smooth muscle were lower in ZF than in ZL rats. Obesity impairs urethral sphincter function via IMCL deposition and leads to atrophy and distortion of urethral striated muscle. The ZF rats could be a consistent and reliable animal model in which to study obesity-associated SUI. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

Research on the traditional Chinese medicine treating gastrointestinal motility in diabetic rats by improving biomechanical remodeling and neuroendocrine regulation

PubMed Central

Tian, Jiaxing; Li, Min; Zhao, Jingbo; Li, Junling; Liu, Guifang; Zhen, Zhong; Cao, Yang; Gregersen, Hans; Tong, Xiaolin

2017-01-01

Previous studies have demonstrated that TWA, a Chinese herbal medicine, could significantly improve the symptoms of patients with diabetic gastrointestinal dysfunction. However, the specific mechanism of regulating intestinal peristalsis has not been found. This study aimed to discover TWA’s therapeutic mechanism for regulating intestinal motility. The intestinal propulsion rate of diabetic rats was significantly increased after treatment with TWA for 8 weeks. Aiming at the mechanical structure, biomechanical testing indicated that TWA can significantly decrease the no-load intestinal wall thickness, cross-sectional area, and angular spread in a zero-stress state. Notably, intestinal stress-strain curve shifted to the right, which indicated TWA can inhibit intestinal hyperplasia and hardening and improve biomechanical remodeling. Further study of the mechanism revealed that TWA significantly inhibited the expression of AGE in the villi, crypt, and muscle and RAGE in crypt and upregulated the expression of nerve regulator (PSD95, C-kit and SCF). Radioimmunoassay showed TWA treatment decreased levels of serum somatostatin and vasoactive intestinal peptide. Moreover, associations were found between the intestinal propulsion rate with the morphologic and biomechanical remodeling parameters, changes of nerve factors, and endocrine hormones. Morphologic and biomechanical remodeling of the intestinal wall are the pathologic basis of gastrointestinal dysfunction. TWA can benefit intestinal motility by improving biomechanical and morphologic remodeling and by regulating expression of neuroendocrine factors. The results showed that the effect of TWA was dose-dependent, the higher the dose, the greater is the improvement. Thus, traditional Chinese medicine might be a valuable tool for treating diabetic gastrointestinal dysfunction. PMID:28559973

Ergothioneine prevents endothelial dysfunction induced by mercury chloride.

PubMed

Gökçe, Göksel; Arun, Mehmet Zuhuri; Ertuna, Elif

2018-06-01

Exposure to mercury has detrimental effects on the cardiovascular system, particularly the vascular endothelium. The present study aimed to investigate the effects of ergothioneine (EGT) on endothelial dysfunction induced by low-dose mercury chloride (HgCl 2 ). Agonist-induced contractions and relaxations were evaluated in isolated aortic rings from 3-month-old male Wistar rats treated by intra-muscular injection to caudal hind leg muscle with HgCl 2 (first dose, 4.6 µg/kg; subsequent doses, 0.07 µg/kg/day for 15 days) and optionally with EGT (2 µg/kg for 30 days). Reactive oxygen species (ROS) in aortic rings were measured by means of lucigenin- and luminol-enhanced chemiluminescence. The protein level of endothelial nitric oxide synthase was evaluated by ELISA. Blood glutathione (GSH) and catalase levels, lipid peroxidation and total nitrite were measured spectrophotometrically. The results indicated that low-dose HgCl 2 administration impaired acetylcholine (ACh)-induced relaxation and potentiated phenylephrine- and serotonin-induced contractions in rat aortas. In addition, HgCl 2 significantly increased the levels of ROS in the aortic tissue. EGT prevented the loss of ACh-induced relaxations and the increase in contractile responses. These effects were accompanied by a significant decrease in ROS levels. EGT also improved the ratio of reduced GSH to oxidized GSH and catalase levels with a concomitant decrease in lipid peroxidation. In conclusion, to the best of our knowledge, the present study was the first to report that EGT prevents endothelial dysfunction induced by low-dose HgCl 2 administration. EGT may serve as a therapeutic tool to reduce mercury-associated cardiovascular complications via improving the antioxidant status.

Metabolic myopathies

NASA Technical Reports Server (NTRS)

Martin, A.; Haller, R. G.; Barohn, R.; Blomqvist, C. G. (Principal Investigator)

1994-01-01

Metabolic myopathies are disorders of muscle energy production that result in skeletal muscle dysfunction. Cardiac and systemic metabolic dysfunction may coexist. Symptoms are often intermittent and provoked by exercise or changes in supply of lipid and carbohydrate fuels. Specific disorders of lipid and carbohydrate metabolism in muscle are reviewed. Evaluation often requires provocative exercise testing. These tests may include ischemic forearm exercise, aerobic cycle exercise, and 31P magnetic resonance spectroscopy with exercise.

Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes.

PubMed

Shima, Takeru; Matsui, Takashi; Jesmin, Subrina; Okamoto, Masahiro; Soya, Mariko; Inoue, Koshiro; Liu, Yu-Fan; Torres-Aleman, Ignacio; McEwen, Bruce S; Soya, Hideaki

2017-03-01

Type 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by hippocampal glycometabolic dysfunction. If so, such dysfunction should also be ameliorated with moderate exercise by normalising hippocampal glycometabolism, since 4 weeks of moderate exercise enhances memory function and local hippocampal glycogen levels in normal animals. The hippocampal glycometabolism in OLETF rats (model of human type 2 diabetes) was assessed and, subsequently, the effects of exercise on memory function and hippocampal glycometabolism were investigated. OLETF rats, which have memory dysfunction, exhibited higher levels of glycogen in the hippocampus than did control rats, and breakdown of hippocampal glycogen with a single bout of exercise remained unimpaired. However, OLETF rats expressed lower levels of hippocampal monocarboxylate transporter 2 (MCT2, a transporter for lactate to neurons). Four weeks of moderate exercise improved spatial memory accompanied by further increase in hippocampal glycogen levels and restoration of MCT2 expression independent of neurotrophic factor and clinical symptoms in OLETF rats. Our findings are the first to describe detailed profiles of glycometabolism in the type 2 diabetic hippocampus and to show that 4 weeks of moderate exercise improves memory dysfunction in type 2 diabetes via amelioration of dysregulated hippocampal glycometabolism. Dysregulated hippocampal lactate-transport-related glycometabolism is a possible aetiology of type-2-diabetes-mediated memory dysfunction.

Emblic Leafflower (Phyllanthus emblica L.) Fruits Ameliorate Vascular Smooth Muscle Cell Dysfunction in Hyperglycemia: An Underlying Mechanism Involved in Ellagitannin Metabolite Urolithin A

PubMed Central

Zhou, Junxuan; Zhang, Cong

2018-01-01

Ellagitannins in Phyllanthus emblica L. (emblic leafflower fruits) have been thought of as the beneficial constituents for ameliorating endocrinal and metabolic diseases including diabetes. However, the effect of emblic leafflower fruits on diabetic vascular complications involved in ellagitannin-derived urolithin metabolites is still rare. In this study, acetylcholine-induced endothelium-independent relaxation in aortas was facilitated upon emblic leafflower fruit consumption in the single dose streptozotocin-induced hyperglycemic rats. Emblic leafflower fruit consumption also suppressed the phosphorylation of Akt (Thr308) in the hyperglycemic aortas. More importantly, urolithin A (UroA) and its derived phase II metabolites were identified as the metabolites upon emblic leafflower fruit consumption by HPLC-ESI-Q-TOF-MS. Moreover, UroA reduced the protein expressions of phosphor-Akt (Thr308) and β-catenin in a high glucose-induced A7r5 vascular smooth muscle cell proliferation model. Furthermore, accumulation of β-catenin protein and activation of Wnt signaling in LiCl-triggered A7r5 cells were also ameliorated by UroA treatment. In conclusion, our data demonstrate that emblic leafflower fruit consumption facilitates the vascular function in hyperglycemic rats by regulating Akt/β-catenin signaling, and the effects are potentially mediated by the ellagitannin metabolite urolithin A. PMID:29692859

Contribution of cytochrome P450 1B1 to hypertension and associated pathophysiology: a novel target for antihypertensive agents.

PubMed

Malik, Kafait U; Jennings, Brett L; Yaghini, Fariborz A; Sahan-Firat, Seyhan; Song, Chi Young; Estes, Anne M; Fang, Xiao R

2012-08-01

The aim of this review is to discuss the contribution of cytochrome P450 (CYP) 1B1 in vascular smooth muscle cell growth, hypertension, and associated pathophysiology. CYP1B1 is expressed in cardiovascular and renal tissues, and mediates angiotensin II (Ang II)-induced activation of NADPH oxidase and generation of reactive oxygen species (ROS), and vascular smooth muscle cell migration, proliferation, and hypertrophy. Moreover, CYP1B1 contributes to the development and/or maintenance of hypertension produced by Ang II-, deoxycorticosterone (DOCA)-salt-, and N(ω)-nitro-L-arginine methyl ester-induced hypertension and in spontaneously hypertensive rats. The pathophysiological changes, including cardiovascular hypertrophy, increased vascular reactivity, endothelial and renal dysfunction, injury and inflammation associated with Ang II- and/or DOCA-salt induced hypertension in rats, and Ang II-induced hypertension in mice are minimized by inhibition of CYP1B1 activity with 2,4,3',5'-tetramethoxystilbene or by Cyp1b1 gene disruption in mice. These pathophysiological changes appear to be mediated by increased production of ROS via CYP1B1-dependent NADPH oxidase activity and extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src. Copyright © 2011 Elsevier Inc. All rights reserved.

Contribution of Cytochrome P450 1B1 to Hypertension and Associated Pathophysiology: A Novel Target for Antihypertensive Agents

PubMed Central

Malik, Kafait U.; Jennings, Brett L.; Yaghini, Fariborz A.; Sahan-Firat, Seyhan; Song, Chi Young; Estes, Anne M.; Fang, Xiao R.

2012-01-01

The aim of this review is to discuss the contribution of cytochrome P450 (CYP) 1B1 in vascular smooth muscle cell growth, hypertension, and associated pathophysiology. CYP1B1 is expressed in cardiovascular and renal tissues, and mediates angiotensin II (Ang II)-induced activation of NADPH oxidase and generation of reactive oxygen species (ROS), and vascular smooth muscle cell migration, proliferation, and hypertrophy. Moreover, CYP1B1 contributes to the development and/or maintenance of hypertension produced by Ang II-, deoxycorticosterone Nω-nitro-(DOCA)-salt-, and L-arginine methyl ester-induced hypertension and in spontaneously hypertensive rats. The pathophysiological changes, including cardiovascular hypertrophy, increased vascular reactivity, endothelial and renal dysfunction, injury and inflammation associated with Ang II- and/or DOCA-salt induced hypertension in rats, and Ang II-induced hypertension in mice are minimized by inhibition of CYP1B1 activity with 2,4,3′,5′-tetramethoxystilbene or by Cyp1b1 gene disruption in mice. These pathophysiological changes appear to be mediated by increased production of ROS via CYP1B1-dependent NADPH oxidase activity and extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src. PMID:22210049

Chlorogenic acid inhibits hypoxia-induced pulmonary artery smooth muscle cells proliferation via c-Src and Shc/Grb2/ERK2 signaling pathway.

PubMed

Li, Qun-Yi; Zhu, Ying-Feng; Zhang, Meng; Chen, Li; Zhang, Zhen; Du, Yong-Li; Ren, Guo-Qiang; Tang, Jian-Min; Zhong, Ming-Kang; Shi, Xiao-Jin

2015-03-15

Chlorogenic acid (CGA), abundant in coffee and particular fruits, can modulate hypertension and vascular dysfunction. Hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation has been tightly linked to vascular remodeling in pulmonary arterial hypertension (PAH). Thus, the present study was designed to investigate the effect of CGA on hypoxia-induced proliferation in cultured rat PASMCs. The data showed that CGA potently inhibited PASMCs proliferation and DNA synthesis induced by hypoxia. These inhibitory effects were associated with G1 cell cycle arrest and down-regulation of cell cycle proteins. Treatment with CGA reduced hypoxia-induced hypoxia inducible factor 1α (HIF-1α) expression and trans-activation. Furthermore, hypoxia-evoked c-Src phosphorylation was inhibited by CGA. In vitro ELISA-based tyrosine kinase assay indicated that CGA was a direct inhibitor of c-Src. Moreover, CGA attenuated physical co-association of c-Src/Shc/Grb2 and ERK2 phosphorylation in PASMCs. These results suggest that CGA inhibits hypoxia-induced proliferation in PASMCs via regulating c-Src-mediated signaling pathway. In vivo investigation showed that chronic CGA treatment inhibits monocrotaline-induced PAH in rats. These findings presented here highlight the possible therapeutic use of CGA in hypoxia-related PAH. Copyright © 2015 Elsevier B.V. All rights reserved.

Synthesis of amino acids in weight bearing and non-weight bearing leg muscles of suspended rats

NASA Technical Reports Server (NTRS)

Tischler, M. E.; Jaspers, S. R.

1982-01-01

The effect of hypokinesia (HYP) for 6 days on the de novo synthesis of glutamine (GLN) and glutamate (GLU), and of alanine was tested in isolated leg muscles of intact, adrenalectomized (ADX) and ADX cortisol-treated rats. The net synthesis of GLN and GLU was lower in soleus muscles of HYP animals of these three groups of rats. The synthesis of alanine was lowered by HYP in ADX animals and apparently raised by HYP in ADX cortisol-treated rats. No HYP effect was seen in the extensor digitorum longus (EDL) muscles of these animals. Although ADX lowered the synthesis of GLN and GLU in soleus muscles of control rats, while cortisol treatment restored this process to near normal, neither ADX nor cortisol treatment produced any effect in the HYP animals. However, effects of ADX and cortisol treatment on synthesis of GLN and GLU in EDL muscles and of alanine in both muscles seemed normal in HYP animals.

Overexpression of protein kinase C ɛ improves retention and survival of transplanted mesenchymal stem cells in rat acute myocardial infarction.

PubMed

He, H; Zhao, Z-H; Han, F-S; Liu, X-H; Wang, R; Zeng, Y-J

2016-01-21

We assessed the effects of protein kinase C ɛ (PKCɛ) for improving stem cell therapy for acute myocardial infarction (AMI). Primary mesenchymal stem cells (MSCs) were harvested from rat bone marrow. PKCɛ-overexpressed MSCs and control MSCs were transplanted into infarct border zones in a rat AMI model. MSCs and PKCɛ distribution and expression of principal proteins involved in PKCɛ signaling through the stromal cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4) axis and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway were analyzed by immunofluorescence and western blot 1 day after transplantation. Echocardiographic measurements and histologic studies were performed at 4 weeks after transplantation, and MSC survival, expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor β (TGFβ), cardiac troponin I (cTnI), von Willebrand factor (vWF), smooth muscle actin (SMA) and factor VIII and apoptosis in infarct border zones were assessed. Rat heart muscles retained more MSCs and SDF-1, CXCR4, PI3K and phosphorylated AKT increased with PKCɛ overexpression 1 day after transplantation. MSC survival and VEGF, bFGF, TGFβ, cTnI, vWF, SMA and factor VIII expression increased in animals with PKCɛ-overexpressed MSCs at 4 weeks after transplantation and cardiac dysfunction and remodeling improved. Infarct size and apoptosis decreased as well. Inhibitory actions of CXCR4 or PI3K partly attenuated the effects of PKCɛ. Activation of PKCɛ may improve retention, survival and differentiation of transplanted MSCs in myocardia. Augmentation of PKCɛ expression may enhance the therapeutic effects of stem cell therapy for AMI.

Adaptive and regulatory mechanisms in aged rats with postoperative cognitive dysfunction

PubMed Central

Bi, Yanlin; Liu, Shuyun; Yu, Xinjuan; Wang, Mingshan; Wang, Yuelan

2014-01-01

Inflammation may play a role in postoperative cognitive dysfunction. 5′ Adenosine monophosphate-activated protein kinase, nuclear factor-kappa B, interleukin-1β, and tumor necrosis factor-α are involved in inflammation. Therefore, these inflammatory mediators may be involved in postoperative cognitive dysfunction. Western immunoblot analysis revealed 5′ adenosine monophosphate-activated protein kinase and nuclear factor-kappa B in the hippocampus of aged rats were increased 1–7 days after splenectomy. Moreover, interleukin-1β and tumor necrosis factor-α were upregulated and gradually decreased. Therefore, these inflammatory mediators may participate in the splenectomy model of postoperative cognitive dysfunction in aged rats. PMID:25206851

Curcumin attenuates skeletal muscle mitochondrial impairment in COPD rats: PGC-1α/SIRT3 pathway involved.

PubMed

Zhang, Ming; Tang, Jingjing; Li, Yali; Xie, Yingying; Shan, Hu; Chen, Mingxia; Zhang, Jie; Yang, Xia; Zhang, Qiuhong; Yang, Xudong

2017-11-01

Curcumin has been widely used to treat numerous diseases due to its antioxidant property. The aim of the present study is to investigate the effect of curcumin on skeletal muscle mitochondria in chronic obstructive pulmonary disease (COPD) and its underlying mechanism. The rat model of COPD was established by cigarette smoke exposure combined with intratracheal administration of lipopolysaccharide. Airway inflammation and emphysema were notably ameliorated by the treatment with curcumin. Oral administration of curcumin significantly improved muscle fiber atrophy, myofibril disorganization, interstitial fibrosis and mitochondrial structure damage in the skeletal muscle of COPD rats. Mitochondrial enzyme activities of cytochrome c oxidase, succinate dehydrogenase, Na + /K + -ATPase and Ca 2+ -ATPase in skeletal muscle mitochondria from COPD rats were significantly increased after treatment with curcumin. Moreover, curcumin significantly decreased oxidative stress and inflammation by determining the levels of malondialdehyde, manganese superoxide dismutase, glutathione peroxidase, catalase, IL-6 and TNF-α in skeletal muscle of COPD rats. Furthermore, curcumin significantly increased the mRNA and protein expression of PGC-1α and SIRT3 in the skeletal muscle tissues of COPD rats. These results suggested that curcumin can attenuate skeletal muscle mitochondrial impairment in COPD rats possibly by the up-regulation of PGC-1α/SIRT3 signaling pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

Amalaki rasayana, a traditional Indian drug enhances cardiac mitochondrial and contractile functions and improves cardiac function in rats with hypertrophy.

PubMed

Kumar, Vikas; Aneesh, Kumar A; Kshemada, K; Ajith, Kumar G S; Binil, Raj S S; Deora, Neha; Sanjay, G; Jaleel, A; Muraleedharan, T S; Anandan, E M; Mony, R S; Valiathan, M S; Santhosh, Kumar T R; Kartha, C C

2017-08-17

We evaluated the cardioprotective effect of Amalaki Rasayana (AR), a rejuvenating Ayurvedic drug prepared from Phyllanthus emblica fruits in the reversal of remodeling changes in pressure overload left ventricular cardiac hypertrophy (LVH) and age-associated cardiac dysfunction in male Wistar rats. Six groups (aging groups) of 3 months old animals were given either AR or ghee and honey (GH) orally; seventh group was untreated. Ascending aorta was constricted using titanium clips in 3 months old rats (N = 24; AC groups) and after 6 months, AR or GH was given for further 12 months to two groups; one group was untreated. Histology, gene and protein expression analysis were done in heart tissues. Chemical composition of AR was analyzed by HPLC, HPTLC and LC-MS. AR intake improved (P < 0.05) cardiac function in aging rats and decreased LVH (P < 0.05) in AC rats as well as increased (P < 0.05) fatigue time in treadmill exercise in both groups. In heart tissues of AR administered rats of both the groups, SERCA2, CaM, Myh11, antioxidant, autophagy, oxidative phosphorylation and TCA cycle proteins were up regulated. ADRB1/2 and pCREB expression were increased; pAMPK, NF-kB were decreased. AR has thus a beneficial effect on myocardial energetics, muscle contractile function and exercise tolerance capacity.

Evaluation of the Effect of Different Doses of Low Energy Shock Wave Therapy on the Erectile Function of Streptozotocin (STZ)-Induced Diabetic Rats

PubMed Central

Liu, Jing; Zhou, Feng; Li, Guang-Yong; Wang, Lin; Li, Hui-Xi; Bai, Guang-Yi; Guan, Rui-Li; Xu, Yong-De; Gao, Ze-Zhu; Tian, Wen-Jie; Xin, Zhong-Cheng

2013-01-01

To investigate the therapeutic effect of different doses of low energy shock wave therapy (LESWT) on the erectile dysfunction (ED) in streptozotocin (STZ) induced diabetic rats. SD rats (n = 75) were randomly divided into 5 groups (normal control, diabetic control, 3 different dose LESWT treated diabetic groups). Diabetic rats were induced by intra-peritoneal injection of STZ (60 mg/kg) and rats with fasting blood glucose ≥ 300 mg/dL were selected as diabetic models. Twelve weeks later, different doses of LESWT (100, 200 and 300 shocks each time) treatment on penises were used to treat ED (7.33 MPa, 2 shocks/s) three times a week for two weeks. The erectile function was evaluated by intracavernous pressure (ICP) after 1 week washout period. Then the penises were harvested for histological study. The results showed LESWT could significantly improve the erectile function of diabetic rats, increase smooth muscle and endothelial contents, up-regulate the expression of α-SMA, vWF, nNOS and VEGF, and down- regulate the expression of RAGE in corpus cavernosum. The therapeutic effect might relate to treatment dose positively, and the maximal therapeutic effect was noted in the LESWT300 group. Consequently, 300 shocks each time might be the ideal LESWT dose for diabetic ED treatment. PMID:23698784

Evaluation of the effect of different doses of low energy shock wave therapy on the erectile function of streptozotocin (STZ)-induced diabetic rats.

PubMed

Liu, Jing; Zhou, Feng; Li, Guang-Yong; Wang, Lin; Li, Hui-Xi; Bai, Guang-Yi; Guan, Rui-Li; Xu, Yong-De; Gao, Ze-Zhu; Tian, Wen-Jie; Xin, Zhong-Cheng

2013-05-21

To investigate the therapeutic effect of different doses of low energy shock wave therapy (LESWT) on the erectile dysfunction (ED) in streptozotocin (STZ) induced diabetic rats. SD rats (n = 75) were randomly divided into 5 groups (normal control, diabetic control, 3 different dose LESWT treated diabetic groups). Diabetic rats were induced by intra-peritoneal injection of STZ (60 mg/kg) and rats with fasting blood glucose ≥ 300 mg/dL were selected as diabetic models. Twelve weeks later, different doses of LESWT (100, 200 and 300 shocks each time) treatment on penises were used to treat ED (7.33 MPa, 2 shocks/s) three times a week for two weeks. The erectile function was evaluated by intracavernous pressure (ICP) after 1 week washout period. Then the penises were harvested for histological study. The results showed LESWT could significantly improve the erectile function of diabetic rats, increase smooth muscle and endothelial contents, up-regulate the expression of α-SMA, vWF, nNOS and VEGF, and down- regulate the expression of RAGE in corpus cavernosum. The therapeutic effect might relate to treatment dose positively, and the maximal therapeutic effect was noted in the LESWT300 group. Consequently, 300 shocks each time might be the ideal LESWT dose for diabetic ED treatment.

Effects of OXPHOS complex deficiencies and ESA dysfunction in working intact skeletal muscle: implications for mitochondrial myopathies.

PubMed

Korzeniewski, Bernard

2015-10-01

The effects of inborn oxidative phosphorylation (OXPHOS) complex deficiencies or possible each-step activation (ESA) dysfunction on the bioenergetic system in working intact skeletal muscle are studied using a computer model of OXPHOS published previously. The curves representing the dependencies of V˙O2 and metabolite concentrations on single complex activity, entire OXPHOS activity or ESA intensity exhibit a characteristic threshold at some OXPHOS complex activity/ESA intensity. This threshold for V˙O2 of single complex activities is significantly lower in intact muscle during moderate and heavy work, than in isolated mitochondria in state 3. Metabolite concentrations and pH in working muscle start to change significantly at much higher OXPHOS complex activities/ESA intensities than V˙O2. The effect of entire OXPHOS deficiency or ESA dysfunction is potentially much stronger than the effect of a single complex deficiency. Implications of these findings for the genesis of mitochondrial myopathies are discussed. It is concluded that V˙O2 in state 3 and its dependence on complex activity in isolated mitochondria is not a universal quantitative determinant of the effect of mitochondrial dysfunctions in vivo. Moderate and severe mitochondria dysfunctions are defined: the former affect significantly only metabolite concentrations and pH, while the latter also decrease significantly V˙O2 in intact skeletal muscle during work. The dysfunction-caused decrease in V˙O2/oxidative ATP synthesis flux, disturbance of metabolite homeostasis, elevated ROS production and anaerobic glycolysis recruitment can account for such mitochondrial myopathy symptoms as muscle weakness, exercise intolerance (exertional fatigue) and lactic acidosis. Copyright © 2015 Elsevier B.V. All rights reserved.

Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Xiao, Wen Hua; Bennett, Gary J; Padi, Satyanarayana S V; Zhang, Ji; Coderre, Terence J

2013-01-01

Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Aldosterone Contributes to Sympathoexcitation in Renovascular Hypertension.

PubMed

Lincevicius, Gisele S; Shimoura, Caroline G; Nishi, Erika E; Perry, Juliana C; Casarini, Dulce E; Gomes, Guiomar N; Bergamaschi, Cássia T; Campos, Ruy R

2015-09-01

Although angiotensin II (Ang II) is essential to the development of renovascular hypertension, aldosterone plays a role as well. Recent studies have demonstrated a cross-talk between Ang II type 1 and mineralocorticoid receptors in the brain and kidneys. However, the role of aldosterone in the autonomic and renal dysfunction of renovascular hypertension is not well understood. The current study evaluated whether aldosterone contributes to cardiovascular and renal dysfunction in the 2 kidney-1 clip (2K1C) model. Mean arterial pressure (MAP) and baroreceptor reflex for control of the heart rate were evaluated in 2K1C treated or not treated with spironolactone (200mg/kg/day, 7 days). Tonic and reflex control of renal sympathetic nerve activity (rSNA) were assessed in urethane-anaesthetized rats. Plasma renin activity (PRA), kidney renin protein expression, renal injury, and central AT1 receptor protein expression were assessed. Spiro reduced MAP (198±4 vs. 170±9mm Hg; P < 0.05), normalized rSNA (147±9 vs. 96±10 pps; P < 0.05), and increased renal baroreceptor reflex sensitivity in the 2K1C rats. Spiro reduced α-smooth muscle actin expression in the nonclipped kidney in the 2K1C group (5±0.6 vs. 1.1±0.2%; P < 0.05). There was no change in PRA; however, a decrease in renin protein expression in the nonclipped kidney was found in the 2K1C treated group (217±30 vs. 160±19%; P < 0.05). Spiro treatment decreased AT1 receptor in the central nervous system (CNS) only in 2K1C rats (138±10 vs. 84±12%; P < 0.05). Aldosterone contributes to autonomic dysfunction and intrarenal injury in 2K1C, these effects are mediated by the CNS. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Effects of Exercise on Pharmacokinetics and Pharmacodynamics of Physostigmine in Rats

DTIC Science & Technology

1991-02-15

combination of the two, regulate the biosynthetic and degradative enzymes of ACh in EDL (extensor digitorum longus) - fast muscle and soleus - slow muscle...and trained exercise on ChAT activities in fast and slow muscles of rat 100 17. Effect of subacute Phy (70 4g/kg, i.m.) and endurance training on...AChE activities in EDL and soleus muscles of rat 100 18. ChAT and AChE activities (% of control) in fast (EDL) and slow (soleus) muscle in subacute Phy

Cerium oxide nanozyme modulate the ‘exercise’ redox biology of skeletal muscle

NASA Astrophysics Data System (ADS)

Arya, Aditya; Sethy, Niroj Kumar; Gangwar, Anamika; Bhargava, Neelima; Dubey, Amarish; Roy, Manas; Srivastava, Gaurav; Singh, Sushil Kumar; Das, Mainak; Bhargava, Kalpana

2017-05-01

‘Exercise’ is a double-edged sword for the skeletal muscle. Small amount of ROS generated during mild exercise, is essential for normal force generation; whereas large quantity of ROS generated during intense exercise, may cause contractile dysfunction, resulting in muscle weakness and fatigue. One of the key question in skeletal muscle physiology is ‘could antioxidant therapy improve the skeletal muscle endurance? A question, which has resulted in contradictory experimental findings till this date. This work has addressed this ‘very question’ using a synthetic, inorganic, antioxidant nano-material viz., ‘cerium oxide nanozyme’ (CON). It has been introduced in the rat by intramuscular injection, and the skeletal muscle endurance has been evaluated. Intramuscular injections of CON, concurrent with exercise, enhanced muscle mass, glycogen and ATP content, type I fiber ratio, thus resulting in significantly higher muscle endurance. Electron microscope studies confirmed the presence of CON in the vicinity of muscle mitochondria. There was an increase in the number and size of the muscle mitochondria in the CON treated muscle, following exercise, as compared to the untreated group with only exercised muscle. Quantitative proteomics data and subsequent biological network analysis studies, identified higher levels of oxidative phosphorylation, TCA cycle output and glycolysis in CON supplemented exercised muscle over only exercised muscle. This was further associated with significant increase in the mitochondrial respiratory capacity and muscle contraction, primarily due to higher levels of electron transport chain proteins like NDUFA9, SDHA, ATP5B and ATP5D, which were validated by real-time PCR and western blotting. Along with this, persistence of CON in muscle was evaluated with ICP-MS analysis, which revealed clearance of the particles after 90 d, without exhibiting any inflammation or adverse affects on the health of the experimental animals. Thus a higher physiological endurance of the CON supplemented exercised muscle’ opens new avenues in skeletal muscle therapeutic, space and sports medicine.

Smooth muscle‐generated methylglyoxal impairs endothelial cell‐mediated vasodilatation of cerebral microvessels in type 1 diabetic rats

PubMed Central

Alomar, Fadhel; Singh, Jaipaul; Jang, Hee‐Seong; Rozanzki, George J; Shao, Chun Hong; Padanilam, Babu J; Mayhan, William G

2016-01-01

Background and Purpose Endothelial cell‐mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia‐reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined. This study tests the hypothesis that cECs dysregulation in T1D is triggered by increased generation of the mitochondrial toxin, methylglyoxal, by smooth muscle cells in cerebral arterioles (cSMCs). Experimental Approach Endothelial cell‐mediated vasodilatation, vascular transcytosis inflammation, hypoxia and ischaemia‐reperfusion injury were assessed in brains of male Sprague‐Dawley rats with streptozotocin‐induced diabetes and compared with those in diabetic rats with increased expression of methylglyoxal‐degrading enzyme glyoxalase‐I (Glo‐I) in cSMCs. Key Results After 7–8 weeks of T1D, endothelial cell‐mediated vasodilatation of cerebral arterioles was impaired. Microvascular leakage, gliosis, macrophage/neutrophil infiltration, NF‐κB activity and TNF‐α levels were increased, and density of perfused microvessels was reduced. Transient occlusion of a mid‐cerebral artery exacerbated ischaemia‐reperfusion injury. In cSMCs, Glo‐I protein was decreased, and the methylglyoxal‐synthesizing enzyme, vascular adhesion protein 1 (VAP‐1) and methylglyoxal were increased. Restoring Glo‐I protein in cSMCs of diabetic rats to control levels via gene transfer, blunted VAP‐1 and methylglyoxal increases, cECs dysfunction, microvascular leakage, inflammation, ischaemia‐reperfusion injury and increased microvessel perfusion. Conclusions and Implications Methylglyoxal generated by cSMCs induced cECs dysfunction, inflammation, hypoxia and exaggerated ischaemia‐reperfusion injury in diabetic rats. Lowering methylglyoxal produced by cSMCs may be a viable therapeutic strategy to preserve cECs function and blunt deleterious downstream consequences in T1D. PMID:27611446

5-aminoisoquinoline improves renal function and fibrosis during recovery phase of cisplatin-induced acute kidney injury in rats.

PubMed

Quesada, Andrés; O'Valle, Francisco; Montoro-Molina, Sebastián; Gómez-Morales, Mercedes; Caba-Molina, Mercedes; González, Juan Francisco; de Gracia, María C; Osuna, Antonio; Vargas, Félix; Wangensteen, Rosemary

2018-04-27

The aim of the present study is to analyze the effects of 5-aminoisoquinoline (5-AIQ), a poly(ADP-ribose) polymerase-1 (PARP1) inhibitor, over renal dysfunction and fibrosis during recovery phase of cisplatin (CisPt)-induced acute kidney injury (AKI) in rats. Male Wistar rats were distributed in three groups ( n =8 each group): control, CisPt, and CisPt + 5-AIQ. Control and CisPt groups received a subcutaneous injection of either saline or 7 mg/kg CisPt, respectively. CisPt + 5-AIQ group received two intraperitoneal injections of 10 mg/kg 5-AIQ 2 h before and 24 h after CisPt treatment. Thirteen days after the treatment, rats were housed in metabolic cages and 24-h urine collection was made. At day 14, CisPt-treated rats showed increased diuresis, N-acetyl-β-d-glucosaminidase (NAG) excretion, glucosuria and sodium fractional excretion (NaFE), and decreased creatinine clearance (CrCl). 5-AIQ significantly increased CrCl and decreased NAG excretion, glucosuria, and NaFE. In plasma, CisPt increased sodium, urea, and creatinine concentrations, while 5-AIQ treatment decreased these variables to the levels of control group. 5-AIQ completely prevented the body weight loss evoked by CisPt treatment. CisPt also induced an increased renal expression of PAR polymer, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and collagen-IV. These variables were decreased in CisPt + 5-AIQ group. Tubular lesions and renal fibrosis were also decreased by 5-AIQ treatment. We conclude that inhibition of PARP1 with 5-AIQ can attenuate long-term nephrotoxic effects associated with the CisPt treatment, preventing renal dysfunction and body weight decrease and ameliorating tubular lesions and collagen deposition. © 2018 The Author(s).

5-aminoisoquinoline improves renal function and fibrosis during recovery phase of cisplatin-induced acute kidney injury in rats

PubMed Central

Quesada, Andrés; O’Valle, Francisco; Montoro-Molina, Sebastián; Gómez-Morales, Mercedes; Caba-Molina, Mercedes; González, Juan Francisco; de Gracia, María C.; Osuna, Antonio; Vargas, Félix; Wangensteen, Rosemary

2018-01-01

The aim of the present study is to analyze the effects of 5-aminoisoquinoline (5-AIQ), a poly(ADP-ribose) polymerase-1 (PARP1) inhibitor, over renal dysfunction and fibrosis during recovery phase of cisplatin (CisPt)-induced acute kidney injury (AKI) in rats. Male Wistar rats were distributed in three groups (n=8 each group): control, CisPt, and CisPt + 5-AIQ. Control and CisPt groups received a subcutaneous injection of either saline or 7 mg/kg CisPt, respectively. CisPt + 5-AIQ group received two intraperitoneal injections of 10 mg/kg 5-AIQ 2 h before and 24 h after CisPt treatment. Thirteen days after the treatment, rats were housed in metabolic cages and 24-h urine collection was made. At day 14, CisPt-treated rats showed increased diuresis, N-acetyl-β-d-glucosaminidase (NAG) excretion, glucosuria and sodium fractional excretion (NaFE), and decreased creatinine clearance (CrCl). 5-AIQ significantly increased CrCl and decreased NAG excretion, glucosuria, and NaFE. In plasma, CisPt increased sodium, urea, and creatinine concentrations, while 5-AIQ treatment decreased these variables to the levels of control group. 5-AIQ completely prevented the body weight loss evoked by CisPt treatment. CisPt also induced an increased renal expression of PAR polymer, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and collagen-IV. These variables were decreased in CisPt + 5-AIQ group. Tubular lesions and renal fibrosis were also decreased by 5-AIQ treatment. We conclude that inhibition of PARP1 with 5-AIQ can attenuate long-term nephrotoxic effects associated with the CisPt treatment, preventing renal dysfunction and body weight decrease and ameliorating tubular lesions and collagen deposition. PMID:29599129

Electrophysiological, histochemical, and hormonal adaptation of rat muscle after prolonged hindlimb suspension

NASA Astrophysics Data System (ADS)

Kourtidou-Papadeli, Chrysoula; Kyparos, Antonios; Albani, Maria; Frossinis, Athanasios; Papadelis, Christos L.; Bamidis, Panagiotis; Vivas, Ana; Guiba-Tziampiri, Olympia

2004-05-01

The perspective of long-duration flights for future exploration, imply more research in the field of human adaptation. Previous studies in rat muscles hindlimb suspension (HLS), indicated muscle atrophy and a change of fibre composition from slow-to-fast twitch types. However, the contractile responses to long-term unloading is still unclear. Fifteen adult Wistar rats were studied in 45 and 70 days of muscle unweighting and soleus (SOL) muscle as well as extensor digitorum longus (EDL) were prepared for electrophysiological recordings (single, twitch, tetanic contraction and fatigue) and histochemical stainings. The loss of muscle mass observed was greater in the soleus muscle. The analysis of electrophysiological properties of both EDL and SOL showed significant main effects of group, of number of unweighting days and fatigue properties. Single contraction for soleus muscle remained unchanged but there was statistically significant difference for tetanic contraction and fatigue. Fatigue index showed a decrease for the control rats, but increase for the HLS rats. According to the histochemical findings there was a shift from oxidative to glycolytic metabolism during HLS. The data suggested that muscles atrophied, but they presented an adaptation pattern, while their endurance in fatigue was decreased.

Beta 2-agonist fenoterol has greater effects on contractile function of rat skeletal muscles than clenbuterol.

PubMed

Ryall, James G; Gregorevic, Paul; Plant, David R; Sillence, Martin N; Lynch, Gordon S

2002-12-01

Potential treatments for skeletal muscle wasting and weakness ideally possess both anabolic and ergogenic properties. Although the beta(2)-adrenoceptor agonist clenbuterol has well-characterized effects on skeletal muscle, less is known about the therapeutic potential of the related beta(2)-adrenoceptor agonist fenoterol. We administered an equimolar dose of either clenbuterol or fenoterol to rats for 4 wk to compare their effects on skeletal muscle and tested the hypothesis that fenoterol would produce more powerful anabolic and ergogenic effects. Clenbuterol treatment increased fiber cross-sectional area (CSA) by 6% and maximal isometric force (P(o)) by 20% in extensor digitorum longus (EDL) muscles, whereas fiber CSA in soleus muscles decreased by 3% and P(o) was unchanged, compared with untreated controls. In the EDL muscles, fenoterol treatment increased fiber CSA by 20% and increased P(o) by 12% above values achieved after clenbuterol treatment. Soleus muscles of fenoterol-treated rats exhibited a 13% increase in fiber CSA and a 17% increase in P(o) above that of clenbuterol-treated rats. These data indicate that fenoterol has greater effects on the functional properties of rat skeletal muscles than clenbuterol.

Fatigue and contraction of slow and fast muscles in hypokinetic/hypodynamic rats

NASA Technical Reports Server (NTRS)

Fell, R. D.; Gladden, L. B.; Steffen, J. M.; Musacchia, X. J.

1985-01-01

The effects of hypokinesia/hypodynamia (H/H) on the fatigability and contractile properties of the rat soleus (S) and gastrocnemius (G) muscles have been investigated experimentally. Whole body suspension for one week was used to induce H/H, and fatigue was brought on by train stimulation for periods of 45 and 16 minutes. Following stimulation, rapid rates of fatigue were observed in the G-muscles of the suspended rats, while minimal fatigue was observed in the S-muscles. The twitch and tetanic contractile properties of the muscles were measured before and after train stimulation. It is found that H/H suspension increased twitch tension in the G-muscles, but did not change any contractile properties in the S-muscles. The peak twitch, train, tetanic tensions and time to peak were unchanged in the S-muscles of the suspended rats. On the basis of the experimental results, it is concluded that 1 wk of muscle atropy induced by H/H significantly increases fatigability in G-muscles, but does not affect the contractile properties of fast-twitch and slow-twitch muscles.

Naringin Improves Diet-Induced Cardiovascular Dysfunction and Obesity in High Carbohydrate, High Fat Diet-Fed Rats

PubMed Central

Alam, Md. Ashraful; Kauter, Kathleen; Brown, Lindsay

2013-01-01

Obesity, insulin resistance, hypertension and fatty liver, together termed metabolic syndrome, are key risk factors for cardiovascular disease. Chronic feeding of a diet high in saturated fats and simple sugars, such as fructose and glucose, induces these changes in rats. Naturally occurring compounds could be a cost-effective intervention to reverse these changes. Flavonoids are ubiquitous secondary plant metabolites; naringin gives the bitter taste to grapefruit. This study has evaluated the effect of naringin on diet-induced obesity and cardiovascular dysfunction in high carbohydrate, high fat-fed rats. These rats developed increased body weight, glucose intolerance, increased plasma lipid concentrations, hypertension, left ventricular hypertrophy and fibrosis, liver inflammation and steatosis with compromised mitochondrial respiratory chain activity. Dietary supplementation with naringin (approximately 100 mg/kg/day) improved glucose intolerance and liver mitochondrial dysfunction, lowered plasma lipid concentrations and improved the structure and function of the heart and liver without decreasing total body weight. Naringin normalised systolic blood pressure and improved vascular dysfunction and ventricular diastolic dysfunction in high carbohydrate, high fat-fed rats. These beneficial effects of naringin may be mediated by reduced inflammatory cell infiltration, reduced oxidative stress, lowered plasma lipid concentrations and improved liver mitochondrial function in rats. PMID:23446977

Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Penghao; Xie, Qihai; Wei, Tong

Objective: Obesity-induced vascular dysfunction is related to chronic low-grade systemic inflammation. Recent studies indicate that NLRP3, a multiprotein complex formed by NOD-like receptor (NLR) family members, is a key component mediating internal sterile inflammation, but the role in obesity-related vascular dysfunction is largely unknown. In the present study, we investigate whether NLRP3 activation is involved in vascular inflammation in obese Otsuka Long-Evans Tokushima Fatty rats (OLETF). Methods and results: Male OLETF with their control Long-Evans Tokushima Otsuka rats (LETO) were studied at 3 and 12 months of age. Aortic relaxation in response to acetylcholine decreased gradually with age in bothmore » strains, with early and persistent endothelium dysfunction in obese OLETF compared with age-matched LETO controls. These changes are associated with parallel changes of aortic endothelial nitric oxide synthase (eNOS) content, macrophage accumulation and intimal thickening. NLRP3 increased in OLETF rats compared to LETO. Consistent with inflammasome activation, the conversion of procaspase-1 to cleaved and activated forms as well as IL-1β markedly increased in OLETF rats. Additionally, we observed increased expression of dynamin-related protein-1 (Drp1) and decreased fusion-relative protein optic atropy-1(OPA1). Altered mitochondrial dynamics was associated with elevated oxidative stress level in OLETF aortas. Conclusions: These results demonstrate that obesity seems to accelerate endothelial dysfunction in OLETFs via the activation of NLRP3 and mitochondrial dysfunction. - Highlights: • NLRP3 is involved in obesity-induced vascular dysfunction. • Impaired mitochondrial dynamics may have been linked to mitochondrial defect and inflammasome activation. • Obesity seems to accelerate vascular dysfunction via NLRP3 activation and mitochondrial dysfunction.« less

Botulinum toxin in masticatory muscles of the adult rat induces bone loss at the condyle and alveolar regions of the mandible associated with a bone proliferation at a muscle enthesis.

PubMed

Kün-Darbois, Jean-Daniel; Libouban, Hélène; Chappard, Daniel

2015-08-01

In man, botulinum toxin type A (BTX) is injected in masticatory muscles for several indications such as trismus, bruxism, or masseter hypertrophy. Bone changes in the mandible following BTX injections in adult animal have therefore became a subject of interest. The aim of this study was to analyze condylar and alveolar bone changes following BTX unilateral injections in masseter and temporal muscles in adult rats. Mature male rats (n = 15) were randomized into 2 groups: control (CTRL; n = 6) and BTX group (n= 9). Rats of the BTX group received a single injection of BTX into right masseter and temporal muscles. Rats of the CTRL group were similarly injected with saline solution. Rats were sacrificed 4 weeks after injections. Masticatory muscles examination and microcomputed tomography (microCT) were performed. A significant difference of weight was found between the 2 groups at weeks 2, 3 and 4 (p < 0.05). Atrophy of the right masseter and temporal muscles was observed in all BTX rats. MicroCT analysis showed significant bone loss in the right alveolar and condylar areas in BTX rats. Decrease in bone volume reached -20% for right alveolar bone and -35% for right condylar bone. A hypertrophic bone metaplasia at the digastric muscle enthesis was found on every right hemimandible in the BTX group and none in the CTRL group. BTX injection in masticatory muscles leads to a significant and major mandible bone loss. These alterations can represent a risk factor for fractures in human. The occurrence of a hypertrophic bone metaplasia at the Mus Digastricus enthesis may constitute an etiological factor for tori. Copyright © 2015 Elsevier Inc. All rights reserved.

Aspartic acid in the hippocampus: a biomarker for postoperative cognitive dysfunction

PubMed Central

Hu, Rong; Huang, Dong; Tong, Jianbin; Liao, Qin; Hu, Zhonghua; Ouyang, Wen

2014-01-01

This study established an aged rat model of cognitive dysfunction using anesthesia with 2% isoflurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly impaired cognitive function in aged rats. Gas chromatography-mass spectrometry results showed that isoflurane also significantly increased the levels of N,N-diethylacetamide, n-ethylacetamide, aspartic acid, malic acid and arabinonic acid in the hippocampus of isoflurane-treated rats. Moreover, aspartic acid, N,N-diethylacetamide, n-ethylacetamide and malic acid concentration was positively correlated with the degree of cognitive dysfunction in the isoflurane-treated rats. It is evident that hippocampal metabolite changes are involved in the formation of cognitive dysfunction after isoflurane anesthesia. To further verify these results, this study cultured hippocampal neurons in vitro, which were then treated with aspartic acid (100 μmol/L). Results suggested that aspartic acid concentration in the hippocampus may be a biomarker for predicting the occurrence and disease progress of cognitive dysfunction. PMID:25206795

Aspartic acid in the hippocampus: a biomarker for postoperative cognitive dysfunction.

PubMed

Hu, Rong; Huang, Dong; Tong, Jianbin; Liao, Qin; Hu, Zhonghua; Ouyang, Wen

2014-01-15

This study established an aged rat model of cognitive dysfunction using anesthesia with 2% isoflurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly impaired cognitive function in aged rats. Gas chromatography-mass spectrometry results showed that isoflurane also significantly increased the levels of N,N-diethylacetamide, n-ethylacetamide, aspartic acid, malic acid and arabinonic acid in the hippocampus of isoflurane-treated rats. Moreover, aspartic acid, N,N-diethylacetamide, n-ethylacetamide and malic acid concentration was positively correlated with the degree of cognitive dysfunction in the isoflurane-treated rats. It is evident that hippocampal metabolite changes are involved in the formation of cognitive dysfunction after isoflurane anesthesia. To further verify these results, this study cultured hippocampal neurons in vitro, which were then treated with aspartic acid (100 μmol/L). Results suggested that aspartic acid concentration in the hippocampus may be a biomarker for predicting the occurrence and disease progress of cognitive dysfunction.

Age-related deficits in skeletal muscle recovery following disuse are associated with neuromuscular junction instability and ER stress, not impaired protein synthesis.

PubMed

Baehr, Leslie M; West, Daniel W D; Marcotte, George; Marshall, Andrea G; De Sousa, Luis Gustavo; Baar, Keith; Bodine, Sue C

2016-01-01

Age-related loss of muscle mass and strength can be accelerated by impaired recovery of muscle mass following a transient atrophic stimulus. The aim of this study was to identify the mechanisms underlying the attenuated recovery of muscle mass and strength in old rats following disuse-induced atrophy. Adult (9 month) and old (29 month) male F344BN rats underwent hindlimb unloading (HU) followed by reloading. HU induced significant atrophy of the hindlimb muscles in both adult (17-38%) and old (8-29%) rats, but only the adult rats exhibited full recovery of muscle mass and strength upon reloading. Upon reloading, total RNA and protein synthesis increased to a similar extent in adult and old muscles. At baseline and upon reloading, however, proteasome-mediated degradation was suppressed leading to an accumulation of ubiquitin-tagged proteins and p62. Further, ER stress, as measured by CHOP expression, was elevated at baseline and upon reloading in old rats. Analysis of mRNA expression revealed increases in HDAC4, Runx1, myogenin, Gadd45a, and the AChRs in old rats, suggesting neuromuscular junction instability/denervation. Collectively, our data suggests that with aging, impaired neuromuscular transmission and deficits in the proteostasis network contribute to defects in muscle fiber remodeling and functional recovery of muscle mass and strength.

Age-related deficits in skeletal muscle recovery following disuse are associated with neuromuscular junction instability and ER stress, not impaired protein synthesis

PubMed Central

Baehr, Leslie M.; West, Daniel W.D.; Marcotte, George; Marshall, Andrea G.; De Sousa, Luis Gustavo; Baar, Keith; Bodine, Sue C.

2016-01-01

Age-related loss of muscle mass and strength can be accelerated by impaired recovery of muscle mass following a transient atrophic stimulus. The aim of this study was to identify the mechanisms underlying the attenuated recovery of muscle mass and strength in old rats following disuse-induced atrophy. Adult (9 month) and old (29 month) male F344BN rats underwent hindlimb unloading (HU) followed by reloading. HU induced significant atrophy of the hindlimb muscles in both adult (17-38%) and old (8-29%) rats, but only the adult rats exhibited full recovery of muscle mass and strength upon reloading. Upon reloading, total RNA and protein synthesis increased to a similar extent in adult and old muscles. At baseline and upon reloading, however, proteasome-mediated degradation was suppressed leading to an accumulation of ubiquitin-tagged proteins and p62. Further, ER stress, as measured by CHOP expression, was elevated at baseline and upon reloading in old rats. Analysis of mRNA expression revealed increases in HDAC4, Runx1, myogenin, Gadd45a, and the AChRs in old rats, suggesting neuromuscular junction instability/denervation. Collectively, our data suggests that with aging, impaired neuromuscular transmission and deficits in the proteostasis network contribute to defects in muscle fiber remodeling and functional recovery of muscle mass and strength. PMID:26826670

The effects of running exercise on oxidative capacity and PGC-1α mRNA levels in the soleus muscle of rats with metabolic syndrome.

PubMed

Nagatomo, Fumiko; Fujino, Hidemi; Kondo, Hiroyo; Kouzaki, Motoki; Gu, Ning; Takeda, Isao; Tsuda, Kinsuke; Ishihara, Akihiko

2012-03-01

Skeletal muscles in animals with metabolic syndrome exhibit reduced oxidative capacity. We investigated the effects of running exercise on fiber characteristics, oxidative capacity, and mRNA levels in the soleus muscles of rats with metabolic syndrome [SHR/NDmcr-cp (cp/cp); CP]. We divided 5-week-old CP rats into non-exercise (CP) and exercise (CP-Ex) groups. Wistar-Kyoto rats (WKY) were used as the control group. CP-Ex rats were permitted voluntary exercise on running wheels for 10 weeks. Triglyceride levels were higher and adiponectin levels lower in the CP and CP-Ex groups than in the WKY group. However, triglyceride levels were lower and adiponectin levels higher in the CP-Ex group than in the CP group. The soleus muscles in CP-Ex rats contained only high-oxidative type I fibers, whereas those in WKY and CP rats contained type I, IIA, and IIC fibers. Muscle succinate dehydrogenase (SDH) activity was higher in the CP-Ex group than in the CP group; there was no difference in SDH activity between the WKY and CP-Ex groups. Muscle proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA levels were higher in the CP-Ex group than in the CP group; there was no difference in PGC-1α mRNA levels between the WKY and CP-Ex groups. In CP-Ex rats, longer running distance was associated with increased muscle SDH activity and PGC-1α mRNA levels. We concluded that running exercise restored decreased muscle oxidative capacity and PGC-1α mRNA levels and improved hypertriglyceridemia in rats with metabolic syndrome.

Pelvic floor muscle strength of women consulting at the gynecology outpatient clinics and its correlation with sexual dysfunction: A cross-sectional study.

PubMed

Ozdemir, Filiz Ciledag; Pehlivan, Erkan; Melekoglu, Rauf

2017-01-01

To investigate the pelvic floor muscle strength of the women andevaluateits possible correlation with sexual dysfunction. In this cross-sectional type study, stratified clusters were used for the sampling method. Index of Female Sexual Function (IFSF) worksheetwere used for questions on sexual function. The pelvic floor muscle strength of subjects was assessed byperineometer. The chi-squared test, logistic regression and Pearson's correlation analysis were used for the statistical analysis. Four hundred thirty primiparous women, mean age 38.5 participated in this study. The average pelvic floor muscle strength value was found 31.4±9.6 cm H 2 O and the average Index of Female Sexual Function (IFSF) score was found 26.5±6.9. Parity (odds ratio OR=5.546) and age 40 or higher (OR=3.484) were found correlated with pelvic floor muscle weakness (p<0.05). The factors directly correlated with sexual dysfunction were found being overweight (OR=2.105) and age 40 or higher (OR=2.451) (p<0.05). Pearson's correlation analysis showed that there was a statistically significantlinear correlation between the muscular strength of the pelvic floor and sexual function (p=0.001). The results suggested subjects with decreased pelvic floor muscle strength value had higher frequency of sexual dysfunction.

Management of tetanus complication

NASA Astrophysics Data System (ADS)

Somia, I. K. A.

2018-03-01

The mortality rate of tetanus is still high; it is because of various complications due to muscle spasms, autonomic dysfunction, as well as due to prolonged critical care. Management of tetanus with its complications is in intensive care facilities. Management goals include stopping toxin production, neutralization of unbound toxin, management of the airway, muscle spasm control, treatment of autonomic dysfunction and general supportive management. Currently, diazepam is still an effective medication to control of muscle spasm and rigidity. Therapy for autonomic dysfunction that supported by evidence is MgSO4. Also, general supportive management for long-term care remains necessary to prevent other complications such as thromboembolism, infection, malnutrition, and others.

The effect of amino acid infusion on anesthesia-induced hypothermia in muscle atrophy model rats.

PubMed

Kanazawa, Masahiro; Ando, Satoko; Tsuda, Michio; Suzuki, Toshiyasu

2010-01-01

An infusion of amino acids stimulates heat production in skeletal muscle and then attenuates the anesthesia-induced hypothermia. However, in a clinical setting, some patients have atrophic skeletal muscle caused by various factors. The present study was therefore conducted to investigate the effect of amino acids on the anesthesia-induced hypothermia in the state of muscle atrophy. As the muscle atrophy model, Sprague-Dawley rats were subjected to hindlimb immobilization for 2 wk. Normal rats and atrophy model rats were randomly assigned to one of the two treatment groups: saline or amino acids (n=8 for each group). Test solutions were administered intravenously to the rats under sevoflurane anesthesia for 180 min, and the rectal temperature was measured. Plasma samples were collected for measurement of insulin, blood glucose, and free amino acids. The rectal temperature was significantly higher in the normal-amino acid group than in the muscle atrophy-amino acid group from 75 to 180 min. The plasma insulin level was significantly higher in the rats given amino acids than in the rats given saline in both normal and model groups. In the rats given amino acids, plasma total free amino acid concentration was higher in the model group than in the normal group. These results indicate that skeletal muscle plays an important role in changes in body temperature during anesthesia and the effect of amino acids on anesthesia-induced hypothermia decreases in the muscle atrophy state. In addition, intravenous amino acids administration during anesthesia induces an increase in the plasma insulin level.

Increased myocardial short-range forces in a rodent model of diabetes reflect elevated content of β myosin heavy chain.

PubMed

Chung, Charles S; Mitov, Mihail I; Callahan, Leigh Ann; Campbell, Kenneth S

2014-06-15

Diastolic dysfunction is a clinically significant problem for patients with diabetes and often reflects increased ventricular stiffness. Attached cross-bridges contribute to myocardial stiffness and produce short-range forces, but it is not yet known whether these forces are altered in diabetes. In this study, we tested the hypothesis that cross-bridge-based short-range forces are increased in the streptozotocin (STZ) induced rat model of type 1 diabetes. Chemically permeabilized myocardial preparations were obtained from 12week old rats that had been injected with STZ or vehicle 4weeks earlier, and activated in solutions with pCa (=-log10[Ca(2+)]) values ranging from 9.0 to 4.5. The short-range forces elicited by controlled length changes were ∼67% greater in the samples from the diabetic rats than in the control preparations. This change was mostly due to an increased elastic limit (the length change at the peak short-range force) as opposed to increased passive muscle stiffness. The STZ-induced increase in short-ranges forces is thus unlikely to reflect changes to titin and/or collagen filaments. Gel electrophoresis showed that STZ increased the relative expression of β myosin heavy chain. This molecular mechanism can explain the increased short-ranges forces observed in the diabetic tissue if β myosin molecules remain bound between the filaments for longer durations than α molecules during imposed movements. These results suggest that interventions that decrease myosin attachment times may be useful treatments for diastolic dysfunction associated with diabetes. Copyright © 2013 Elsevier Inc. All rights reserved.

The Kv7/KCNQ channel blocker XE991 protects nigral dopaminergic neurons in the 6-hydroxydopamine rat model of Parkinson's disease.

PubMed

Liu, Haixia; Jia, Lu; Chen, Xiaoyan; Shi, Limin; Xie, Junxia

2018-03-01

The excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that supply the striatum with dopamine (DA) determines the function of the nigrostriatal system for motor coordination. We previously showed that 4-pyridinylmethyl-9(10H)-anthracenone (XE991), a specific blocker of Kv7/KCNQ channels, enhanced the excitability of nigral DA neurons and resulted in attenuation of haloperidol-induced catalepsy in a Parkinson's disease (PD) rat model. However, whether XE991 exhibits neuroprotective effects towards DA neuron degeneration remains unknown. The aim of this study was to investigate the effects of Kv7/KCNQ channel blocker, XE991, on 6-hydroxydopamine (6-OHDA)-induced nigral DA neuron degeneration and motor dysfunction. Using immunofluorescence staining and western blotting, we showed that intracerebroventricular administration of XE991 prevented the 6-OHDA-induced decrease in tyrosine hydroxylase (TH)-positive neurons and TH protein expression in the SNc. High-performance liquid chromatography with electrochemical detection (HPLC-ECD) also revealed that XE991 partly restored the levels of DA and its metabolites in the striatum. Moreover, XE991 decreased apomorphine (APO)-induced contralateral rotations, enhanced balance and coordination, and attenuated muscle rigidity in 6-OHDA-treated rats. Importantly, all neuroprotective effects by XE991 were abolished by co-application of Kv7/KCNQ channel opener retigabine and XE991. Thus, Kv7/KCNQ channel inhibition by XE991 can exert neuroprotective effects against 6-OHDA-induced degeneration of the nigrostriatal DA system and motor dysfunction. Copyright © 2017. Published by Elsevier Inc.

Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes

PubMed Central

Bogdani, Marika; Henschel, Angela M.; Kansra, Sanjay; Fuller, Jessica M.; Geoffrey, Rhonda; Jia, Shuang; Kaldunski, Mary L.; Pavletich, Scott; Prosser, Simon; Chen, Yi-Guang; Lernmark, Åke; Hessner, Martin J.

2014-01-01

Islet-level oxidative stress has been proposed as a trigger for type 1 diabetes (T1D), and release of cytokines by infiltrating immune cells further elevates reactive oxygen species (ROS), exacerbating β cell duress. To identify genes/mechanisms involved with diabeto-genesis at the β cell level, gene expression profiling and targeted follow-up studies were used to investigate islet activity in the biobreeding (BB) rat. Forty-day-old spontaneously diabetic lymphopenic BB DRlyp/lyp rats (before T cell insulitis) as well as nondiabetic BB DR+/+ rats, nondiabetic but lymphopenic F344lyp/lyp rats, and healthy Fischer (F344) rats were examined. Gene expression profiles of BB rat islets were highly distinct from F344 islets and under-expressed numerous genes involved in ROS metabolism, including glutathione S-transferase (GST) family members (Gstm2, Gstm4, Gstm7, Gstt1, Gstp1, and Gstk1), superoxide dismutases (Sod2 and Sod3), peroxidases, and peroxiredoxins. This pattern of under-expression was not observed in brain, liver, or muscle. Compared with F344 rats, BB rat pancreata exhibited lower GST protein levels, while plasma GST activity was found significantly lower in BB rats. Systemic administration of the antioxidant N-acetyl cysteine to DRlyp/lyp rats altered abundances of peripheral eosinophils, reduced severity of insulitis, and significantly delayed but did not prevent diabetes onset. We find evidence of β cell dysfunction in BB rats independent of T1D progression, which includes lower expression of genes related to antioxidative defense mechanisms during the pre-onset period that may contribute to overall T1D susceptibility. PMID:23111281

Soluble Milk Proteins Improve Muscle Mass Recovery after Immobilization-Induced Muscle Atrophy in Old Rats but Do not Improve Muscle Functional Property Restoration.

PubMed

Verney, J; Martin, V; Ratel, S; Chavanelle, V; Bargetto, M; Etienne, M; Chaplais, E; Le Ruyet, P; Bonhomme, C; Combaret, L; Guillet, C; Boisseau, N; Sirvent, P; Dardevet, D

2017-01-01

Effect of 3 different dairy protein sources on the recovery of muscle function after limb immobilization in old rats. Longitudinal animal study. Institut National de la Recherche Agronomique (INRA). The study took part in a laboratory setting. Old rats were subjected to unilateral hindlimb immobilization for 8 days and then allowed to recover with 3 different dietary proteins: casein, soluble milk proteins or whey proteins for 49 days. Body weight, muscle mass, muscle fibre size, isometric, isokinetic torque, muscle fatigability and muscle oxidative status were measured before and at the end of the immobilization period and during the recovery period i.e 7, 21, 35 and 49 days post immobilization. In contrast to the casein diet, soluble milk proteins and whey proteins were efficient to favor muscle mass recovery after cast immobilization during aging. By contrast, none of the 3 diary proteins was able to improve muscle strength, power and fatigability showing a discrepancy between the recovery of muscle mass and function. However, the soluble milk proteins allowed a better oxidative capacity in skeletal muscle during the rehabilitation period. Whey proteins and soluble milk proteins improve muscle mass recovery after immobilization-induced muscle atrophy in old rats but do not allow muscle functional property restoration.

The Correlation of Skeletal and Cardiac Muscle Dysfunction in Duchenne Muscular Dystrophy.

PubMed

Posner, Andrew D; Soslow, Jonathan H; Burnette, W Bryan; Bian, Aihua; Shintani, Ayumi; Sawyer, Douglas B; Markham, Larry W

2016-01-01

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle and cardiac dysfunction. While skeletal muscle dysfunction precedes cardiomyopathy, the relationship between the progressive decline in skeletal and cardiac muscle function is unclear. This relationship is especially important given that the myocardial effects of many developing DMD therapies are largely unknown. Our objective was to assess the relationship between progression of skeletal muscle weakness and onset of cardiac dysfunction in DMD. A total of 77 DMD subjects treated at a single referral center were included. Demographic information, quantitative muscle testing (QMT), subjective muscle strength, cardiac function, and current and retrospective medications were collected. A Spearman rank correlation was used to evaluate for an association between subjective strength and fractional shortening. The effects of total QMT and arm QMT on fractional shortening were examined in generalized least square with and without adjustments for age, ambulatory status, and duration of corticosteroids and cardiac specific medications. We found a significant correlation between maintained subjective skeletal muscle arm and leg strength and maintained cardiac function as defined by fractional shortening (rho=0.47, p=0.004 and rho=0.48, p=0.003, respectively). We also found a significant association between QMT and fractional shortening among non-ambulatory DMD subjects (p=0.03), while this association was not significant in ambulatory subjects. Our findings allow us to conclude that in this population, there exists a significant relationship between skeletal muscle and cardiac function in non-ambulatory DMD patients. While this does not imply a causal relationship, a possible association between skeletal and cardiac muscle function suggests that researchers should carefully monitor cardiac function, even when the primary outcome measures are not cardiac in nature.

The role of MicroRNAs in COPD muscle dysfunction and mass loss: implications on the clinic.

PubMed

Barreiro, Esther

2016-09-01

Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease and a leading cause of morbidity and mortality worldwide. In COPD, comorbidities, acute exacerbations, and systemic manifestations negatively influence disease severity, prognosis, and progression regardless of the respiratory condition. Several factors and biological mechanisms are involved in the pathophysiology of COPD muscle dysfunction. The non-coding microRNAs were shown to be differentially expressed in the respiratory and limb muscles of patients with COPD. Moreover, a differential expression profile of muscle-specific microRNAs has also been demonstrated in the lower limb muscles of COPD patients with and without muscle mass loss and weakness. All these features are reviewed herein. The most relevant articles on the topic in question were selected from PubMed to write this review. Expert commentary: MicroRNAs are excellent targets for the design of specific therapeutic interventions in patients with muscle weakness. Selective enhancers of microRNAs that promote myogenesis (proliferation and differentiation of satellite cells) should be designed to alleviate the negative impact of skeletal muscle dysfunction and mass loss in COPD regardless of the degree of the airway obstruction.

Cavin4b/Murcb Is Required for Skeletal Muscle Development and Function in Zebrafish.

PubMed

Housley, Michael P; Njaine, Brian; Ricciardi, Filomena; Stone, Oliver A; Hölper, Soraya; Krüger, Marcus; Kostin, Sawa; Stainier, Didier Y R

2016-06-01

Skeletal muscles provide metazoans with the ability to feed, reproduce and avoid predators. In humans, a heterogeneous group of genetic diseases, termed muscular dystrophies (MD), lead to skeletal muscle dysfunction. Mutations in the gene encoding Caveolin-3, a principal component of the membrane micro-domains known as caveolae, cause defects in muscle maintenance and function; however it remains unclear how caveolae dysfunction underlies MD pathology. The Cavin family of caveolar proteins can form membrane remodeling oligomers and thus may also impact skeletal muscle function. Changes in the distribution and function of Cavin4/Murc, which is predominantly expressed in striated muscles, have been reported to alter caveolae structure through interaction with Caveolin-3. Here, we report the generation and phenotypic analysis of murcb mutant zebrafish, which display impaired swimming capacity, skeletal muscle fibrosis and T-tubule abnormalities during development. To understand the mechanistic importance of Murc loss of function, we assessed Caveolin-1 and 3 localization and found it to be abnormal. We further identified an in vivo function for Murc in Erk signaling. These data link Murc with developmental defects in T-tubule formation and progressive muscle dysfunction, thereby providing a new candidate for the etiology of muscular dystrophy.

Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in The Health Improvement Network

PubMed Central

Rowan, Christopher G.; Brunelli, Steven M.; Munson, Jeffrey; Flory, James; Reese, Peter P.; Hennessy, Sean; Lewis, James; Mines, Daniel; Barrett, Jeffrey S.; Bilker, Warren; Strom, Brian L.

2014-01-01

Objective To compare the relative hazard of muscle toxicity, renal dysfunction, and hepatic dysfunction associated with the drug interaction between statins and concomitant medications that inhibit the CYP3A4 isoenzyme. Background Although statins provide important clinical benefits related to mitigating the risk of cardiovascular events, this class of medications also has the potential for severe adverse reactions. The risk for adverse events may be potentiated by concomitant use of medications that interfere with statin metabolism. Methods Data from The Health Improvement Network (THIN) from 1990 to 2008 were used to conduct a retrospective cohort study. Cohorts were created to evaluate each outcome (muscle toxicity, renal dysfunction, and hepatic dysfunction) independently. Each cohort included new statin initiators and compared the relative hazard of the outcome. The interaction ratio (I*R) was the primary contrast of interest. The I*R represents the relative effect of each statin type (statin 3A4 substrate vs. statin non-3A4 substrate) with a CYP3A4 inhibitor, independent of the effect of the statin type without a CYP3A4 inhibitor. We adjusted for confounding variables using the multinomial propensity score. Results The median follow-up time per cohort was 1.5 years. There were 7889 muscle toxicity events among 362 809 patients and 792 665 person-years. The adjusted muscle toxicity I*R was 1.22 (95% confidence interval [CI] = 0.90–1.66). There were 1449 renal dysfunction events among 272,099 patients and 574 584 person-years. The adjusted renal dysfunction I*R was 0.91 (95%CI = 0.58–1.44). There were 1434 hepatic dysfunction events among 367 612 patients and 815 945 person-years. The adjusted hepatic dysfunction I*R was 0.78 (95%CI = 0.45–1.31). Conclusions Overall, this study found no difference in the relative hazard of muscle toxicity, renal dysfunction, or hepatic dysfunction for patients prescribed a statin 3A4 substrate versus a statin non-3A4 substrate with CYP3A4 inhibitor concomitancy. PMID:22422642

Skeletal muscle response to spaceflight, whole body suspension, and recovery in rats

NASA Technical Reports Server (NTRS)

Musacchia, X. J.; Steffen, J. M.; Fell, R. D.; Dombrowski, M. J.

1990-01-01

The effects of a 7-day spaceflight (SF), 7- and 14-day-long whole body suspension (WBS), and 7-day-long recovery on the muscle weight and the morphology of the soleus and the extensor digitorum longus (EDL) of rats were investigated. It was found that the effect of 7-day-long SF and WBS were highly comparable for both the soleus and the EDL, although the soleus muscle from SF rats showed greater cross-sectional area reduction than that from WBS rats. With a longer duration of WBS, there was a continued reduction in cross-sectional fast-twitch fiber area. Muscle plasticity, in terms of fiber and capillary responses, showed differences in responses of the two types of muscles, indicating that antigravity posture muscles are highly susceptible to unloading.

Muscle Stem Cells: A Model System for Adult Stem Cell Biology.

PubMed

Cornelison, Ddw; Perdiguero, Eusebio

2017-01-01

Skeletal muscle stem cells, originally termed satellite cells for their position adjacent to differentiated muscle fibers, are absolutely required for the process of skeletal muscle repair and regeneration. In the last decade, satellite cells have become one of the most studied adult stem cell systems and have emerged as a standard model not only in the field of stem cell-driven tissue regeneration but also in stem cell dysfunction and aging. Here, we provide background in the field and discuss recent advances in our understanding of muscle stem cell function and dysfunction, particularly in the case of aging, and the potential involvement of muscle stem cells in genetic diseases such as the muscular dystrophies.

[Structural changes in the soleus muscle of rats on the Kosmos-series biosatellites and in hypokinesia].

PubMed

Il'ina-Kakueva, E I; Portugalov, V V

1981-01-01

Structural changes in the soleus muscle of rats used in flight and synchronous experiments of the Cosmos program and hypokinetic studies have been investigated. It is hypothesized that focal edema and dystrophic changes observed in flight, synchronous and hypokinetic rats can be caused by circulation disorders of different etiology. In flight and synchronous rats they develop two days postflight due to the deconditioning of the muscle tissue and intraorgan vascular system which fail to meet the requirements after transition from 0 g to 1 g. In hypokinetic rats circulation disorders occur on the first experimental day due to mechanical causes (paws are pressed against the cage floor impeding venous outflow) and muscle pump deficiency. In all cases circulation disorders seem to be associated with peculiar features of angioarchitectonics of the soleus muscle.

Pelvic Muscle Rehabilitation: A Standardized Protocol for Pelvic Floor Dysfunction

PubMed Central

Pedraza, Rodrigo; Nieto, Javier; Ibarra, Sergio; Haas, Eric M.

2014-01-01

Introduction. Pelvic floor dysfunction syndromes present with voiding, sexual, and anorectal disturbances, which may be associated with one another, resulting in complex presentation. Thus, an integrated diagnosis and management approach may be required. Pelvic muscle rehabilitation (PMR) is a noninvasive modality involving cognitive reeducation, modification, and retraining of the pelvic floor and associated musculature. We describe our standardized PMR protocol for the management of pelvic floor dysfunction syndromes. Pelvic Muscle Rehabilitation Program. The diagnostic assessment includes electromyography and manometry analyzed in 4 phases: (1) initial baseline phase; (2) rapid contraction phase; (3) tonic contraction and endurance phase; and (4) late baseline phase. This evaluation is performed at the onset of every session. PMR management consists of 6 possible therapeutic modalities, employed depending on the diagnostic evaluation: (1) down-training; (2) accessory muscle isolation; (3) discrimination training; (4) muscle strengthening; (5) endurance training; and (6) electrical stimulation. Eight to ten sessions are performed at one-week intervals with integration of home exercises and lifestyle modifications. Conclusions. The PMR protocol offers a standardized approach to diagnose and manage pelvic floor dysfunction syndromes with potential advantages over traditional biofeedback, involving additional interventions and a continuous pelvic floor assessment with management modifications over the clinical course. PMID:25006337

Insulin effect on amino acid uptake by unloaded rat hindlimb muscles

NASA Technical Reports Server (NTRS)

Jaspers, S. R.; Tischler, M. E.

1988-01-01

The effect of insulin on the uptake of alpha-amino-isobutyric acid (AIB) by unloaded rat hindlimb muscles was investigated using soleus and extensor digitorum longus (EDL) muscles from intact and adrenalectomized (ADX) rats that were tail-casted for six days. It was found that, at insulin levels above 0.00001 units/ml, the in vitro rate of AIB uptake by muscles from intact animals was stimulated more in the weight bearing muscles than in unloaded ones. In ADX animals, this differential response to insulin was abolished.

Increased arterial smooth muscle Ca2+ signaling, vasoconstriction, and myogenic reactivity in Milan hypertensive rats

PubMed Central

Linde, Cristina I.; Karashima, Eiji; Raina, Hema; Zulian, Alessandra; Wier, Withrow G.; Hamlyn, John M.; Ferrari, Patrizia; Blaustein, Mordecai P.

2012-01-01

The Milan hypertensive strain (MHS) rats are a genetic model of hypertension with adducin gene polymorphisms linked to enhanced renal tubular Na+ reabsorption. Recently we demonstrated that Ca2+ signaling is augmented in freshly isolated mesenteric artery myocytes from MHS rats. This is associated with greatly enhanced expression of Na+/Ca2+ exchanger-1 (NCX1), C-type transient receptor potential (TRPC6) protein, and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) compared with arteries from Milan normotensive strain (MNS) rats. Here, we test the hypothesis that the enhanced Ca2+ signaling in MHS arterial smooth muscle is directly reflected in augmented vasoconstriction [myogenic and phenylephrine (PE)-evoked responses] in isolated mesenteric small arteries. Systolic blood pressure was higher in MHS (145 ± 1 mmHg) than in MNS (112 ± 1 mmHg; P < 0.001; n = 16 each) rats. Pressurized mesenteric resistance arteries from MHS rats had significantly augmented myogenic tone and reactivity and enhanced constriction to low-dose (1–100 nM) PE. Isolated MHS arterial myocytes exhibited approximately twofold increased peak Ca2+ signals in response to 5 μM PE or ATP in the absence and presence of extracellular Ca2+. These augmented responses are consistent with increased vasoconstrictor-evoked sarcoplasmic reticulum (SR) Ca2+ release and increased Ca2+ entry, respectively. The increased SR Ca2+ release correlates with a doubling of inositol 1,4,5-trisphosphate receptor type 1 and tripling of SERCA2 expression. Pressurized MHS arteries also exhibited a ∼70% increase in 100 nM ouabain-induced vasoconstriction compared with MNS arteries. These functional alterations reveal that, in a genetic model of hypertension linked to renal dysfunction, multiple mechanisms within the arterial myocytes contribute to enhanced Ca2+ signaling and myogenic and vasoconstrictor-induced arterial constriction. MHS rats have elevated plasma levels of endogenous ouabain, which may initiate the protein upregulation and enhanced Ca2+ signaling. These molecular and functional changes provide a mechanism for the increased peripheral vascular resistance (whole body autoregulation) that underlies the sustained hypertension. PMID:22140038

Comparison of sarcoplasmic reticulum capabilities in toadfish (Opsanus tau) sonic muscle and rat fast twitch muscle.

PubMed

Feher, J J; Waybright, T D; Fine, M L

1998-08-01

The sonic muscle of the oyster toadfish, Opsanus tau, can produce unfused contractions at 300 Hz. Electron microscopy shows a great abundance of the Sarcoplasmic reticulum (SR) in this muscle, but no functional characterization of the capabilities of the SR has been reported. We measured the oxalate-supported Ca2+ uptake rate and capacities of homogenates of toadfish sonic muscle and rat extensor digitorum longus (EDL) muscle, and estimated the number of pump units by titration with thapsigargin, a high-affinity, specific inhibitor of the SR Ca-ATPase. The Ca2+ uptake rate averaged 70.9 +/- 9.5 mumol min -1 per g tissue for the toad fish sonic muscle, and 73.5 +/- 3.7 mumol min -1 g-1 for rat EDL. The capacity for Ca2+ -oxalate uptake was 161 +/- 20 mumol g -1 and 33 +/- 2 mumol g -1 for toadfish sonic muscle and rat EDL, respectively. Thus, the rates of Ca2+ uptake were similar in the two muscles, but the toadfish sonic muscle had about five times the capacity of the rat EDL. The number of pumps as estimated by thapsigargin titration was 68 +/- 4 nmol of Ca-ATPase per g tissue in the toadfish, and 42 +/- 5 nmol Ca-ATPase per g tissue in the rat EDL. The turnover number, defined as the Ca2+ uptake divided by the number of pumps, was 1065 +/- 150 min -1 for toadfish and 1786 +/- 230 min -1 for rat EDL (p < 0.05) at 37 degrees C. The Ca2+ uptake rate of toadfish sonic muscle at 22 degree C, a typical temperature for calling toadfish, averaged 42 +/- 1% of its rate at 37 degree C. At these operating temperatures, the toadfish SR is likely to be slower than the rat fast-twitch SR, yet the toadfish sonic muscle supports more rapid contractions. One explanation for this is that the voluminous SR provides activator Ca2+ for contraction, but the abundant parvalbumin plays a major role in relaxation.

Sericin and swimming on histomorphometric parameters of denervated plantar muscle in Wistar rats.

PubMed

Santana, André Junior; Debastiani, Jean Carlos; Buratti, Pâmela; Peretti, Ana Luiza; Kunz, Regina Inês; Brancalhão, Rose Meire Costa; Ribeiro, Lucinéia de Fátima Chasko; Torrejais, Márcia Miranda; Bertolini, Gladson Ricardo Flor

2018-01-01

Objective To analyze the combined effects of the silk protein sericin and swimming exercise on histomorphometry of the plantar muscle in Wistar rats. Methods Forty adult rats were randomly allocated into 5 groups comprising 8 animals each, as follows: Control, Injury, Sericin, Swim, and Swim plus Sericin. Three days after crushing of the sciatic nerve the rats in the Swim and Swim plus Sericin Groups were submitted to swimming exercise for 21 days. Rats were then euthanized and the plantar muscle harvested and processed. Results Cross-sectional area, peripheral nuclei and muscle fiber counts, nucleus/fiber ratio and smallest muscle fiber width did not differ significantly between groups. Morphological analysis revealed hypertrophic fibers in the Swim Group and evident muscle damage in the Swim plus Sericin and Injury Groups. The percentage of intramuscular collagen was apparently maintained in the Swim Group compared to remaining groups. Conclusion Combined treatment with sericin and swimming exercise did not improve muscle properties. However, physical exercise alone was effective in maintaining intramuscular connective tissue and preventing progression of deleterious effects of peripheral nerve injury.

Effects of aging and calorie restriction on rat skeletal muscle glycogen synthase and glycogen phosphorylase

PubMed Central

Montori-Grau, Marta; Minor, Robin; Lerin, Carles; Allard, Joanne; Garcia-Martinez, Celia; de Cabo, Rafael; Gómez-Foix, Anna M.

2016-01-01

Calorie restriction’s (CR) effects on age-associated changes in glycogen-metabolizing enzymes were studied in rat soleus (SOL) and tibialis anterior (TA) muscles. Old (24 months) compared to young (6 months) rats maintained ad libitum on a standard diet had reduced glycogen synthase (GS) activity, lower muscle GS protein levels, increased phosphorylation of GS at site 3a with less activation in SOL. Age-associated impairments in GS protein and activation-phosphorylation were also shown in TA. There was an age-associated reduction in glycogen phosphorylase (GP) activity level in SOL, while brain/muscle isoforms (B/M) of GP protein levels were higher. GP activity and protein levels were preserved, but GP was inactivated in TA with age. Glycogen content was unchanged in both muscles. CR did not alter GS or GP activity/protein levels in young rats. CR hindered age-related decreases in GS activity/protein, unrelated to GS mRNA levels, and GS inactivation-phosphorylation; not on GP. In older rats, CR enhanced glycogen accumulation in SOL. Short-term fasting did not recapitulate CR effects in old rats. Thus, the predominant age-associated impairments on skeletal muscle GS and GP activities occur in the oxidative SOL muscle of rats, and CR can attenuate the loss of GS activity/activation and stimulate glycogen accumulation. PMID:19341787

Alternate-Day High-Fat Diet Induces an Increase in Mitochondrial Enzyme Activities and Protein Content in Rat Skeletal Muscle.

PubMed

Li, Xi; Higashida, Kazuhiko; Kawamura, Takuji; Higuchi, Mitsuru

2016-04-06

Long-term high-fat diet increases muscle mitochondrial enzyme activity and endurance performance. However, excessive calorie intake causes intra-abdominal fat accumulation and metabolic syndrome. The purpose of this study was to investigate the effect of an alternating day high-fat diet on muscle mitochondrial enzyme activities, protein content, and intra-abdominal fat mass in rats. Male Wistar rats were given a standard chow diet (CON), high-fat diet (HFD), or alternate-day high-fat diet (ALT) for 4 weeks. Rats in the ALT group were fed a high-fat diet and standard chow every other day for 4 weeks. After the dietary intervention, mitochondrial enzyme activities and protein content in skeletal muscle were measured. Although body weight did not differ among groups, the epididymal fat mass in the HFD group was higher than those of the CON and ALT groups. Citrate synthase and beta-hydroxyacyl CoA dehydrogenase activities in the plantaris muscle of rats in HFD and ALT were significantly higher than that in CON rats, whereas there was no difference between HFD and ALT groups. No significant difference was observed in muscle glycogen concentration or glucose transporter-4 protein content among the three groups. These results suggest that an alternate-day high-fat diet induces increases in mitochondrial enzyme activities and protein content in rat skeletal muscle without intra-abdominal fat accumulation.

Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells.

PubMed

Tsai, J C; Jain, M; Hsieh, C M; Lee, W S; Yoshizumi, M; Patterson, C; Perrella, M A; Cooke, C; Wang, H; Haber, E; Schlegel, R; Lee, M E

1996-02-16

Pyrrolidinedithiocarbamate (PDTC) and N-acetylcysteine (NAC) have been used as antioxidants to prevent apoptosis in lymphocytes, neurons, and vascular endothelial cells. We report here that PDTC and NAC induce apoptosis in rat and human smooth muscle cells. In rat aortic smooth muscle cells, PDTC induced cell shrinkage, chromatin condensation, and DNA strand breaks consistent with apoptosis. In addition, overexpression of Bcl-2 suppressed vascular smooth muscle cell death caused by PDTC and NAC. The viability of rat aortic smooth muscle cells decreased within 3 h of treatment with PDTC and was reduced to 30% at 12 h. The effect of PDTC and NAC on smooth muscle cells was not species specific because PDTC and NAC both caused dose-dependent reductions in viability in rat and human aortic smooth muscle cells. In contrast, neither PDTC nor NAC reduced viability in human aortic endothelial cells. The use of antioxidants to induce apoptosis in vascular smooth muscle cells may help prevent their proliferation in arteriosclerotic lesions.

Physical exercise during muscle regeneration improves recovery of the slow/oxidative phenotype.

PubMed

Koulmann, Nathalie; Richard-Bulteau, Hélène; Crassous, Brigitte; Serrurier, Bernard; Pasdeloup, Marielle; Bigard, Xavier; Banzet, Sébastien

2017-01-01

As skeletal muscle mass recovery after extensive injury is improved by contractile activity, we explored whether concomitant exercise accelerates recovery of the contractile and metabolic phenotypes after muscle injury. After notexin-induced degeneration of a soleus muscle, Wistar rats were assigned to active (running exercise) or sedentary groups. Myosin heavy chains (MHC), metabolic enzymes, and calcineurin were studied during muscle regeneration at different time points. The mature MHC profile recovered earlier in active rats (21 days after injury) than in sedentary rats (42 days). Calcineurin was higher in the active degenerated than in the sedentary degenerated muscles at day 14. Citrate synthase and total lactate dehydrogenase (LDH) activity decreased after injury and were similarly recovered in both active and sedentary groups at 14 or 42 days, respectively. H-LDH isozyme activity recovered earlier in the active rats. Exercise improved recovery of the slow/oxidative phenotype after soleus muscle injury. Muscle Nerve 55: 91-100, 2017. © 2016 Wiley Periodicals, Inc.

Calorie restriction attenuates cardiac remodeling and diastolic dysfunction in a rat model of metabolic syndrome.

PubMed

Takatsu, Miwa; Nakashima, Chieko; Takahashi, Keiji; Murase, Tamayo; Hattori, Takuya; Ito, Hiromi; Murohara, Toyoaki; Nagata, Kohzo

2013-11-01

Calorie restriction (CR) can modulate the features of obesity-related metabolic and cardiovascular diseases. We have recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. DS/obese rats develop hypertension and manifest left ventricular remodeling and diastolic dysfunction, as well as increased cardiac oxidative stress and inflammation. We have now investigated the effects of CR on cardiac pathophysiology in DS/obese rats. DS/obese rats were fed either normal laboratory chow ad libitum or a calorie-restricted diet (65% of the average food intake for ad libitum) from 9 to 13 weeks. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+) or DS/lean) littermates served as controls. CR reduced body weight in both DS/obese and DS/lean rats, as well as attenuated the development of hypertension in DS/obese rats without affecting blood pressure in DS/lean rats. CR also reduced body fat content, ameliorated left ventricular hypertrophy, fibrosis, and diastolic dysfunction, and attenuated cardiac oxidative stress and inflammation in DS/obese rats. In addition, it increased serum adiponectin concentration, as well as downregulated the expression of angiotensin-converting enzyme and angiotensin II type 1A receptor genes in the heart of DS/obese rats. Our results thus show that CR attenuated obesity and hypertension, as well as left ventricular remodeling and diastolic dysfunction in DS/obese rats, with these latter effects being associated with reduced cardiac oxidative stress and inflammation.

Recombinant proteins secreted from tissue-engineered bioartificial muscle improve cardiac dysfunction and suppress cardiomyocyte apoptosis in rats with heart failure.

PubMed

Rong, Shu-Ling; Wang, Yong-Jin; Wang, Xiao-Lin; Lu, Yong-Xin; Wu, Yin; Liu, Qi-Yun; Mi, Shao-Hua; Xu, Yu-Lan

2010-12-01

Tissue-engineered bioartificial muscle-based gene therapy represents a promising approach for the treatment of heart diseases. Experimental and clinical studies suggest that systemic administration of insulin-like growth factor-1 (IGF-1) protein or overexpression of IGF-1 in the heart exerts a favorable effect on cardiovascular function. This study aimed to investigate a chronic stage after myocardial infarction (MI) and the potential therapeutic effects of delivering a human IGF-1 gene by tissue-engineered bioartificial muscles (BAMs) following coronary artery ligation in Sprague-Dawley rats. Ligation of the left coronary artery or sham operation was performed. Primary skeletal myoblasts were retrovirally transduced to synthesize and secrete recombinant human insulin-like growth factor-1 (rhIGF-1), and green fluorescent protein (GFP), and tissue-engineered into implantable BAMs. The rats that underwent ligation were randomly assigned to 2 groups: MI-IGF group (n = 6) and MI-GFP group (n = 6). The MI-IGF group received rhIGF-secreting BAM (IGF-BAMs) transplantation, and the MI-GFP group received GFP-secreting BAM (GFP-BAMs) transplantation. Another group of rats served as the sham operation group, which was also randomly assigned to 2 subgroups: S-IGF group (n = 6) and S-GFP group (n = 6). The S-IGF group underwent IGF-1-BAM transplantation, and S-GFP group underwent GFP-BAM transplantation. IGF-1-BAMs and GFP-BAMs were implanted subcutaneously into syngeneic rats after two weeks of operation was performed. Four weeks after the treatment, hemodynamics was performed. IGF-1 was measured by radioimmunoassay, and then the rats were sacrificed and ventricular samples were subjected to immunohistochemistry. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine the mRNA expression of bax and Bcl-2. TNF-α and caspase 3 expression in myocardium was examined by Western blotting. Primary rat myoblasts were retrovirally transduced to secrete rhIGF-1 and tissue-engineered into implantable BAMs containing parallel arrays of postmitotic myofibers. In vitro, they secreted consistent levels of hIGF (0.4 - 1.2 µg×BAM(-1)×d(-1)). When implanted into syngeneic rat, IGF-BAMs secreted and delivered rhIGF. Four weeks after therapy, the hemodynamics was improved significantly in MI rats treated with IGF-BAMs compared with those treated with GFP-BAMs. The levels of serum IGF-1 were increased significantly in both MI and sham rats treated with IGF-BAM. The mRNA expression of bax was lower and Bcl-2 expression was higher in MI-IGF group than MI-GFP group (P < 0.05). Western blotting assay showed TNF-α and caspase 3 expression was lower in MI-IGF group than MI-GFP group after therapy. rhIGF-1 significantly improves left ventricular function and suppresses cardiomyocyte apoptosis in rats with chronic heart failure. Genetically modified tissue-engineered BAMs provide a method delivering recombinant protein for the treatment of heart failure.

Differences in Age-Related Alterations in Muscle Contraction Properties in Rat Tongue and Hindlimb

ERIC Educational Resources Information Center

Connor, Nadine P.; Ota, Fumikazu; Nagai, Hiromi; Russell, John A.; Leverson, Glen

2008-01-01

Purpose: Because of differences in muscle architecture and biomechanics, the purpose of this study was to determine whether muscle contractile properties of rat hindlimb and tongue were differentially affected by aging. Method: Deep peroneal and hypoglossal nerves were stimulated in 6 young and 7 old Fischer 344-Brown Norway rats to allow…

Effects of nandrolone on recovery after neurotization of chronically denervated muscle in a rat model.

PubMed

Isaacs, Jonathan; Feher, Joseph; Shall, Mary; Vota, Scott; Fox, Michael A; Mallu, Satya; Razavi, Ashkon; Friebe, Ilvy; Shah, Sagar; Spita, Nathalie

2013-10-01

Suboptimal recovery following repair of major peripheral nerves has been partially attributed to denervation atrophy. Administration of anabolic steroids in conjunction with neurotization may improve functional recovery of chronically denervated muscle. The purpose of this study was to evaluate the effect of the administration of nandrolone on muscle recovery following prolonged denervation in a rat model. Eight groups of female Sprague-Dawley rats (15 rats per group, 120 in all) were divided into 3- or 6-month denervated hind limb and sham surgery groups and, then, nandrolone treatment groups and sham treatment groups. Evaluation of treatment effects included nerve conduction, force of contraction, comparative morphology, histology (of muscle fibers), protein electrophoresis (for muscle fiber grouping), and immunohistochemical evaluation. Although a positive trend was noted, neither reinnervated nor normal muscle showed a statistically significant increase in peak muscle force following nandrolone treatment. Indirect measures, including muscle mass (weight and diameter), muscle cell size, muscle fiber type, and satellite cell counts, all failed to support significant anabolic effect. There does not seem to be a functional benefit from nandrolone treatment following reinnervation of either mild or moderately atrophic muscle (related to prolonged denervation) in a rodent model.

An evaluation of the reliability of muscle fiber cross-sectional area and fiber number measurements in rat skeletal muscle

USDA-ARS?s Scientific Manuscript database

Background: The reliability of estimating muscle fiber cross-sectional area (measure of muscle fiber size) and fiber number from only a subset of fibers in rat hindlimb muscle cross-sections has not been systematically evaluated. This study examined the variability in mean estimates of fiber cross-s...

Accumulation of ceramide in slow-twitch muscle contributes to the development of insulin resistance in the obese JCR:LA-cp rat.

PubMed

Fillmore, Natasha; Keung, Wendy; Kelly, Sandra E; Proctor, Spencer D; Lopaschuk, Gary D; Ussher, John R

2015-06-01

What is the central question of this study? The aim was to determine whether the accumulation of ceramide contributes to skeletal muscle insulin resistance in the JCR obese rat. What is the main finding and its importance? Our main new finding is that ceramides accumulate only in slow-twitch skeletal muscle in the JCR obese rat and that reducing ceramide content in this muscle type by inhibition of serine palmitoyl transferase-1 halts the progression of insulin resistance in this rat model predisposed to early development of type 2 diabetes. Our findings highlight the importance of assessing insulin signalling/sensitivity and lipid intermediate accumulation in different muscle fibre types. It has been postulated that insulin resistance results from the accumulation of cytosolic lipid metabolites (i.e. diacylglycerol/ceramide) that impede insulin signalling and impair glucose homeostasis. De novo ceramide synthesis is catalysed by serine palmitoyl transferase-1. Our aim was to determine whether de novo ceramide synthesis plays a role during development of insulin resistance in the JCR:LA-cp obese rat. Ten-week-old JCR:LA-cp obese rats were supplemented with either vehicle or the serine palmitoyl transferase-1 inhibitor l-cycloserine (360 mg l(-1) ) in their drinking water for a 2 week period, and glycaemia was assessed by meal tolerance testing. Treatment of JCR:LA-cp obese rats with l-cycloserine improved their plasma glucose and insulin levels during a meal tolerance test. Examination of muscle lipid metabolites and protein phosphorylation patterns revealed differential signatures in slow-twitch (soleus) versus fast-twitch muscle (gastrocnemius), in that ceramide levels were increased in soleus but not gastrocnemius muscles of JCR:LA-cp obese rats. Likewise, improved glycaemia in l-cycloserine-treated JCR:LA-cp obese rats was associated with enhanced Akt and pyruvate dehydrogenase signalling in soleus but not gastrocnemius muscles, probably as a result of l-cycloserine reducing elevated ceramides in this muscle type. Potential mechanisms of ceramide-mediated insulin resistance involve activation of atypical protein kinase Cζ/λ and protein phosphatase 2A; however, neither of these was altered in muscles of JCR:LA-cp obese rats. Our results suggest a key role for ceramide in the development of insulin resistance in the JCR:LA-cp obese rat, while supporting serine palmitoyl transferase-1 inhibition as a novel target for treatment of obesity-associated insulin resistance. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

[Contractile properties of skeletal muscles of rats after flight on "Kosmos-1887"].

PubMed

Oganov, V S; Skuratova, S A; Murashko, L M

1991-01-01

Contractile properties of skeletal muscles of rats were investigated using glycerinated muscle preparations that were obtained from Cosmos-1887 animals flown for 13 days (plus 2 days on the ground) and from rats that remained hypokinetic for 13 days on the ground. In the flow rats, the absolute mass of postural muscles remained unchanged while their relative mass increased; this may be attributed to their enhanced hydration which developed during the first 2 days after landing. Strength losses of the postural muscles were less significant than after previous flights. Comparison of the Cosmos-1887 and hypokinesia control data has shown that even 2-day exposure to 1 G after 13-day flight can modify drastically flight-induced changes.

Higher insulin sensitivity in EDL muscle of rats fed a low-protein, high-carbohydrate diet inhibits the caspase-3 and ubiquitin-proteasome proteolytic systems but does not increase protein synthesis.

PubMed

Dos Santos, Maísa Pavani; Batistela, Emanuele; Pereira, Mayara Peron; Paula-Gomes, Silvia; Zanon, Neusa Maria; Kettelhut, Isis do Carmo; Karatzaferi, Christina; Andrade, Claudia Marlise Balbinotti; de França, Suélem Aparecida; Baviera, Amanda Martins; Kawashita, Nair Honda

2016-08-01

Compared with the extensor digitorum longus (EDL) muscle of control rats (C), the EDL muscle of rats fed a low-protein, high-carbohydrate diet (LPHC) showed a 36% reduction in mass. Muscle mass is determined by the balance between protein synthesis and proteolysis; thus, the aim of this work was to evaluate the components involved in these processes. Compared with the muscle from C rats, the EDL muscle from LPHC diet-fed rats showed a reduction (34%) in the in vitro basal protein synthesis and a 22% reduction in the in vitro basal proteolysis suggesting that the reduction in the mass can be associated with a change in the rate of the two processes. Soon after euthanasia, in the EDL muscles of the rats fed the LPHC diet for 15days, the activity of caspase-3 and that of components of the ubiquitin-proteasome system (atrogin-1 content and chymotrypsin-like activity) were decreased. The phosphorylation of p70(S6K) and 4E-BP1, proteins involved in protein synthesis, was also decreased. We observed an increase in the insulin-stimulated protein content of p-Akt. Thus, the higher insulin sensitivity in the EDL muscle of LPHC rats seemed to contribute to the lower proteolysis in LPHC rats. However, even with the higher insulin sensitivity, the reduction in p-E4-BP1 and p70(S6K) indicates a reduction in protein synthesis, showing that factors other than insulin can have a greater effect on the control of protein synthesis. Copyright © 2016 Elsevier Inc. All rights reserved.

Type 2 diabetes mellitus and exercise impairment.

PubMed

Reusch, Jane E B; Bridenstine, Mark; Regensteiner, Judith G

2013-03-01

Limitations in physical fitness, a consistent finding in individuals with both type I and type 2 diabetes mellitus, correlate strongly with cardiovascular and all-cause mortality. These limitations may significantly contribute to the persistent excess cardiovascular mortality affecting this group. Exercise impairments in VO2 peak and VO2 kinetics manifest early on in diabetes, even with good glycemic control and in the absence of clinically apparent complications. Subclinical cardiac dysfunction is often present but does not fully explain the observed defect in exercise capacity in persons with diabetes. In part, the cardiac limitations are secondary to decreased perfusion with exercise challenge. This is a reversible defect. Similarly, in the skeletal muscle, impairments in nutritive blood flow correlate with slowed (or inefficient) exercise kinetics and decreased exercise capacity. Several correlations highlight the likelihood of endothelial-specific impairments as mediators of exercise dysfunction in diabetes, including insulin resistance, endothelial dysfunction, decreased myocardial perfusion, slowed tissue hemoglobin oxygen saturation, and impairment in mitochondrial function. Both exercise training and therapies targeted at improving insulin sensitivity and endothelial function improve physical fitness in subjects with type 2 diabetes. Optimization of exercise functions in people with diabetes has implications for diabetes prevention and reductions in mortality risk. Understanding the molecular details of endothelial dysfunction in diabetes may provide specific therapeutic targets for the remediation of this defect. Rat models to test this hypothesis are under study.

Impaired translocation of GLUT4 results in insulin resistance of atrophic soleus muscle.

PubMed

Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

2015-01-01

Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats.

Impaired Translocation of GLUT4 Results in Insulin Resistance of Atrophic Soleus Muscle

PubMed Central

Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

2015-01-01

Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats. PMID:25713812

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

PubMed Central

Shibata, Taiga; Naruse, Keiko; Kamiya, Hideki; Kozakae, Mika; Kondo, Masaki; Yasuda, Yutaka; Nakamura, Nobuhisa; Ota, Kimiko; Tosaki, Takahiro; Matsuki, Takashi; Nakashima, Eitaro; Hamada, Yoji; Oiso, Yutaka; Nakamura, Jiro

2008-01-01

OBJECTIVE—Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats. RESEARCH DESIGN AND METHODS—MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number–to–muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated. RESULTS—VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number–to–muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation. CONCLUSIONS—These results suggest that MSC transplantation could have therapeutic effects on DPN through paracrine actions of growth factors secreted by MSCs. PMID:18728233

[Effects of 100 Hz sinusoidal vibration on H reflex and M wave in rat soleus muscle following immobilization].

PubMed

Zhao, Xue-hong; Fan, Xiao-li; Song, Xin-ai; Shi, Lei

2011-09-01

To investigate the effects of 100 Hz sinusoidal vibration on H reflex and M wave in rat soleus muscle following immobilization. The immobilization of rat soleus muscle was induced as a disuse muscle model, and 100 Hz sinusoidal vibration was generated by a vibrator and applied to the immobilized soleus muscle, then the changes of H reflex and M wave in muscle were observed after 14 d. Compared to control, after 14 d of immobilization M(max) in soleus muscle decreased (P<0.01), stimulus threshold and S(max) increased (P<0.01); Hmax and H(max)/M(max) decreased (P<0.05, S(max) increased (P<0.05). Compared to immobilized soleus muscle, after 14 d of immobilization with 100 Hz sinusoidal vibration, the M(max) increased(P<0.01), stimulus threshold and S(Mmax) decreased (P<0.05), H(max) (P<0.01) increased and H(max)/M(max) increased (P<0.05). 100 Hz sinusoidal vibration plays a significant antagonist role against the changes in H reflex and M wave in rat soleus muscle following immobilization.

Sex, stress and sleep apnoea: Decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females.

PubMed

O'Halloran, Ken D; Lewis, Philip; McDonald, Fiona

2017-11-01

Obstructive sleep apnoea syndrome (OSAS) is a devastating respiratory control disorder more common in men than women. The reasons for the sex difference in prevalence are multifactorial, but are partly attributable to protective effects of oestrogen. Indeed, OSAS prevalence increases in post-menopausal women. OSAS is characterized by repeated occlusions of the pharyngeal airway during sleep. Dysfunction of the upper airway muscles controlling airway calibre and collapsibility is implicated in the pathophysiology of OSAS, and sex differences in the neuro-mechanical control of upper airway patency are described. It is widely recognized that chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoea, drives many of the morbid consequences characteristic of the disorder. In rodents, exposure to CIH-related redox stress causes upper airway muscle weakness and fatigue, associated with mitochondrial dysfunction. Of interest, in adults, there is female resilience to CIH-induced muscle dysfunction. Conversely, exposure to CIH in early life, results in upper airway muscle weakness equivalent between the two sexes at 3 and 6 weeks of age. Ovariectomy exacerbates the deleterious effects of exposure to CIH in adult female upper airway muscle, an effect partially restored by oestrogen replacement therapy. Intriguingly, female advantage intrinsic to upper airway muscle exists with evidence of substantially greater loss of performance in male muscle during acute exposure to severe hypoxic stress. Sex differences in upper airway muscle physiology may have relevance to human OSAS. The oestrogen-oestrogen receptor α axis represents a potential therapeutic target in OSAS, particularly in post-menopausal women. Copyright © 2016 Elsevier B.V. All rights reserved.

Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy

PubMed Central

Oki, Kentaro; Halievski, Katherine; Vicente, Laura; Xu, Youfen; Zeolla, Donald; Poort, Jessica; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Wiseman, Robert W.; Breedlove, S. Marc

2015-01-01

Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics. PMID:25663674

Gated /sup 31/P NMR study of tetanic contraction in rat muscle depleted of phosphocreatine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shoubridge, E.A.; Radda, G.K.

1987-05-01

Rats were fed a diet containing 1% ..beta..-guanidino-propionic acid (GPA) for 6-12 wk to deplete their muscles of phosphocreatine (PCr). Gated /sup 31/P nuclear magnetic resonance (NMR) spectra were obtained from the gastrocnemius-plantaris muscle at various time points during either a 1- or 3-s isometric tetanic contraction using a surface coil. The energy cost of a 1-s tetanus in unfatigued control rat muscle was 48.4 ..mu..mol ATP x g dry wt/sup -1/ x s/sup -1/ and was largely supplied by PCr; anaerobic glycogenolysis was negligible. In GPA-fed rats PCr was undetectable after 400 ms. This had no effect on initialmore » force generated per gram, which was not significantly different from controls. Developed tension in a 3-s tetanus in GPA-fed rats could be divided into a peak phase (duration 0.8-0.9 s) and a plateau phase (65% peak tension) in which PCr was undetectable and the (ATP) was < 20% of that in control muscle. Energy from glycogenolysis was sufficient to maintain force generation at this submaximal level. Mean net glycogen utilization per 3-s tetanus was 78% greater than in control muscle. However, the observed decrease in intracellular pH was less than that expected from energy budget calculations, suggesting either increased buffering capacity or modulation of ATP hydrolysis in the muscles of GPA-fed rats. The results demonstrate that the transport role of PCr is not essential in contracting muscle in GPA-fed rats. PCr is probably important in this regard in the larger fibers of control muscle. Although fast-twitch muscles depleted of PCr have nearly twice the glycogen reserves of control muscle, glycogenolysis is limited in its capacity to fill the role of PCr as an energy buffer under conditions of maximum ATP turnover.« less

Different effect of losartan and amlodipine on penile structures in male spontaneously hypertensive rats.

PubMed

Toblli, Jorge Eduardo; Stella, Inés; Mazza, Osvaldo Néstor; Ferder, León; Inserra, Felipe

2004-01-01

Erectile dysfunction is highly prevalent in hypertensive patients. Since both angiotensin II receptor type-1 blockers (ARBs) and calcium antagonists are current and effective antihypertensive drugs, the aim of this study was to determine possible differences between ARBs and calcium antagonists concerning the protection of penile structures from the deleterious effects of arterial hypertension. During 6 months, 3 groups of male spontaneously hypertensive rats (SHR) and 1 of Wistar-Kyoto (WKY) rats, as a control group, were studied: SHR without treatment; SHR with losartan (L) 30 mg/kg/day; SHR with amlodipine (A) 3 mg/kg/day, and WKY without treatment. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, cavernous tissue fibrosis and collagen type III (COL III) were evaluated. After 6 months, SHR+L and SHR+A showed a similar reduction in blood pressure compared with untreated SHR. However, only SHR+L and control WKY presented significantly lower values of: CSM (p < 0.01), VSM (p < 0.01), and COL III (p < 0.01) when compared with either untreated SHR or SHR+A. There was also a positive correlation between left ventricular mass and proteinuria with VSM from cavernous arteries, CSM and COL III in untreated SHR and SHR+A. These relations were not present in SHR+L and WKY. Although losartan and amlodipine achieved similar blood pressure control, losartan but not amlodipine showed a significant protective role against structural changes in the vessels and cavernous spaces of the erectile tissue caused by arterial hypertension. Copyright 2004 S. Karger AG, Basel

Dietary HMB and β-alanine co-supplementation does not improve in situ muscle function in sedentary, aged male rats.

PubMed

Russ, David W; Acksel, Cara; Boyd, Iva M; Maynard, John; McCorkle, Katherine W; Edens, Neile K; Garvey, Sean M

2015-12-01

This study evaluated the effects of dietary β-hydroxy-β-methylbutyrate (HMB) combined with β-alanine (β-Ala) in sedentary, aged male rats. It has been suggested that dietary HMB or β-Ala supplementation may mitigate age-related declines in muscle strength and fatigue resistance. A total of 20 aged Sprague-Dawley rats were studied. At age 20 months, 10 rats were administered a control, purified diet and 10 rats were administered a purified diet supplemented with both HMB and β-Ala (HMB+β-Ala) for 8 weeks (approximately equivalent to 3 and 2.4 g per day human dose). We measured medial gastrocnemius (MG) size, force, fatigability, and myosin composition. We also evaluated an array of protein markers related to muscle mitochondria, protein synthesis and breakdown, and autophagy. HMB+β-Ala had no significant effects on body weight, MG mass, force or fatigability, myosin composition, or muscle quality. Compared with control rats, those fed HMB+β-Ala exhibited a reduced (41%, P = 0.039) expression of muscle RING-finger protein 1 (MURF1), a common marker of protein degradation. Muscle from rats fed HMB+β-Ala also exhibited a 45% reduction (P = 0.023) in p70s6K phosphorylation following fatiguing stimulation. These data suggest that HMB+β-Ala at the dose studied may reduce muscle protein breakdown by reducing MURF1 expression, but has minimal effects on muscle function in this model of uncomplicated aging. They do not, however, rule out potential benefits of HMB+β-Ala co-supplementation at other doses or durations of supplementation in combination with exercise or in situations where extreme muscle protein breakdown and loss of mass occur (e.g., bedrest, cachexia, failure-to-thrive).

Resistance exercise attenuates skeletal muscle oxidative stress, systemic pro-inflammatory state, and cachexia in Walker-256 tumor-bearing rats.

PubMed

Padilha, Camila Souza; Borges, Fernando Henrique; Costa Mendes da Silva, Lilian Eslaine; Frajacomo, Fernando Tadeu Trevisan; Jordao, Alceu Afonso; Duarte, José Alberto; Cecchini, Rubens; Guarnier, Flávia Alessandra; Deminice, Rafael

2017-09-01

The aim of this study was to investigate the effects of resistance exercise training (RET) on oxidative stress, systemic inflammatory markers, and muscle wasting in Walker-256 tumor-bearing rats. Male (Wistar) rats were divided into 4 groups: sedentary controls (n = 9), tumor-bearing (n = 9), exercised (n = 9), and tumor-bearing exercised (n = 10). Exercised and tumor-bearing exercised rats were exposed to resistance exercise of climbing a ladder apparatus with weights tied to their tails for 6 weeks. The physical activity of control and tumor-bearing rats was confined to the space of the cage. After this period, tumor-bearing and tumor-bearing exercised animals were inoculated subcutaneously with Walker-256 tumor cells (11.0 × 10 7 cells in 0.5 mL of phosphate-buffered saline) while control and exercised rats were injected with vehicle. Following inoculation, rats maintained resistance exercise training (exercised and tumor-bearing exercised) or sedentary behavior (control and tumor-bearing) for 12 more days, after which they were euthanized. Results showed muscle wasting in the tumor-bearing group, with body weight loss, increased systemic leukocytes, and inflammatory interleukins as well as muscular oxidative stress and reduced mTOR signaling. In contrast, RET in the tumor-bearing exercised group was able to mitigate the reduced body weight and muscle wasting with the attenuation of muscle oxidative stress and systemic inflammatory markers. RET also prevented loss of muscle strength associated with tumor development. RET, however, did not prevent the muscle proteolysis signaling via FBXO32 gene messenger RNA expression in the tumor-bearing group. In conclusion, RET performed prior tumor implantation prevents cachexia development by attenuating tumor-induced systemic pro-inflammatory condition with muscle oxidative stress and muscle damage.

Muscle protein turnover in rats treated with corticosterone (CC) or/and nandrolone decanoate (ND) and fed an adequate or a low-protein diet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Santidrian, S.; Cuevillas, F.; Goena, M.

1986-03-01

In order to investigate the possible antagonistic effect between glucocorticoids and androgens on muscle protein turnover, the authors have measured the fractional rates of gastrocnemius muscle protein synthesis (k/sub s/) and degradation (k/sub d/) by the constant-intravenous-infusion method using L-//sup 14/C/-tyrosine in rats receiving via s.c. per 100 g b.wt. 10 mg of CC, or 2 mg of ND or CC+ND at the indicated doses, and fed either an 18% or 5% protein diets over a period of 5 days. As an additional index of protein synthesis, RNA activity (g of synthesized protein/day/g RNA) was determined as well. Results showedmore » that as compared to vehicle-injected animals fed the adequate diet, CC-treated rats exhibited a reduction of muscle k/sub d/, while ND-treated rats had an outstanding increase of muscle k/sub s/. However, rats receiving CC+ND showed k/sub s/ and k/sub d/ values similar to those displayed by control animals. Nevertheless, when the steroids were injected to rats fed the low-protein diet, CC has a catabolic effect on muscle protein but by reducing k/sub s/, while the anabolic action of ND is still displayed but by a significant reduction of muscle k/sub d/. CC+ND given to these protein-deficient rats caused an increase in muscle k/sub s/ and a reduction in k/sub d/. These results might indicate that, at least in part, ND antagonizes the catabolic action of high doses of CC on muscle protein metabolism.« less

Therapeutic effect of Tripterygium wilfordii Hook F multiglycosides on gut barrier dysfunction in rats with acute necrotizing pancreatitis.

PubMed

Wang, Jie; Wu, Gang; Ma, Baojin; Wu, Jianhua; Cai, Duan

2013-02-01

The aim of the current study was to investigate the therapeutic effect of Tripterygium wilfordii Hook F multiglycosides (TWG) on gut barrier dysfunction in rats with acute necrotizing pancreatitis (ANP). ANP was induced in rats using 3.5% sodium taurocholate. The rats were divided into 3 groups: the sham operation (SO), ANP and ANP+TWG groups. Biochemical and pathological change of pancreatic tissue and ileal mucosa, bacterial cultures and the survival rate were measured following surgery and treatment. TWG treatment significantly decreased amylase and lipase activities and plasma endotoxin and D-lactate levels. Edema and inflammation in the pancreas and ileal mucosa were alleviated. Positive bacterial cultures were significantly reduced. The survival rate of the rats in the ANP+TWG group was higher than that of the rats in the ANP group. TWG treatment showed beneficial effects by protecting the pancreas from bacterial infection caused by gut barrier dysfunction and improving the outcomes of the rats with ANP.

Muscle function in COPD: a complex interplay

PubMed Central

Donaldson, Anna V; Maddocks, Matthew; Martolini, Dario; Polkey, Michael I; Man, William D-C

2012-01-01

The skeletal muscles play an essential role in life, providing the mechanical basis for respiration and movement. Skeletal muscle dysfunction is prevalent in all stages of chronic obstructive pulmonary disease (COPD), and significantly influences symptoms, functional capacity, health related quality of life, health resource usage and even mortality. Furthermore, in contrast to the lungs, the skeletal muscles are potentially remedial with existing therapy, namely exercise-training. This review summarizes clinical and laboratory observations of the respiratory and peripheral skeletal muscles (in particular the diaphragm and quadriceps), and current understanding of the underlying etiological processes. As further progress is made in the elucidation of the molecular mechanisms of skeletal muscle dysfunction, new pharmacological therapies are likely to emerge to treat this important extra-pulmonary manifestation of COPD. PMID:22973093

Impaired Regeneration: A Role for the Muscle Microenvironment in Cancer Cachexia

PubMed Central

Talbert, Erin E.; Guttridge, Denis C.

2016-01-01

While changes in muscle protein synthesis and degradation have long been known to contribute to muscle wasting, a body of literature has arisen which suggests that regulation of the satellite cell and its ensuing regenerative program are impaired in atrophied muscle. Lessons learned from cancer cachexia suggest that this regulation is simply not a consequence, but a contributing factor to the wasting process. In addition to satellite cells, evidence from mouse models of cancer cachexia also suggests that non-satellite progenitor cells from the muscle microenvironment are also involved. This chapter in the series reviews the evidence of dysfunctional muscle repair in multiple wasting conditions. Potential mechanisms for this dysfunctional regeneration are discussed, particularly in the context of cancer cachexia. PMID:26385617

Supplementing healthy rats with a high-niacin dose has no effect on muscle fiber distribution and muscle metabolic phenotype.

PubMed

Scholz, Kristen; Kynast, Anna Marie; Couturier, Aline; Mooren, Frank-Christoph; Krüger, Karsten; Most, Erika; Eder, Klaus; Ringseis, Robert

2014-08-01

It was recently shown that niacin prevents the obesity-induced type I to type II fiber switching in skeletal muscle of obese rats and favors the development of a more oxidative metabolic phenotype and thereby increases whole body utilization of fatty acids. Whether niacin also causes type II to type I fiber switching in skeletal muscle of healthy rats has not been investigated yet. Thus, the present study aimed to investigate whether niacin supplementation influences fiber distribution and metabolic phenotype of different skeletal muscles with a distinct type I-to-type II fiber ratio in healthy rats. Twenty-four male, 10-week-old Sprague-Dawley rats were randomly assigned into two groups of 12 rats each and fed either a control diet with 30 mg supplemented niacin/kg diet (control group) or a high-niacin diet with 780 mg supplemented niacin/kg diet (high-niacin group). After 27 days of treatment, the percentage number of type I fibers in rectus femoris, gastrocnemius, and tibialis anterior muscles was 5-10% greater in the niacin group than in the control group, but did not differ between groups in soleus and vastus intermedius muscles. Transcript levels of genes encoding transcription factors regulating fiber switching, fiber-specific myosin heavy chain isoforms, and proteins involved in fatty acid utilization, oxidative phosphorylation, and angiogenesis did not differ between groups. The results show that niacin has only negligible effects on fiber distribution and its regulation as well as the metabolic phenotype of skeletal muscle in healthy rats.

Oxidized LDL Is Strictly Limited to Hyperthyroidism Irrespective of Fat Feeding in Female Sprague Dawley Rats.

PubMed

Zelzer, Sieglinde; Mangge, Harald; Pailer, Sabine; Ainoedhofer, Herwig; Kieslinger, Petra; Stojakovic, Tatjana; Scharnagl, Hubert; Prüller, Florian; Weghuber, Daniel; Datz, Christian; Haybaeck, Johannes; Obermayer-Pietsch, Barbara; Trummer, Christian; Gostner, Johanna; Gruber, Hans-Jürgen

2015-05-21

Metabolic dysfunctions might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of a controlled diet (normal versus high fat feeding) on hypothyroid and hyperthyroid Sprague Dawley rats. Female Sprague Dawley rats (n = 66) were grouped into normal diet (n = 30) and high-fat diet (n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment metabolic parameters, such as oxidized LDL (oxLDL), malondialdehyde (MDA), 4-hydroxynonenal (HNE), the lipid profile, body weight and food intake parameters were analyzed. Successfully induced thyroid dysfunctions were shown by T3 levels, both under normal and high fat diet. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight as well as in the lipid profile. In detail, hypothyroid rats showed significantly decreased oxLDL levels, whereas hyperthyroid rats showed significantly increased oxLDL levels. These effects were seen under high fat diet and were less pronounced with normal feeding. Taken together, we showed for the first time in female SD rats that only hyper-, but not hypothyroidism, is associated with high atherogenic oxidized LDL irrespective of normal or high-fat diet in Sprague Dawley rats.

Neuromuscular electrical stimulation improves GLUT-4 and morphological characteristics of skeletal muscle in rats with heart failure.

PubMed

de Leon, E B; Bortoluzzi, A; Rucatti, A; Nunes, R B; Saur, L; Rodrigues, M; Oliveira, U; Alves-Wagner, A B; Xavier, L L; Machado, U F; Schaan, B D; Dall'Ago, P

2011-02-01

Changes in skeletal muscle morphology and metabolism are associated with limited functional capacity in heart failure, which can be attenuated by neuromuscular electrical stimulation (ES). The purpose of the present study was to analyse the effects of ES upon GLUT-4 protein content, fibre structure and vessel density of the skeletal muscle in a rat model of HF subsequent to myocardial infarction. Forty-four male Wistar rats were assigned to one of four groups: sham (S), sham submitted to ES (S+ES), heart failure (HF) and heart failure submitted to ES (HF+ES). The rats in the ES groups were submitted to ES of the left leg during 20 days (2.5 kHz, once a day, 30 min, duty cycle 50%- 15 s contraction/15 s rest). After this period, the left tibialis anterior muscle was collected from all the rats for analysis. HF+ES rats showed lower values of lung congestion when compared with HF rats (P = 0.0001). Although muscle weight was lower in HF rats than in the S group, thus indicating hypotrophy, 20 days of ES led to their recovery (P < 0.0001). In both groups submitted to ES, there was an increase in muscle vessel density (P < 0.04). Additionally, heart failure determined a 49% reduction in GLUT-4 protein content (P < 0.03), which was recovered by ES (P < 0.01). In heart failure, ES improves morphological changes and raises GLUT-4 content in skeletal muscle. © 2010 The Authors. Acta Physiologica © 2010 Scandinavian Physiological Society.

[Effects of TWP on capacity of muscle contraction].

PubMed

Zhang, Yun; Yu, Jingrui; Lü, Guangneng; Li, Keyong; Xu, Jianguo

2003-04-01

To investigate the direct effects of Tripterygium Wilfordii Polyglycosidium (TWP) on capability of muscle contraction. Using electronic stimulator to stimulate the phrenic nerve of the isolated phrenic nerve diaphragm preparation of 30 rats or directly stimulate the isolated gastrocnemius muscle preparation of 45 toads in vitro, we studied the effects of TWP on capability of muscle intrinsic contraction. TWP in 20 mg/L increased the amplitude of muscle contraction in initial 60 min but did not make further increase of the amplitude of muscle contraction from 60 min to 90 min in the isolated phrenic nerve diaphragm preparation of rat under one-third optimal stimulus. TWP in 40 mg/L and in 60 mg/L did not cause decrease of amplitude of muscle contraction in initial 60 min in isolated phrenic nerve diaphragm preparation of rat under one-third optimal stimulus. TWP in 60 mg/L did not cause decrease of tension of signal-contraction in initial 30 min in isolated gastrocnemius muscle preparation of toad under one-third optimal direct stimulus. Solvent DMSO could obviously reduce the tension of muscle contraction both in isolated phrenic nerve diaphragm preparation of rat and in isolated gastrocnemius muscle preparation of toad under one-third optimal stimulus. TWP can limitedly enhance the capability of muscle contraction; Solvent DMSO can restrain muscle contraction.

Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation.

PubMed

Wu, Yao; Si, Feifei; Ji, Xiaojuan; Jiang, Kunfeng; Song, Sijie; Yi, Qijian

2017-01-01

Background . This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods . Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results . The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions . The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281.

Trinitrobenzenesulfonic Acid Colitis Induces Changes in the Contractile Response of Circular Smooth Muscle in the Distal Colon

DTIC Science & Technology

1996-03-27

contractile response of circular smooth muscle in the rat distal colon" Name of Candidate: Jeanette M. Hosseini Doctor of Philosophy Degree 27 March 1996... muscle in the rat distal colon" beyond brief excerpts is with the pennission of the copyright owner, and will save and hold harmless the Unifonned...induces changes in the contractile response of circular smooth muscle 10 the rat colon. Jeanette Marie Hosseini, 1996 Dissertation directed by: Terez

The Impact of Muscle Disuse on Muscle Atrophy in Severely Burned Rats

DTIC Science & Technology

2010-12-01

Following muscle collection from the right hindlimb, muscle isometric force of PL and SL was measured simultaneously in the left hindlimb under...37.5°C by manually adjusting the temperature of cir culating water in the rat surgical bed. The isometric force of the PL and SL muscles was then...the physiologic cross sectional area (CSA) of PL and SL was calculated using the following formula: CSA= ( muscle mass) × cos θ ( muscle fiber

Muscles involved in naris dilation and nose motion in rat

PubMed Central

Deschênes, Martin; Haidarliu, Sebastian; Demers, Maxime; Moore, Jeffrey; Kleinfeld, David; Ahissar, Ehud

2016-01-01

In a number of mammals muscle dilator nasi (naris) is known as a muscle that reduces nasal airflow resistance by dilating the nostrils. Here we show that in rats the tendon of this muscle inserts into the aponeurosis above the nasal cartilage. Electrical stimulation of this muscle lifts the nose and deflects it sideway towards the side of stimulation, but does not change the size of the nares. In the head-fixed alert rat, electromyographic activity of muscle dilator nasi is tightly coupled to nose motion, not to opening of the nares. Yet, contraction of muscle dilator nasi occurs during the pre-inspiratory phase of the respiratory cycle, suggesting a role in sniffing and sampling odorants. We also show that opening of the nares results from contraction of pars maxillaris profunda of the muscle nasolabialis profundus. This muscle attaches to the outer wall of the nasal cartilage and to the plate of the mystacial pad. Contraction of this muscle exerts a dual action: it pulls the lateral nasal cartilage outwardly, thus dilating the naris, and it drags the plate of the mystacial pad rostralward, provoking a slight retraction of the whiskers. On the basis of these results, we propose that muscle dilator nasi of the rat be renamed muscle deflector nasi, and that pars maxillaris profunda of the muscle nasolabialis profundus be named muscle dilator nasi. PMID:25257748

The alterations in adenosine nucleotides and lactic acid in striated muscles of rats during Rigor mortis following death with drowning or cervical dislocation.

PubMed

Pençe, Halime Hanim; Pençe, Sadrettin; Kurtul, Naciye; Yilmaz, Necat; Kocoglu, Hasan; Bakan, Ebubekir

2003-01-01

In this study, adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and lactic acid in the muscles of masseter, triceps, and quadriceps obtained from right and left sides of Spraque-Dawley rats following death were investigated. The samples were taken immediately and 120 minutes after death occurred. The rats were killed either by cervical dislocation or drowning. ATP concentrations in the muscles of masseter, triceps, and quadriceps were lower in samples obtained 120 minutes after death than in those obtained immediately after death. ADP, AMP, and lactic acid concentrations in these muscles were higher in samples obtained 120 minutes after death than those obtained immediately after death. A positive linear correlation was determined between ATP and ADP concentrations in quadriceps muscles of the rats killed with cervical dislocation and in triceps muscles of the rats killed with drowning. When rats killed with cervical dislocation and with drowning were compared, ADP, AMP, and lactic acid concentrations were lower in the former than in the latter for both times (immediately and 120 minutes after death occurred). In the case of drowning, ATP is consumed faster because of hard exercise or severe physical activity, resulting in a faster rigor mortis. Higher lactic acid levels were determined in muscles of the rats killed with drowning than the other group. In the control and electric shock rats, ATP decreased in different levels in the three different muscle types mentioned above in control group, being much decline in masseter and then in quadriceps. This may be caused by lower mass and less glycogen storage of masseter. No different ATP levels were measured in drowning group with respect to the muscle type possibly because of the severe activity of triceps and quadriceps and because of smaller mass of masseter. One can conclude that the occurrence of rigor mortis is closely related to the mode of death.

No effect of NOS inhibition on skeletal muscle glucose uptake during in situ hindlimb contraction in healthy and diabetic Sprague-Dawley rats.

PubMed

Hong, Yet Hoi; Betik, Andrew C; Premilovac, Dino; Dwyer, Renee M; Keske, Michelle A; Rattigan, Stephen; McConell, Glenn K

2015-05-15

Nitric oxide (NO) has been shown to be involved in skeletal muscle glucose uptake during contraction/exercise, especially in individuals with Type 2 diabetes (T2D). To examine the potential mechanisms, we examined the effect of local NO synthase (NOS) inhibition on muscle glucose uptake and muscle capillary blood flow during contraction in healthy and T2D rats. T2D was induced in Sprague-Dawley rats using a combined high-fat diet (23% fat wt/wt for 4 wk) and low-dose streptozotocin injections (35 mg/kg). Anesthetized animals had one hindlimb stimulated to contract in situ for 30 min (2 Hz, 0.1 ms, 35 V) with the contralateral hindlimb rested. After 10 min, the NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME; 5 μM) or saline was continuously infused into the femoral artery of the contracting hindlimb until the end of contraction. Surprisingly, there was no increase in skeletal muscle NOS activity during contraction in either group. Local NOS inhibition had no effect on systemic blood pressure or muscle contraction force, but it did cause a significant attenuation of the increase in femoral artery blood flow in control and T2D rats. However, NOS inhibition did not attenuate the increase in muscle capillary recruitment during contraction in these rats. Muscle glucose uptake during contraction was significantly higher in T2D rats compared with controls but, unlike our previous findings in hooded Wistar rats, NOS inhibition had no effect on glucose uptake during contraction. In conclusion, NOS inhibition did not affect muscle glucose uptake during contraction in control or T2D Sprague-Dawley rats, and this may have been because there was no increase in NOS activity during contraction. Copyright © 2015 the American Physiological Society.

Neutrophil dysfunction in rats with natural gingivitis.

PubMed

Isogai, E; Wakizaka, H; Miura, H; Isogai, H; Hayashi, M

1993-01-01

The functions of polymorphonuclear neutrophils (PMN) from SUS rats with naturally occurring gingivitis were examined by the luminol-dependent chemiluminescence (CL), adherence and bactericidal tests. SUS rats with pre-gingivitis showed lower CL responses of isolated PMNs and whole blood than control rats (RES rats). After plague formation and progression of gingivitis, the CL response gradually increased in SUS rats. RES rats had healthy gingiva and showed no increase in CL responses. Impaired PMN adherence was observed in SUS rats with pre-gingivitis but not in RES rats. PMNs from SUS rats with pre-gingivitis also showed lower bactericidal activity than those from RES rats. Dysfunction of PMNs might induce gingivitis as a result of decreased protection against periodontal pathogens and an elevated level of CL response can be recognized with progression of gingivitis.

Cavin4b/Murcb Is Required for Skeletal Muscle Development and Function in Zebrafish

PubMed Central

Housley, Michael P.; Njaine, Brian; Ricciardi, Filomena; Stone, Oliver A.; Hölper, Soraya; Krüger, Marcus; Kostin, Sawa; Stainier, Didier Y. R.

2016-01-01

Skeletal muscles provide metazoans with the ability to feed, reproduce and avoid predators. In humans, a heterogeneous group of genetic diseases, termed muscular dystrophies (MD), lead to skeletal muscle dysfunction. Mutations in the gene encoding Caveolin-3, a principal component of the membrane micro-domains known as caveolae, cause defects in muscle maintenance and function; however it remains unclear how caveolae dysfunction underlies MD pathology. The Cavin family of caveolar proteins can form membrane remodeling oligomers and thus may also impact skeletal muscle function. Changes in the distribution and function of Cavin4/Murc, which is predominantly expressed in striated muscles, have been reported to alter caveolae structure through interaction with Caveolin-3. Here, we report the generation and phenotypic analysis of murcb mutant zebrafish, which display impaired swimming capacity, skeletal muscle fibrosis and T-tubule abnormalities during development. To understand the mechanistic importance of Murc loss of function, we assessed Caveolin-1 and 3 localization and found it to be abnormal. We further identified an in vivo function for Murc in Erk signaling. These data link Murc with developmental defects in T-tubule formation and progressive muscle dysfunction, thereby providing a new candidate for the etiology of muscular dystrophy. PMID:27294373

Importance of SERCA2a on early isolated diastolic dysfunction induced by supravalvular aortic stenosis in rats

PubMed Central

Silveira, C.F.S.M.P.; Campos, D.H.S.; Freire, P.P.; Deus, A.F.; Okoshi, K.; Padovani, C.R.; Cicogna, A.C.

2017-01-01

Cardiac remodeling is defined as changes in shape and function of the heart in response to aggression (pressure overload). The sarcoplasmic reticulum calcium ATPase cardiac isoform 2a (SERCA2a) is a known factor that influences function. A wide spectrum of studies report a decrease in SERCA2a in heart failure, but none evaluate it's the role in early isolated diastolic dysfunction in supravalvular aortic stenosis (AoS). Our hypothesis was that SERCA2a participates in such dysfunction. Thirty-day-old male Wistar rats (60-80 g) were divided into AoS and Sham groups, which were submitted to surgery with or without aorta clipping, respectively. After 6 weeks, the animals were submitted to echocardiogram and functional analysis by isolated papillary muscle (IPM) in basal condition, hypoxia, and SERCA2a blockage with cyclopiazonic acid at calcium concentrations of 0.5, 1.5, and 2.5 mM. Western-blot analyses were used for SERCA2a and phospholamban detection. Data analysis was carried out with Student's t-test and ANOVA. AoS enhanced left atrium and E and A wave ratio, with preserved ejection fraction. Basal condition in IPM showed similar increases in developed tension (DT) and resting tension (RT) in AoS, and hypoxia was similar between groups. After cyclopiazonic acid blockage, final DT was equally decreased and RT was similar between groups, but the speed of relaxation was decreased in the AoS group. Western-blot was uniform in all evaluations. The hypothesis was confirmed, since functional parameters regarding SERCA2a were changed in the AoS group. PMID:28423119

The protective effect of bergamot oil extract on lecitine-like oxyLDL receptor-1 expression in balloon injury-related neointima formation.

PubMed

Mollace, Vincenzo; Ragusa, Salvatore; Sacco, Iolanda; Muscoli, Carolina; Sculco, Francesca; Visalli, Valeria; Palma, Ernesto; Muscoli, Saverio; Mondello, Luigi; Dugo, Paola; Rotiroti, Domenicantonio; Romeo, Francesco

2008-06-01

Lectin-like oxyLDL receptor-1 (LOX-1) has recently been suggested to be involved in smooth muscle cell (SMC) proliferation and neointima formation in injured blood vessels. This study evaluates the effect of the nonvolatile fraction (NVF), the antioxidant component of bergamot essential oil (BEO), on LOX-1 expression and free radical generation in a model of rat angioplasty. Common carotid arteries injured by balloon angioplasty were removed after 14 days for histopathological, biochemical, and immunohistochemical studies. Balloon injury led to a significant restenosis with SMC proliferation and neointima formation, accompanied by increased expression of LOX-1 receptor, malondialdehyde and superoxide formation, and nitrotyrosine staining. Pretreatment of rats with BEO-NVF reduced the neointima proliferation together with free radical formation and LOX-1 expression in a dose-dependent manner. These results suggest that natural antioxidants may be relevant in the treatment of vascular disorders in which proliferation of SMCs and oxyLDL-related endothelial cell dysfunction are involved.

Motor Unit Changes Seen With Skeletal Muscle Sarcopenia in Oldest Old Rats

PubMed Central

Kung, Theodore A.; van der Meulen, Jack H.; Urbanchek, Melanie G.; Kuzon, William M.; Faulkner, John A.

2014-01-01

Sarcopenia leads to many changes in skeletal muscle that contribute to atrophy, force deficits, and subsequent frailty. The purpose of this study was to characterize motor unit remodeling related to sarcopenia seen in extreme old age. Whole extensor digitorum longus muscle and motor unit contractile properties were measured in 19 adult (11–13 months) and 12 oldest old (36–37 months) Brown-Norway rats. Compared with adults, oldest old rats had significantly fewer motor units per muscle, smaller muscle cross-sectional area, and lower muscle specific force. However, mean motor unit force generation was similar between the two groups due to an increase in innervation ratio by the oldest old rats. These findings suggest that even in extreme old age both fast- and slow-twitch motor units maintain the ability to undergo motor unit remodeling that offsets some effects of sarcopenia. PMID:24077596

A comparative study of charge movement in rat and frog skeletal muscle fibres.

PubMed

Hollingworth, S; Marshall, M W

1981-12-01

1. The middle of the fibre voltage--clamp technique (Adrian & Marshall, 1977), modified where necessary for electrically short muscle fibres, has been used to measure non-linear charge movements in mammalian fast twitch (rat extensor digitorum longus), mammalian slow twitch (rat soleus) and frog (sartorius) muscles. 2. The maximum amount of charge moved in mammalian fast twitch muscle at 2 degrees C in hypertonic solution, was 3--5 times greater than in slow twitch muscle. The voltage distribution of fast twitch charge was 10--15 mV more positive when compared to slow twitch. 3. In both mammalian muscle types hypertonic Ringer solution negatively shifted the voltage distribution of charge some 6 mV. The steepness of charge moved around mechanical threshold was unaffected by hypertonicity. 4. The amount of charge in frog sartorius fibres at 2 degrees C in hypertonic solution was about half of that in rat fast twitch muscle; the voltage distribution of the frog charge was similar to rat soleus muscle. 5. Warming between 2 and 15 degrees C had no effect on either the amount of steady-state distribution of charge in mammalian or frog muscles. 6. At 2 degrees C, the kinetics of charge movement in fast and slow twitch mammalian muscles were similar and 2--3 times faster than frog muscle at the same temperature. In fast and slow mammalian fibres at 2 degrees C similar times were taken to shift the same fractions of the total amount of charge. The Q10 of charge movement kinetics was between 1.2 and 2.0 in the three muscles studied.

Effect of Electrical Stimulation on Beta-Adrenergic Receptor Population and Coupling Efficiency in Chicken and Rat Skeleton Muscle Cell Cultures

NASA Technical Reports Server (NTRS)

Young, Ronald B.; Bridge, Kristin Y.; Strietzel, Catherine J.

1999-01-01

Expression of the beta-adrenergic receptor (bAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the bAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the bAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. Thus, in chicken muscle cells an enhanced level of contraction reduced the coupling efficiency of bAR for cyclic AMP production by approximately 55% compared to controls. In contrast, the bAR population in rat muscle cells was increased by approximately 25% by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was also increased by almost two-fold. Thus, in rat muscle cells an enhanced level of contraction increased the coupling efficiency of bAR for cyclic AMP production by approximately 50% compared to controls. The basal levels of intracellular cyclic AMP in both rat muscle cells and chicken muscle cells were not affected by electrical stimulation.

Sinusoidal Endothelial Dysfunction Precedes Inflammation and Fibrosis in a Model of NAFLD

PubMed Central

Pasarín, Marcos; La Mura, Vincenzo; Gracia-Sancho, Jorge; García-Calderó, Héctor; Rodríguez-Vilarrupla, Aina; García-Pagán, Juan Carlos; Bosch, Jaime; Abraldes, Juan G.

2012-01-01

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation. PMID:22509248

Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats.

PubMed

Pourkhodadad, Soheila; Alirezaei, Masoud; Moghaddasi, Mehrnoush; Ahmadvand, Hassan; Karami, Manizheh; Delfan, Bahram; Khanipour, Zahra

2016-09-01

Alzheimer's disease is a progressive neurodegenerative disorder with decline in memory. The role of oxidative stress is well known in the pathogenesis of the disease. The purpose of this study was to evaluate pretreatment effects of oleuropein on oxidative status and cognitive dysfunction induced by colchicine in the hippocampal CA1 area. Male Wistar rats were pretreated orally once daily for 10 days with oleuropein at doses of 10, 15 and 20 mg/kg. Thereafter, colchicine (15 μg/rat) was administered into the CA1 area of the hippocampus to induce cognitive dysfunction. The Morris water maze was used to assess learning and memory. Biochemical parameters such as glutathione peroxidase and catalase activities, nitric oxide and malondialdehyde concentrations were measured to evaluate the antioxidant status in the rat hippocampus. Our results indicated that colchicine significantly impaired spatial memory and induced oxidative stress; in contrast, oleuropein pretreatment significantly improved learning and memory retention, and attenuated the oxidative damage. The results clearly indicate that oleuropein has neuroprotective effects against colchicine-induced cognitive dysfunction and oxidative damage in rats.

Cyclosporine A normalizes mitochondrial coupling, reactive oxygen species production, and inflammation and partially restores skeletal muscle maximal oxidative capacity in experimental aortic cross-clamping.

PubMed

Pottecher, Julien; Guillot, Max; Belaidi, Elise; Charles, Anne-Laure; Lejay, Anne; Gharib, Abdallah; Diemunsch, Pierre; Geny, Bernard

2013-04-01

By binding to cyclophilin D, cyclosporine A (CsA) inhibits mitochondrial permeability transition pore (mPTP) opening and prevents mitochondrial dysfunction and ultimately cell death after ischemia-reperfusion (IR) injury in cardiac muscle. This study tested whether CsA would decrease skeletal muscle oxidative stress and mitochondrial dysfunctions after aortic cross-clamping related IR. Forty-five Wistar rats were investigated. The sham group (n = 8) had aortic exposure but no ischemia, the IR group (n = 10) had aortic cross-clamping for 3 hours followed by 2 hours of reperfusion, and the IR+CsA group (n = 9) had two intraperitoneal injections of 10 mg of CsA at 90 and 150 minutes of ischemia before reperfusion. Mitochondrial coupling (acceptor control ratio) and mitochondrial respiratory chain complexes' activities were measured. Reactive oxygen species (ROS) production, cyclophilin D expression, and muscle inflammation were determined using dihydroethidium staining, Western blot, and immunohistochemistry, respectively. An additional 18 sham rats were investigated to determine CsA blood levels and the effects of CsA on mitochondrial respiration and calcium retention capacity, a marker of mPTP opening, both in myocardium and gastrocnemius with and without CsA. Compared with sham, IR decreased mitochondrial coupling (1.38 ± 0.06 vs 1.98 ± 0.20; P = .0092), increased ROS production (3992 ± 706 arbitrary units [AU] vs 1812 ± 322 AU; P = .033), was associated with macrophage infiltration, and decreased maximal oxidative capacity (V(max): 4.08 ± 0.38 μmol O(2)/min/g vs 5.98 ± 0.56 μmol O(2)/min/g; P = .015). Despite IR, CsA treatment totally restored mitochondrial coupling (1.93 ± 0.12; P = .023 vs IR), normalized ROS (1569 ± 348 AU; P = .0098 vs IR), and decreased inflammation. The V(max) was slightly enhanced (5.02 ± 0.39 μmol O(2)/min/g; P = .33 vs IR; P = .35 vs sham). Compared with myocardium, gastrocnemius muscle was characterized by a decreased cyclophilin D content (-50%) associated with an earlier opening of mPTP (calcium retention capacity increased from 10.85 ± 1.35 μM/mg dry weight [DW] to 12.11 ± 2.77 μM/mg DW; P = .65; and from 11.07 ± 1.67 to 37.65 ± 11.41 μM/mg DW; P = .0098 in gastrocnemius and heart, respectively). Cyclosporine A normalized ROS production, decreased inflammation, and restored mitochondrial coupling during aortic cross-clamping. Incomplete Vmax protection might be due to low cyclophilin D expression in gastrocnemius, preventing CsA from blocking mPTP opening. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Vildagliptin and caloric restriction for cardioprotection in pre-diabetic rats.

PubMed

Tanajak, Pongpan; Pintana, Hiranya; Siri-Angkul, Natthaphat; Khamseekaew, Juthamas; Apaijai, Nattayaporn; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2017-02-01

Long-term high-fat diet (HFD) consumption causes cardiac dysfunction. Although calorie restriction (CR) has been shown to be useful in obesity, we hypothesized that combined CR with dipeptidyl peptidase-4 (DPP-4) inhibitor provides greater efficacy than monotherapy in attenuating cardiac dysfunction and metabolic impairment in HFD-induced obese-insulin resistant rats. Thirty male Wistar rats were divided into 2 groups to be fed on either a normal diet (ND, n = 6) or a HFD (n = 24) for 12 weeks. Then, HFD rats were divided into 4 subgroups (n = 6/subgroup) to receive just the vehicle, CR diet (60% of mean energy intake and changed to ND), vildagliptin (3 mg/kg/day) or combined CR and vildagliptin for 4 weeks. Metabolic parameters, heart rate variability (HRV), cardiac mitochondrial function, left ventricular (LV) and fibroblast growth factor (FGF) 21 signaling pathway were determined. Rats on a HFD developed insulin and FGF21 resistance, oxidative stress, cardiac mitochondrial dysfunction and impaired LV function. Rats on CR alone showed both decreased body weight and visceral fat accumulation, whereas vildagliptin did not alter these parameters. Rats in CR, vildagliptin and CR plus vildagliptin subgroups had improved insulin sensitivity and oxidative stress. However, vildagliptin improved heart rate variability (HRV), cardiac mitochondrial function and LV function better than the CR. Chronic HFD consumption leads to obese-insulin resistance and FGF21 resistance. Although CR is effective in improving metabolic regulation, vildagliptin provides greater efficacy in preventing cardiac dysfunction by improving anti-apoptosis and FGF21 signaling pathways and attenuating cardiac mitochondrial dysfunction in obese-insulin-resistant rats. © 2017 Society for Endocrinology.

[Forskolin inhibits spontaneous contraction of gastric antral smooth muscle in rats].

PubMed

Jiang, Jing-Zhi; Sun, Qian; Xu, Dong-Yuan; Zhang, Mo-Han; Piao, Li-Hua; Cai, Ying-Lan; Jin, Zheng

2013-04-25

The aim of the present study was to investigate the effects of cyclic adenosine monophosphate (cAMP) on rat gastric antral circular smooth muscle function. Forskolin, a direct activator of adenylyl cyclase (AC), was used to observe the influences of cAMP. Multi-channel physiological recorder was used to record spontaneous contraction activity of gastric antral circular muscle from Wistar rats. And ELISA method was used to detect the change of cAMP production in perfusate. The results showed that forskolin concentration-dependently suppressed the amplitude and frequency of the spontaneous contraction of the gastric antral muscle, and lowered the baseline of contraction movement significantly. Forskolin concentration-dependently increased the production of cAMP in the perfusate, which showed a significant negative correlation with the contraction amplitude of gastric antral ring muscle. The inhibitory effect of forskolin on spontaneous contraction activity of rat gastric antral circular muscle could be blocked by cAMP-dependent protein kinase (PKA) inhibitor H-89. These results suggest forskolin increases cAMP production and then activates PKA pathway, resulting in the inhibition of the spontaneous contraction activity of rat gastric antral circular smooth muscle.

Daily muscle stretching enhances blood flow, endothelial function, capillarity, vascular volume and connectivity in aged skeletal muscle.

PubMed

Hotta, Kazuki; Behnke, Bradley J; Arjmandi, Bahram; Ghosh, Payal; Chen, Bei; Brooks, Rachael; Maraj, Joshua J; Elam, Marcus L; Maher, Patrick; Kurien, Daniel; Churchill, Alexandra; Sepulveda, Jaime L; Kabolowsky, Max B; Christou, Demetra D; Muller-Delp, Judy M

2018-05-15

In aged rats, daily muscle stretching increases blood flow to skeletal muscle during exercise. Daily muscle stretching enhanced endothelium-dependent vasodilatation of skeletal muscle resistance arterioles of aged rats. Angiogenic markers and capillarity increased in response to daily stretching in muscles of aged rats. Muscle stretching performed with a splint could provide a feasible means of improving muscle blood flow and function in elderly patients who cannot perform regular aerobic exercise. Mechanical stretch stimuli alter the morphology and function of cultured endothelial cells; however, little is known about the effects of daily muscle stretching on adaptations of endothelial function and muscle blood flow. The present study aimed to determine the effects of daily muscle stretching on endothelium-dependent vasodilatation and muscle blood flow in aged rats. The lower hindlimb muscles of aged Fischer rats were passively stretched by placing an ankle dorsiflexion splint for 30 min day -1 , 5 days week -1 , for 4 weeks. Blood flow to the stretched limb and the non-stretched contralateral limb was determined at rest and during treadmill exercise. Endothelium-dependent/independent vasodilatation was evaluated in soleus muscle arterioles. Levels of hypoxia-induced factor-1α, vascular endothelial growth factor A and neuronal nitric oxide synthase were determined in soleus muscle fibres. Levels of endothelial nitric oxide synthase and superoxide dismutase were determined in soleus muscle arterioles, and microvascular volume and capillarity were evaluated by microcomputed tomography and lectin staining, respectively. During exercise, blood flow to plantar flexor muscles was significantly higher in the stretched limb. Endothelium-dependent vasodilatation was enhanced in arterioles from the soleus muscle from the stretched limb. Microvascular volume, number of capillaries per muscle fibre, and levels of hypoxia-induced factor-1α, vascular endothelial growth factor and endothelial nitric oxide synthase were significantly higher in the stretched limb. These results indicate that daily passive stretching of muscle enhances endothelium-dependent vasodilatation and induces angiogenesis. These microvascular adaptations may contribute to increased muscle blood flow during exercise in muscles that have undergone daily passive stretch. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Rapid determination of myosin heavy chain expression in rat, mouse, and human skeletal muscle using multicolor immunofluorescence analysis.

PubMed

Bloemberg, Darin; Quadrilatero, Joe

2012-01-01

Skeletal muscle is a heterogeneous tissue comprised of fibers with different morphological, functional, and metabolic properties. Different muscles contain varying proportions of fiber types; therefore, accurate identification is important. A number of histochemical methods are used to determine muscle fiber type; however, these techniques have several disadvantages. Immunofluorescence analysis is a sensitive method that allows for simultaneous evaluation of multiple MHC isoforms on a large number of fibers on a single cross-section, and offers a more precise means of identifying fiber types. In this investigation we characterized pure and hybrid fiber type distribution in 10 rat and 10 mouse skeletal muscles, as well as human vastus lateralis (VL) using multicolor immunofluorescence analysis. In addition, we determined fiber type-specific cross-sectional area (CSA), succinate dehydrogenase (SDH) activity, and α-glycerophosphate dehydrogenase (GPD) activity. Using this procedure we were able to easily identify pure and hybrid fiber populations in rat, mouse, and human muscle. Hybrid fibers were identified in all species and made up a significant portion of the total population in some rat and mouse muscles. For example, rat mixed gastrocnemius (MG) contained 12.2% hybrid fibers whereas mouse white tibialis anterior (WTA) contained 12.1% hybrid fibers. Collectively, we outline a simple and time-efficient method for determining MHC expression in skeletal muscle of multiple species. In addition, we provide a useful resource of the pure and hybrid fiber type distribution, fiber CSA, and relative fiber type-specific SDH and GPD activity in a number of rat and mouse muscles.

Dietary protein deficiency reduces lysosomal and nonlysosomal ATP-dependent proteolysis in muscle

NASA Technical Reports Server (NTRS)

Tawa, N. E. Jr; Kettelhut, I. C.; Goldberg, A. L.

1992-01-01

When rats are fed a protein deficient (PD) diet for 7 days, rates of proteolysis in skeletal muscle decrease by 40-50% (N. E. Tawa, Jr., and A. L. Goldberg. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E317-325, 1992). To identify the underlying biochemical adaptations, we measured different proteolytic processes in incubated muscles. The capacity for intralysosomal proteolysis, as shown by sensitivity to methylamine or lysosomal protease inhibitors, fell 55-75% in muscles from PD rats. Furthermore, extracts of muscles of PD rats showed 30-70% lower activity of many lysosomal proteases, including cathepsins B, H, and C, and carboxypeptidases A and C, as well as other lysosomal hydrolases. The fall in cathepsin B and proteolysis was evident by 3 days on the PD diet, and both returned to control levels 3 days after refeeding of the normal diet. In muscles maintained under optimal conditions, 80-90% of protein breakdown occurs by nonlysosomal pathways. In muscles of PD rats, this ATP-dependent process was also 40-60% slower. Even though overall proteolysis decreased in muscles of PD rats, their capacity for Ca(2+)-dependent proteolysis increased (by 66%), as did the activity of the calpains (+150-250%). Thus the lysosomal and the ATP-dependent processes decrease coordinately and contribute to the fall in muscle proteolysis in PD animals.

Expression of uncoupling protein 3 is upregulated in skeletal muscle during sepsis.

PubMed

Sun, Xiaoyan; Wray, Curtis; Tian, Xintian; Hasselgren, Per-Olof; Lu, James

2003-09-01

Uncoupling protein 3 (UCP3) is a member of the mitochondrial transporter superfamily that is expressed primarily in skeletal muscle. UCP3 is upregulated in various conditions characterized by skeletal muscle atrophy, including hyperthyroidism, fasting, denervation, diabetes, cancer, lipopolysaccharide (LPS), and treatment with glucocorticoids (GCs). The influence of sepsis, another condition characterized by muscle cachexia, on UCP3 expression and activity is not known. We examined UCP3 gene and protein expression in skeletal muscles from rats after cecal ligation and puncture and from sham-operated control rats. Sepsis resulted in a two- to threefold increase in both mRNA and protein levels of UCP3 in skeletal muscle. Treatment of rats with the glucocorticoid receptor antagonist RU-38486 prevented the sepsis-induced increase in gene and protein expression of UCP3. The UCP3 mRNA and protein levels were increased 2.4- to 3.6-fold when incubated muscles from normal rats were treated with dexamethasone (DEX) and/or free fatty acids (FFA) ex vivo. In addition, UCP3 mRNA and protein levels were significantly increased in normal rat muscles in vivo with treatment of either DEX or FFA. The results suggest that sepsis upregulates the gene and protein expression of UCP3 in skeletal muscle, which may at least in part be mediated by GCs and FFA.

Glycogen supercompensation masks the effect of a traininginduced increase in GLUT-4 on muscle glucose transport.

PubMed

Host, H H; Hansen, P A; Nolte, L A; Chen, M M; Holloszy, J O

1998-07-01

Endurance exercise training induces a rapid increase in the GLUT-4 isoform of the glucose transporter in muscle. In fasted rats, insulin-stimulated muscle glucose transport is increased in proportion to the increase in GLUT-4. There is evidence that high muscle glycogen may decrease insulin-stimulated glucose transport. This study was undertaken to determine whether glycogen supercompensation interferes with the increase in glucose transport associated with an exercise-induced increase in GLUT-4. Rats were trained by means of swimming for 6 h/day for 2 days. Rats fasted overnight after the last exercise bout had an approximately twofold increase in epitrochlearis muscle GLUT-4 and an associated approximately twofold increase in maximally insulin-stimulated glucose transport activity. Epitrochlearis muscles of rats fed rodent chow after exercise were glycogen supercompensated (86.4 +/- 4.8 micromol/g wet wt) and showed no significant increase in maximally insulin-stimulated glucose transport above the sedentary control value despite an approximately twofold increase in GLUT-4. Fasting resulted in higher basal muscle glucose transport rates in both sedentary and trained rats but did not significantly increase maximally insulin-stimulated transport in the sedentary group. We conclude that carbohydrate feeding that results in muscle glycogen supercompensation prevents the increase in maximally insulin-stimulated glucose transport associated with an exercise training-induced increase in muscle GLUT-4.

Kinetics of GLUT4 Trafficking in Rat and Human Skeletal Muscle

PubMed Central

Karlsson, Håkan K.R.; Chibalin, Alexander V.; Koistinen, Heikki A.; Yang, Jing; Koumanov, Francoise; Wallberg-Henriksson, Harriet; Zierath, Juleen R.; Holman, Geoffrey D.

2009-01-01

OBJECTIVE In skeletal muscle, insulin stimulates glucose transport activity three- to fourfold, and a large part of this stimulation is associated with a net translocation of GLUT4 from an intracellular compartment to the cell surface. We examined the extent to which insulin or the AMP-activated protein kinase activator AICAR can lead to a stimulation of the exocytosis limb of the GLUT4 translocation pathway and thereby account for the net increase in glucose transport activity. RESEARCH DESIGN AND METHODS Using a biotinylated photoaffinity label, we tagged endogenous GLUT4 and studied the kinetics of exocytosis of the tagged protein in rat and human skeletal muscle in response to insulin or AICAR. Isolated epitrochlearis muscles were obtained from male Wistar rats. Vastus lateralis skeletal muscle strips were prepared from open muscle biopsies obtained from six healthy men (age 39 ± 11 years and BMI 25.8 ± 0.8 kg/m2). RESULTS In rat epitrochlearis muscle, insulin exposure leads to a sixfold stimulation of the GLUT4 exocytosis rate (with basal and insulin-stimulated rate constants of 0.010 and 0.067 min−1, respectively). In human vastus lateralis muscle, insulin stimulates GLUT4 translocation by a similar sixfold increase in the exocytosis rate constant (with basal and insulin-stimulated rate constants of 0.011 and 0.075 min−1, respectively). In contrast, AICAR treatment does not markedly increase exocytosis in either rat or human muscle. CONCLUSIONS Insulin stimulation of the GLUT4 exocytosis rate constant is sufficient to account for most of the observed increase in glucose transport activity in rat and human muscle. PMID:19188436

Anabolic effects of clenbuterol after long-term treatment and withdrawal in t the rat.

PubMed

Cartañà, J; Segués, T; Yebras, M; Rothwell, N J; Stock, M J

1994-09-01

Injection of rats with the beta 2-adrenoceptor agonist clenbuterol (1 mg/kg/d for 15 days) stimulated an increase in body weight (9%) and protein (8%) and water (7%) content, but reduced food intake (4%) and epididymal fat pad mass (39%). Nine days after termination of treatment, ex-clenbuterol rats were heavier (5%) and had a greater protein (7%) and water (6%) content and lower fat pad mass (32%) than controls. Clenbuterol-fed rats (2 mg/kg diet for 10 days, providing an average of 0.04 mg clenbuterol/kg/d) increased body weight (7%), muscle mass (15% to 21%), and muscle protein content (9% to 26%), whereas epididymal fat pad weight and muscle glycogen content were reduced. During the withdrawal period, the greater body weight of ex-clenbuterol rats was sustained overall (ANOVA, P < .00005), but by day 10 this difference was no longer significant. At this point, gastrocnemius muscle mass was still higher (11%) when compared with that of control animals, but soleus muscle mass, muscle glycogen concentration, and epididymal fat pad weight had reverted to control values. These results were corroborated in a subsequent experiment using older rats. It was concluded that, unlike other beta-adrenoceptor-mediated effects, muscle protein accumulated during clenbuterol treatment can be maintained in certain muscles after removal of the drug for a period of time that is at least equivalent to the duration of treatment. This could have implications for the potential therapeutic use of this class of compound, and differences in the response observed between muscle types may help to elucidate the mechanisms responsible for the muscle protein deposition induced by clenbuterol.

Effect of experimental hyperthyroidism on skeletal-muscle proteolysis.

PubMed

Carter, W J; van der Weijden Benjamin, W S; Faas, F H

1981-03-15

It is not clear whether the muscle wasting commonly observed in hyperthyroidism is due to alteration in the rate of protein synthesis or degradation. The effect of experimental hyperthyroidism on skeletal-muscle proteolysis in the rat was studied by measuring alanine and tyrosine release from isolated skeletal muscles in vitro and 3-methyl-histidine excretion in vivo. Alanine release from the isolated epitrochlaris-muscle preparation was increased as soon as 24h after a 25 microgram dose of L-tri-iodothyronine in vivo. Conversely, alanine release from muscles of hypothyroid rats was decreased, but restored by L-tri-iodothyronine supplementation before death. Furthermore, 3-methylhistidine excretion was increased in hyperthyroid rats throughout an 18-day treatment period. The increased amino acid release from isolated muscles and the increased 3-methylhistidine excretion in vivo strongly suggests that hyperthyroidism increases skeletal-muscle proteolysis. Furthermore, the thyroid-hormone concentration may be an important factor in regulating muscle proteolysis.

Effect of experimental hyperthyroidism on skeletal-muscle proteolysis.

PubMed Central

Carter, W J; van der Weijden Benjamin, W S; Faas, F H

1981-01-01

It is not clear whether the muscle wasting commonly observed in hyperthyroidism is due to alteration in the rate of protein synthesis or degradation. The effect of experimental hyperthyroidism on skeletal-muscle proteolysis in the rat was studied by measuring alanine and tyrosine release from isolated skeletal muscles in vitro and 3-methyl-histidine excretion in vivo. Alanine release from the isolated epitrochlaris-muscle preparation was increased as soon as 24h after a 25 microgram dose of L-tri-iodothyronine in vivo. Conversely, alanine release from muscles of hypothyroid rats was decreased, but restored by L-tri-iodothyronine supplementation before death. Furthermore, 3-methylhistidine excretion was increased in hyperthyroid rats throughout an 18-day treatment period. The increased amino acid release from isolated muscles and the increased 3-methylhistidine excretion in vivo strongly suggests that hyperthyroidism increases skeletal-muscle proteolysis. Furthermore, the thyroid-hormone concentration may be an important factor in regulating muscle proteolysis. PMID:7306017

Modulation of the cytosolic androgen receptor in striated muscle by sex steroids

NASA Technical Reports Server (NTRS)

Rance, N. E.; Max, S. E.

1982-01-01

The influence of orchiectomy (GDX) and steroid administration on the level of the cytosolic androgen receptor in the rat levator ani muscle and in rat skeletal muscles (tibialis anterior and extensor digitorum longus) was studied. Androgen receptor binding to muscle cytosol was measured using H-3 methyltrienolone (R1881) as ligand, 100 fold molar excess unlabeled R1881 to assess nonspecific binding, and 500 fold molar excess of triamcinolone acetonide to prevent binding to glucocorticoid and progestin receptors. Results demonstrate that modification of the levels of sex steroids can alter the content of androgen receptors of rat striated muscle. Data suggest that: (1) cytosolic androgen receptor levels increase after orchiectomy in both levator ani muscle and skeletal muscle; (2) the acute increase in receptor levels is blocked by an inhibitor of protein synthesis; and (3) administration of estradiol-17 beta to castrated animals increases receptor binding in levator ani muscle but not in skeletal muscle.

Creatine Supplementation Induces Alteration in Cross-Sectional Area in Skeletal Muscle Fibers of Wistar Rats Under Swimming Training

PubMed Central

Santos, Fernando Farias Dos; Moura, José A. A.; Curi, Rui; Fernandes, Luiz C.

2002-01-01

Creatine has been shown to increase the total muscle mass. In this study, we investigated the effect of oral creatine monohydrate supplementation on cross-sectional area of type I, IIA and IIB fibers of gastrocnemius, extensor digitorum longus - EDL and soleus muscles from male Wistar rats subjected to swimming training for 33 days. Four groups were set up: sedentary with no supplementation (CON), sedentary with creatine supplementation (3.3 mg creatine per g chow) (CR), exercised with no supplementation (EX) and exercised with supplementation (CREX). The rats performed in a special swimming pool and swam five times a week for 1 hour each day, with a extra lead weight corresponding to 15% of their body weight. At the end of 33 days, skeletal muscles of the animals were dissected and the samples got immediately frozen using liquid nitrogen. Muscle samples were allocated to slices of 10 μm by a cryostat at -20°C, which was followed by histochemical analysis in order to identify fiber types of the muscles, and morphometrical analysis to calculate the muscle fiber areas. All groups gained body weight at the end of 33 days but there was no statistical difference among them. The EX and CREX rats had a larger food intake than the sedentary groups (CON and CR), and the CREX group had a larger food intake than CR rats. The cross-sectional area of type I and IIA fibers of the soleus muscle, type IIA and IIB fibers of EDL muscle and type IIA and IIB fibers of the white portion of gastrocnemius muscle were greater in the EX and CREX groups in comparison to sedentary rats. In addition, these fibers were greater in the CREX rats than in the EX group. There was no change in the cross sectional area of type I fibers in EDL muscle among all groups studied. Our results suggest that creatine supplementation enhances the exercise related muscle fiber hypertrophy in rodents. PMID:24701129

Generation of muscular dystrophy model rats with a CRISPR/Cas system.

PubMed

Nakamura, Katsuyuki; Fujii, Wataru; Tsuboi, Masaya; Tanihata, Jun; Teramoto, Naomi; Takeuchi, Shiho; Naito, Kunihiko; Yamanouchi, Keitaro; Nishihara, Masugi

2014-07-09

Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disorder caused by mutations in the Dmd gene encoding Dystrophin. DMD model animals, such as mdx mice and canine X-linked muscular dystrophy dogs, have been widely utilized in the development of a treatment for DMD. Here, we demonstrate the generation of Dmd-mutated rats using a clustered interspaced short palindromic repeats (CRISPR)/Cas system, an RNA-based genome engineering technique that is also adaptive to rats. We simultaneously targeted two exons in the rat Dmd gene, which resulted in the absence of Dystrophin expression in the F0 generation. Dmd-mutated rats exhibited a decline in muscle strength, and the emergence of degenerative/regenerative phenotypes in the skeletal muscle, heart, and diaphragm. These mutations were heritable by the next generation, and F1 male rats exhibited similar phenotypes in their skeletal muscles. These model rats should prove to be useful for developing therapeutic methods to treat DMD.

Chronic Intake of Sucrose Accelerates Sarcopenia in Older Male Rats through Alterations in Insulin Sensitivity and Muscle Protein Synthesis.

PubMed

Gatineau, Eva; Savary-Auzeloux, Isabelle; Migné, Carole; Polakof, Sergio; Dardevet, Dominique; Mosoni, Laurent

2015-05-01

Today, high chronic intake of added sugars is frequent, which leads to inflammation, oxidative stress, and insulin resistance. These 3 factors could reduce meal-induced stimulation of muscle protein synthesis and thus aggravate the age-related loss of muscle mass (sarcopenia). Our aims were to determine if added sugars could accelerate sarcopenia and to assess the capacity of antioxidants and anti-inflammatory agents to prevent this. For 5 mo, 16-mo-old male rats were starch fed (13% sucrose and 49% wheat starch diet) or sucrose fed (62% sucrose and 0% wheat starch diet) with or without rutin (5 g/kg diet), vitamin E (4 times), vitamin A (2 times), vitamin D (5 times), selenium (10 times), and zinc (+44%) (R) supplementation. We measured the evolution of body composition and inflammation, plasma insulin-like growth factor 1 (IGF-I) concentration and total antioxidant status, insulin sensitivity (oral-glucose-tolerance test), muscle weight, superoxide dismutase activity, glutathione concentration, and in vivo protein synthesis rates. Sucrose-fed rats lost significantly more lean body mass (-8.1% vs. -5.4%, respectively) and retained more fat mass (+0.2% vs. -33%, respectively) than starch-fed rats. Final muscle mass was 11% higher in starch-fed rats than in sucrose-fed rats. Sucrose had little effect on inflammation, oxidative stress, and plasma IGF-I concentration but reduced the insulin sensitivity index (divided by 2). Meal-induced stimulation of muscle protein synthesis was significantly lower in sucrose-fed rats (+7.3%) than in starch-fed rats (+22%). R supplementation slightly but significantly reduced oxidative stress and increased muscle protein concentration (+4%) but did not restore postprandial stimulation of muscle protein synthesis. High chronic sucrose intake accelerates sarcopenia in older male rats through an alteration of postprandial stimulation of muscle protein synthesis. This effect could be explained by a decrease of insulin sensitivity rather than by changes in plasma IGF-I, inflammation, and/or oxidative stress. © 2015 American Society for Nutrition.

Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats.

PubMed

Jandric, Ivan; Vrcic, Hrvoje; Jandric Balen, Marica; Kolenc, Danijela; Brcic, Luka; Radic, Bozo; Drmic, Domagoj; Seiwerth, Sven; Sikiric, Predrag

2013-03-12

Since an originally anti-ulcer stable gastric pentadecapeptide BPC 157 (PL 14736) was shown to promote healing of injured striated muscle and smooth muscle in the gastrointestinal tract, we explored its therapeutic potentials for leak point pressure (LPP) recovery in rat stress urinary incontinence (SUI) after transabdominal urethrolysis (TU) and prolonged vaginal dilatation (VD). During a 7-day period, TU-rats and VD-rats (or healthy rats) received BPC 157, either (i) intraperitoneally, 10 µg/kg or 10 ng/kg, once daily (first administration 30 min after surgery, last 24 h before LPP-testing and sacrifice), or (ii) per-orally, 10 µg/kg in drinking water (0.16 µg/mL, 12 mL/rat/day). Vesicourethral segments were harvested for immunohistochemical evaluation. All BPC 157 regimens counteracted decrease of LPP values in TU-rats and VD-rats. Additionally, BPC 157-TU rats (µg-intraperitoneally or per-orally) and BPC 157-VD rats (µg intraperitoneally) reached LPP values originally noted in healthy rats. Conversely, in healthy rats, BPC 157 did not alter LPP. Immunohistochemical studies revealed higher desmin (delineates striated organization of skeletal muscle), smooth muscle actin, and CD34 (angiogenic marker) positivity within the urethral wall in BPC 157-treated rats vs. controls, as well as overall preserved muscle/connective tissue ratio assessed with Mallory's trichrome staining. Pentadecapeptide BPC 157, applied parenterally or per-orally, appears to ameliorate the SUI in rat models, improving the otherwise detrimental course of healing after VD and TU, which may be analogous to human injury. These beneficial effects may possibly be selectively used in future strategies for treatment of SUI.

Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats

PubMed Central

Jandric, Ivan; Vrcic, Hrvoje; Balen, Marica Jandric; Kolenc, Danijela; Brcic, Luka; Radic, Bozo; Drmic, Domagoj; Seiwerth, Sven; Sikiric, Predrag

2013-01-01

Background Since an originally anti-ulcer stable gastric pentadecapeptide BPC 157 (PL 14736) was shown to promote healing of injured striated muscle and smooth muscle in the gastrointestinal tract, we explored its therapeutic potentials for leak point pressure (LPP) recovery in rat stress urinary incontinence (SUI) after transabdominal urethrolysis (TU) and prolonged vaginal dilatation (VD). Material/Methods During a 7-day period, TU-rats and VD-rats (or healthy rats) received BPC 157, either (i) intraperitoneally, 10 μg/kg or 10 ng/kg, once daily (first administration 30 min after surgery, last 24 h before LPP-testing and sacrifice), or (ii) per-orally, 10 μg/kg in drinking water (0.16 μg/mL, 12 mL/rat/day). Vesicourethral segments were harvested for immunohistochemical evaluation. Results All BPC 157 regimens counteracted decrease of LPP values in TU-rats and VD-rats. Additionally, BPC 157-TU rats (μg-intraperitoneally or per-orally) and BPC 157-VD rats (μg intraperitoneally) reached LPP values originally noted in healthy rats. Conversely, in healthy rats, BPC 157 did not alter LPP. Immunohistochemical studies revealed higher desmin (delineates striated organization of skeletal muscle), smooth muscle actin, and CD34 (angiogenic marker) positivity within the urethral wall in BPC 157-treated rats vs. controls, as well as overall preserved muscle/connective tissue ratio assessed with Mallory’s trichrome staining. Conclusions Pentadecapeptide BPC 157, applied parenterally or per-orally, appears to ameliorate the SUI in rat models, improving the otherwise detrimental course of healing after VD and TU, which may be analogous to human injury. These beneficial effects may possibly be selectively used in future strategies for treatment of SUI. PMID:23478678

Muscle Contractile Properties in Severely Burned Rats

DTIC Science & Technology

2010-01-01

slow - twitch muscles such as sloeus (data not shown). In rats, the TA contains predominantly fast ...Hasselgren PO. The molecular regulation of protein breakdown following burn injury is different in fast - and slow - twitch skeletal muscle . Int J Mol Med 1998;1...burn model, it was reported that only fast muscle fibers are affected and slow muscle fibers were mostly preserved [30–32]. We found similar results

Attenuation of endothelial dysfunction by exercise training in STZ-induced diabetic rats.

PubMed

Chakraphan, Daroonwan; Sridulyakul, Patarin; Thipakorn, Bundit; Bunnag, Srichitra; Huxley, Virginia H; Patumraj, Suthiluk

2005-01-01

The protective effects of exercise training on the diabetic-induced endothelial cell (EC) dysfunction were determined using intravital fluorescent microscopy. Male Sprague-Dawley rats were divided into three groups of control (Con), diabetes (DM), and diabetes with exercise--training (DM+Ex). Diabetes was induced by single intravenous injection of streptozotocin (STZ; 50 mg/kg BW). The exercise training protocol consisted of treadmill running, 5 times/week with the velocity of 13-15 m/min, 30 min/day periods for 12 and 24 weeks (wks). 24 wks after the STZ injection, blood glucose (BG), glycosylated hemoglobin (HbA1C), mean arterial blood pressure (MAP) and heart weight (HW) were significantly higher in DM rats (p < 0.001). However, DM+Ex rats had reduced the abnormalities of MAP (p < 0.01) and HW (p < 0.05) compared with DM rats. Furthermore, there was a significant decrease in heart rate (HR) of DM+Ex rats (p < 0.05) relative to Con rats. To examine the influence of exercise training on EC dysfunction, leukocyte-EC interactions in mesenteric venules and vascular reactivity responses to vasodilators in mesenteric arterioles were monitored by using intravital fluorescence microscopy. The diabetic state enhanced leukocyte adhesion in mesenteric postcapillary venules (p < 0.001). Moreover, an impaired vasodilatory response to the EC-dependent vasodilator, acetylcholine (Ach), not to sodium nitroprusside (SNP), was found in 12- and 24-wk diabetic rats (p < 0.01). The leukocyte adhesion and the impairment of EC-dependent vasodilation to Ach were attenuated by exercise training (p < 0.05). In addition, exercise training was also shown to have favorable preventive effects on hyperglycemia induced oxidative stress, as lower malondialdehyde (MDA) levels were observed from both groups of 12 and 24 weeks DM+Ex compared with DM (p < 0.01). In conclusion, our findings indicate that the endothelial dysfunction of diabetic rats could be characterized by increased leukocyte adhesion and impaired endothelium-dependent relaxation. Regular low intensity exercise training could improve both indices of endothelial dysfunction through amelioration of diabetic-induced oxidant/antioxidant levels. These findings support the notion that regular exercise training could be a fundamental form of therapy in preventing diabetic cardiovascular complications potentiated by endothelial dysfunction.

Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension: Relative Contribution of Fibrosis and Myofibril Stiffness.

PubMed

Rain, Silvia; Andersen, Stine; Najafi, Aref; Gammelgaard Schultz, Jacob; da Silva Gonçalves Bós, Denielli; Handoko, M Louis; Bogaard, Harm-Jan; Vonk-Noordegraaf, Anton; Andersen, Asger; van der Velden, Jolanda; Ottenheijm, Coen A C; de Man, Frances S

2016-07-01

The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction. By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction. RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness. © 2016 The Authors.

Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension

PubMed Central

Rain, Silvia; Andersen, Stine; Najafi, Aref; Gammelgaard Schultz, Jacob; da Silva Gonçalves Bós, Denielli; Handoko, M. Louis; Bogaard, Harm-Jan; Vonk-Noordegraaf, Anton; Andersen, Asger; van der Velden, Jolanda; Ottenheijm, Coen A.C.

2016-01-01

Background— The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction. Methods and Results— By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction. Conclusions— RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness. PMID:27370069

Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation.

PubMed

Musolino, Vincenzo; Palus, Sandra; Tschirner, Anika; Drescher, Cathleen; Gliozzi, Micaela; Carresi, Cristina; Vitale, Cristiana; Muscoli, Carolina; Doehner, Wolfram; von Haehling, Stephan; Anker, Stefan D; Mollace, Vincenzo; Springer, Jochen

2016-12-01

Cachexia is a complex metabolic syndrome associated with cancer. One of the features of cachexia is the loss of muscle mass, characterized by an imbalance between protein synthesis and protein degradation. Muscle atrophy is caused by the hyperactivation of some of the main cellular catabolic pathways, including autophagy. Cachexia also affects the cardiac muscle. As a consequence of the atrophy of the heart, cardiac function is impaired and mortality is increased. Anti-cachectic therapy in patients with cancer cachexia is so far limited to nutritional support and anabolic steroids. The use of the appetite stimulant megestrol acetate (MA) has been discussed as a treatment for cachexia. In this study the effects of MA were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Rats were treated daily with 100 mg/kg of MA or placebo starting one day after tumour inoculation, and for a period of 16 days. Body weight and body composition were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and at day 11. Locomotor activity and food intake were assessed before tumour inoculation and at day 11. Autophagic markers were assessed in gastrocnemius muscle and heart by western blot analysis. Treatment with 100 mg/kg/day MA significantly attenuated the loss of body weight (-9 ± 12%, P  < 0.05) and the wasting of lean and fat mass (-7.0 ± 6% and -22.4 ± 3 %, P  < 0.001 and P  < 0.05, respectively). Administration of 100 mg/kg/day MA significantly protected the heart from general atrophy (633.8 ± 30 mg vs. placebo 474 ± 13 mg, P  < 0.001). Tumour-bearing rats displayed cardiac dysfunction, as indicated by the significant impairment of the left ventricular ejection fraction, the left ventricular fractional shortening, the stroke volume, the end dyastolic volume, and the end systolic volume. In contrast, MA significantly improved left ventricular ejection fraction, left ventricular fractional shortening, and left ventricular end systolic volume. Western blotting analysis showed an upregulation of the autophagic pathway in the gastrocnemius and hearts of the placebo-treated tumour-bearing rats. Treatment with MA, however, was able to modulate the autophagic markers (e.g. Beclin-1, p62, TRAF6, and LC3) in the gastrocnemius and in the hearts of tumour-bearing rats. Most importantly, 100 mg/kg/day MA reduced mortality [hazard ratio (HR): 0.44; 95%CI: 0.20-1.00; P  = 0.0486]. Megestrol acetate improved survival and reduced wasting through a marked downregulation of autophagy, occurring in both skeletal and heart muscle, the latter effect leading to a significant improvement of cardiac function. Our data suggest that MA might represent a valuable strategy to counteract the development of cancer cachexia-induced cardiomyopathy.

Effect of high-intensity intermittent swimming training on fatty acid oxidation enzyme activity in rat skeletal muscle.

PubMed

Terada, Shin; Tabata, Izumi; Higuchi, Mitsuru

2004-02-01

We previously reported that high-intensity exercise training significantly increased citrate synthase (CS) activity, a marker of oxidative enzyme, in rat skeletal muscle to a level equaling that attained after low-intensity prolonged exercise training (Terada et al., J Appl Physiol 90: 2019-2024, 2001). Since mitochondrial oxidative enzymes and fatty acid oxidation (FAO) enzymes are often increased simultaneously, we assessed the effect of high-intensity intermittent swimming training on FAO enzyme activity in rat skeletal muscle. Male Sprague-Dawley rats (3 to 4 weeks old) were assigned to a 10-day period of high-intensity intermittent exercise training (HIT), low-intensity prolonged exercise training (LIT), or sedentary control conditions. In the HIT group, the rats repeated fourteen 20 s swimming sessions with a weight equivalent to 14-16% of their body weight. Between the exercise sessions, a 10 s pause was allowed. Rats in the LIT group swam 6 h/day in two 3 h sessions separated by 45 min of rest. CS activity in the triceps muscle of rats in the HIT and LIT groups was significantly higher than that in the control rats by 36 and 39%, respectively. Furthermore, 3-beta hydroxyacyl-CoA dehydrogenase (HAD) activity, an important enzyme in the FAO pathway in skeletal muscle, was higher in the two training groups than in the control rats (HIT: 100%, LIT: 88%). No significant difference in HAD activity was observed between the two training groups. In conclusion, the present investigation demonstrated that high-intensity intermittent swimming training elevated FAO enzyme activity in rat skeletal muscle to a level similar to that attained after 6 h of low-intensity prolonged swimming exercise training.

Exercise training and return to a well-balanced diet activate the neuregulin 1/ErbB pathway in skeletal muscle of obese rats.

PubMed

Ennequin, Gaël; Boisseau, Nathalie; Caillaud, Kevin; Chavanelle, Vivien; Gerbaix, Maude; Metz, Lore; Etienne, Monique; Walrand, Stéphane; Masgrau, Aurélie; Guillet, Christelle; Courteix, Daniel; Niu, Airu; Li, Yi-Ping; Capel, Fréderic; Sirvent, Pascal

2015-06-15

Some studies suggest that neuregulin 1 (NRG1) could be involved in the regulation of skeletal muscle energy metabolism in rodents. Here we assessed whether unbalanced diet is associated with alterations of the NRG1 signalling pathway and whether exercise and diet might restore NRG1 signalling in skeletal muscle of obese rats. We show that diet-induced obesity does not impair NRG1 signalling in rat skeletal muscle. We also report that endurance training and a well-balanced diet activate the NRG1 signalling in skeletal muscle of obese rats, possibly via a new mechanism mediated by the protease ADAM17. These results suggest that some beneficial effects of physical activity and diet in obese rats could be partly explained by stimulation of the NRG1 signalling pathway. Some studies suggest that the signalling pathway of neuregulin 1 (NRG1), a protein involved in the regulation of skeletal muscle metabolism, could be altered by nutritional and exercise interventions. We hypothesized that diet-induced obesity could lead to alterations of the NRG1 signalling pathway and that chronic exercise could improve NRG1 signalling in rat skeletal muscle. To test this hypothesis, male Wistar rats received a high fat/high sucrose (HF/HS) diet for 16 weeks. At the end of this period, NRG1 and ErbB expression/activity in skeletal muscle was assessed. The obese rats then continued the HF/HS diet or were switched to a well-balanced diet. Moreover, in both groups, half of the animals also performed low intensity treadmill exercise training. After another 8 weeks, NRG1 and ErbB expression/activity in skeletal muscle were tested again. The 16 week HF/HS diet induced obesity, but did not significantly affect the NRG1/ErbB signalling pathway in rat skeletal muscle. Conversely, after the switch to a well-balanced diet, NRG1 cleavage ratio and ErbB4 amount were increased. Chronic exercise training also promoted NRG1 cleavage, resulting in increased ErbB4 phosphorylation. This result was associated with increased protein expression and phosphorylation ratio of the metalloprotease ADAM17, which is involved in NRG1 shedding. Similarly, in vitro stretch-induced activation of ADAM17 in rat myoblasts induced NRG1 cleavage and ErbB4 activation. These results show that low intensity endurance training and well-balanced diet activate the NRG1-ErbB4 pathway, possibly via the metalloprotease ADAM17, in skeletal muscle of diet-induced obese rats. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Properties of slow- and fast-twitch muscle fibres in a mouse model of amyotrophic lateral sclerosis.

PubMed

Atkin, Julie D; Scott, Rachel L; West, Jan M; Lopes, Elizabeth; Quah, Alvin K J; Cheema, Surindar S

2005-05-01

This investigation was undertaken to determine if there are altered histological, pathological and contractile properties in presymptomatic or endstage diseased muscle fibres from representative slow-twitch and fast-twitch muscles of SOD1 G93A mice in comparison to wildtype mice. In presymptomatic SOD1 G93A mice, there was no detectable peripheral dysfunction, providing evidence that muscle pathology is secondary to motor neuronal dysfunction. At disease endstage however, single muscle fibre contractile analysis demonstrated that fast-twitch muscle fibres and neuromuscular junctions are preferentially affected by amyotrophic lateral sclerosis-induced denervation, being unable to produce the same levels of force when activated by calcium as muscle fibres from their age-matched controls. The levels of transgenic SOD1 expression, aggregation state and activity were also examined in these muscles but there no was no preference for muscle fibre type. Hence, there is no simple correlation between SOD1 protein expression/activity, and muscle fibre type vulnerability in SOD1 G93A mice.

Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats

PubMed Central

Apaijai, Nattayaporn; Pintana, Hiranya; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2013-01-01

Background and Purpose Long-term high-fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinaemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction and cardiac mitochondrial dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors, vildagliptin and sitagliptin, are oral anti-diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance. Experimental Approach Male Wistar rats weighing 180–200 g, were fed either a normal diet (20% energy from fat) or a HFD (59% energy from fat) for 12 weeks. These rats were then divided into three subgroups to receive vildagliptin (3 mg·kg−1·day−1), sitagliptin (30 mg·kg−1·day−1) or vehicle for another 21 days. Metabolic parameters, oxidative stress, heart rate variability (HRV), cardiac function and cardiac mitochondrial function were determined. Key Results Rats that received HFD developed insulin resistance characterized by increased body weight, plasma insulin, total cholesterol and oxidative stress levels along with a decreased high-density lipoprotein (HDL) level. Moreover, cardiac dysfunction, depressed HRV, cardiac mitochondrial dysfunction and cardiac mitochondrial morphology changes were observed in HFD rats. Both vildagliptin and sitagliptin decreased plasma insulin, total cholesterol and oxidative stress as well as increased HDL level. Furthermore, vildagliptin and sitagliptin attenuated cardiac dysfunction, prevented cardiac mitochondrial dysfunction and completely restored HRV. Conclusions and Implications Both vildagliptin and sitagliptin share similar efficacy in cardioprotection in obese insulin-resistant rats. PMID:23488656

Isolation and characterization of a novel gene sfig in rat skeletal muscle up-regulated by spaceflight (STS-90)

NASA Technical Reports Server (NTRS)

Kano, Mihoko; Kitano, Takako; Ikemoto, Madoka; Hirasaka, Katsuya; Asanoma, Yuki; Ogawa, Takayuki; Takeda, Shinichi; Nonaka, Ikuya; Adams, Gregory R.; Baldwin, Kenneth M.;

Gene Expression and Correlation of Pten and Fabp4 in Liver, Muscle, and Adipose Tissues of Type 2 Diabetes Rats.

PubMed

Su, Di; Zhang, Chuan-Ling; Gao, Ying-Chun; Liu, Xiao-Ying; Li, Cai-Ping; Huangfu, Jian; Xiao, Rui

2015-11-22

The aim of this work was to study the Fabp4 and Pten gene expression and correlation in the liver, muscle, and adipose tissues of type 2 diabetes mellitus (T2DM) rats. Male Wistar rats (8 weeks old) were randomly divided into 2 groups (n=12/group): a control group fed a normal diet for 8 weeks and an experimental group fed a high-fat, high-sugar diet for 8 weeks and that received 25 mg/kg streptozotocin by intraperitoneal injection to induce T2DM. The random blood glucose, fasting blood glucose, and fasting insulin levels were measured. The expression of Pten and Fabp4 in the liver, muscle, and epididymal adipose tissues was estimated by real-time quantitative PCR. Pearson correlation coefficient analysis was used to investigate the expression correlation between Pten and Fabp4 in T2DM rats. The gene expressions of Pten and Fabp4 in the liver, muscle, and adipose tissues of T2DM rats were all significantly higher than those in the control group (P<0.05). Pten was highly expressed in the muscles and Fabp4 was highly expressed in muscle and adipose tissues. Furthermore, expressions of Fabp4 and Pten in the muscle and adipose tissues of T2DM rats were positively correlated (P<0.05), but not in the liver. The increased expression of PTEN and FABP4 in the adipose and muscles of T2DM rats may play an important role in the insulin resistance of T2DM. However, the mechanism by which these 2 genes function in T2DM needs further study.

Antioxidant and triglyceride-lowering effects of vitamin E associated with the prevention of abnormalities in the reactivity and morphology of aorta from streptozotocin-diabetic rats. Antioxidants in Diabetes-Induced Complications (ADIC) Study Group.

PubMed

Karasu, C; Ozansoy, G; Bozkurt, O; Erdoğan, D; Omeroğlu, S

1997-08-01

In this study, we evaluated the effects of vitamin E on the vascular reactivity and structure of thoracic aorta from streptozotocin (STZ)-diabetic rats. Plasma glucose, cholesterol, and triglyceride concentrations in rats were increased markedly by STZ-diabetes. The thiobarbituric acid (TBA) reactivity level as an index of lipid peroxidation was higher in both plasma and aorta of STZ-diabetic rats compared with controls. The rings of thoracic aorta with or without endothelium were mounted in organ chambers for measurement of isometric tension and were contracted by a single dose (10-5 mol/L) and then cumulative doses of noradrenaline ([NA] 10(-9) to 10(-5) mol/L). Pretreatment with methylene blue (MB) or removal of the endothelium resulted in a similar degree of enhancement in NA-induced contraction of control rings. STZ-diabetes increased the fast and slow components of NA-induced contraction in all experiments. The maximal contractile response of aorta to NA was also augmented by STZ-diabetes, whereas the sensitivity (pD2) remained unaltered. STZ-diabetes resulted in significant increases in the maximum contractile response and sensitivity of aorta to KCl. STZ-diabetic rats showed a significant reduction in the percentage of endothelial response (PER). A group of diabetic rats was treated from the time of diabetes induction with a 0.5% dietary supplement of vitamin E. Vitamin E supplementation of STZ-diabetic rats eliminated accumulation of lipid peroxides and returned plasma triglycerides toward normal levels. Diabetes-induced abnormal contractility and endothelial dysfunction were significantly but not completely prevented by vitamin E treatment. The endothelium-independent relaxation response to sodium nitroprusside (SNP) was not affected by diabetes or vitamin E treatment. Electron microscopic examination of thoracic aorta revealed that normal tissue organization was disrupted in STZ-diabetic rats, and that vitamin E treatment can protect the morphological integrity of aorta against STZ-diabetes. The results suggest the following: (1) The increased triglycerides/lipid peroxides may be an important reason for morphological or functional disruption of endothelium and enhanced activation of contractile mechanisms of vascular smooth muscle in STZ-diabetic rats. Both contribute to an increased responsiveness of diabetic aorta to vasoconstrictor agents. (2) Vitamin E treatment of STZ-diabetic rats can prevent the development of abnormal contractility and structure and endothelial dysfunction in aorta. (3) The triglyceride- and/or lipid peroxidation-lowering effect of vitamin E may be crucial for the protective effect of this vitamin on the vasculature.

Impaired regeneration: A role for the muscle microenvironment in cancer cachexia.

PubMed

Talbert, Erin E; Guttridge, Denis C

2016-06-01

While changes in muscle protein synthesis and degradation have long been known to contribute to muscle wasting, a body of literature has arisen which suggests that regulation of the satellite cell and its ensuing regenerative program are impaired in atrophied muscle. Lessons learned from cancer cachexia suggest that this regulation is simply not a consequence, but a contributing factor to the wasting process. In addition to satellite cells, evidence from mouse models of cancer cachexia also suggests that non-satellite progenitor cells from the muscle microenvironment are also involved. This chapter in the series reviews the evidence of dysfunctional muscle repair in multiple wasting conditions. Potential mechanisms for this dysfunctional regeneration are discussed, particularly in the context of cancer cachexia. Copyright © 2015 Elsevier Ltd. All rights reserved.

A mechanism for trauma induced muscle wasting and immune dysfunction

NASA Astrophysics Data System (ADS)

Madihally, S.; Toner, M.; Yarmush, M.; Mitchell, R.

A diverse physiological conditions lead to a hypercatabolic state marked by the loss of proteins, primarily derived from skeletal muscle. The sustained loss of proteins results in loss of muscle mass and strength, poor healing, and long-term hospitalization. These problems are further compounded by the deterioration of immunity to infection which is a leading cause of morbidity and mortality of traumatic patients. In an attempt to understand the signal propagation mechanism(s), we tested the role of Interferon-? (IFN-? ) in an animal burn injury model; IFN-? is best conceptualized as a macrophage activating protein and known to modulate a variety of intracellular processes potentially relevant to muscle wasting and immune dysfunction. Mice congenitally -deficient in IFN-? , and IFN-? -Receptor, and wild type (WT) animals treated with IFN-? neutralizing antibody received either a 20% total body surface area burn or a control sham treatment. At days 1, 2, and 7 following treatment, skeletal muscle, peripheral blood, and spleen were harvested from both groups. Overall body weight, protein turnovers, changes in the lymphocyte subpopulations and alterations in the major histocompatibility complex I expression (MHC I) and proliferation capacity of lymphocytes was measured using mixed lymphocyte reaction (MLR). These results indicate that we can prevent both muscle wasting and immune dysfunction. Based on these observations and our previous other animal model results (using insulin therapy), a novel mechanism of interactions leading to muscle wasting and immune dysfunction will be discussed. Further, implications of these findings on future research and clinical therapies will be discussed in detail.

Beef extract supplementation increases leg muscle mass and modifies skeletal muscle fiber types in rats.

PubMed

Yoshihara, Hiroyuki; Wakamatsu, Jun-Ichiro; Kawabata, Fuminori; Mori, Sunao; Haruno, Atsushi; Hayashi, Toshiya; Sekiguchi, Takeshi; Mizunoya, Wataru; Tatsumi, Ryuichi; Ito, Tatsumi; Ikeuchi, Yoshihide

2006-06-01

The objective of this research was to investigate the effects of beef extract on fat metabolism, muscle mass and muscle fiber types in rats. We also investigated the synergetic effect of endurance exercise. Twenty-four male rats weighing about 270 g were assigned to two diets containing 0 or 6% beef extract (BE). Half the rats fed each diet were subjected to compulsory exercise (CE) for 30 min every other day. After 4 weeks feeding, the blood was collected and various organs were dissected. The muscle fiber type of the soleus and extensor digitorum longus (EDL) muscles were evaluated by histochemical and electrophoretical analyses. Rats supplemented with BE showed a decrease in fat content in liver and abdomen and an increase in the activity of carnitine palmitoyl transferase II in liver. BE as well as exercise increased the relative weights of both soleus and EDL. BE alone and BE plus CE did not affect the distribution of muscle fiber types in soleus. BE without exercise decreased in type IIb of EDL from 54% to 44% with compensatory increase in type IIa from 41% to 49% and type I from 5% to 7% compared with the nonsupplemented, nonexercised control group. No synergetic effect on a fast to slow fiber conversion due to the combination of BE and CE was detected. Thus, BE supplement increased muscle mass and slow type fiber in EDL. The effects of BE supplement on muscle characteristics were similar to those of exercise. beef extract, fat metabolism, muscle fiber type, muscle mass, L-carnitine

Influence of exercise training on the oxidative capacity of rat abdominal muscles

NASA Technical Reports Server (NTRS)

Uribe, J. M.; Stump, C. S.; Tipton, C. M.; Fregosi, R. F.

1992-01-01

Our purpose was to determine if endurance exercise training would increase the oxidative capacity of the abdominal expiratory muscles of the rat. Accordingly, 9 male rats were subjected to an endurance training protocol (1 h/day, 6 days/week, 9 weeks) and 9 litter-mates served as controls. Citrate synthase (CS) activity was used as an index of oxidative capacity, and was determined in the following muscles: soleus, plantaris, costal diaphragm, crural diaphragm, and in all four abdominal muscles: rectus abdominis, transversus abdominis, external oblique, and internal oblique. Compared to their non-trained litter-mates, the trained rats had higher peak whole body oxygen consumption rates (+ 16%) and CS activities in plantaris (+34%) and soleus (+36%) muscles. Thus, the training program caused substantial systemic and locomotor muscle adaptations. The CS activity of costal diaphragm was 20% greater in the trained animals, but no difference was observed in crural diaphragm. The CS activity in the abdominal muscles was less than one-half of that in locomotor and diaphragm muscles, and there were no significant changes with training except in the rectus abdominis where a 26% increase was observed. The increase in rectus abdominis CS activity may reflect its role in postural support and/or locomotion, as none of the primary expiratory pumping muscles adapted to the training protocol. The relatively low levels of CS activity in the abdominal muscles suggests that they are not recruited frequently at rest, and the lack of an increase with training indicates that these muscles do not contribute significantly to the increased ventilatory activity accompanying exercise in the rat.

Vasodilatory and hypoglycaemic effects of two pyrano-isoflavone extractives from Eriosema kraussianum N. E. Br. [Fabaceae] rootstock in experimental rat models.

PubMed

Ojewole, John A O; Drewes, Siegfried E; Khan, Fatima

2006-03-01

Zulu traditional health practitioners have claimed that the roots of Eriosema kraussianum N. E. Br. (Fabaceae) and other Eriosema species (Zulu indigenous umbrella name of "uBangalala") are effective remedies for the treatment of erectile dysfunction (ED) and/or impotence. In order to scientifically appraise the significance and contribution of Eriosema kraussianum to its ethnomedical use as "uBangalala" and "VIAGRA substitute", the present study was undertaken to investigate the vasodilatory and hypoglycaemic properties of the two main bioactive chemical compounds obtained from E. kraussianum, in experimental rat models, using sildenafil citrate (VIAGRA) as the reference drug for comparison. The two E. kraussianum rootstock constituents (K1 and K2, 20-80 mg/kg p.o.) caused dose-dependent and significant (P<0.05-0.001) hypoglycaemia in rats. Relatively low to high concentrations of the plant's extracts (K1 and K2, 100-2000 microg/ml) always produced biphasic effects on rat isolated portal veins. K1- and K2-provoked responses of the isolated portal veins always consisted of concentration-related initial transient, but significant (P<0.05), contractions of the venous muscle preparations, followed by secondary, longer-lasting, highly significant (P<0.01-0.001) relaxations of the venous muscle strips. Sildenafil citrate (VIAGRA, 5-100 microg/ml) always produced concentration-related and highly significant relaxations of the rat isolated portal veins. Unlike K1 and K2 (20-80 mg/kg p.o.), however, sildenafil citrate (VIAGRA, 100 mg/kg p. o.) only caused slight and insignificant (P>0.05) reductions in the blood glucose levels of the experimental animals used. On the other hand, glibenclamide (10 mg/kg p.o.) induced highly significant (P<0.05-0.001), marked reductions in the blood glucose concentrations of the rats. The findings of this laboratory animal study indicate that the two hydro-ethanol extractives of E. kraussianum (K1 and K2) possess hypoglycaemic and secondary, vasorelaxant effects in the experimental paradigms used.

Effects of Exercise on AMPK Signaling and Downstream Components to PI3K in Rat with Type 2 Diabetes

PubMed Central

Cao, Shicheng; Li, Bowen; Yi, Xuejie; Chang, Bo; Zhu, Beibei; Lian, Zhenzhen; Zhang, Zhaoran; Zhao, Gang; Liu, Huili; Zhang, He

2012-01-01

Exercise can increase skeletal muscle sensitivity to insulin, improve insulin resistance and regulate glucose homeostasis in rat models of type 2 diabetes. However, the potential mechanism remains poorly understood. In this study, we established a male Sprague–Dawley rat model of type 2 diabetes, with insulin resistance and β cell dysfunction, which was induced by a high-fat diet and low-dose streptozotocin to replicate the pathogenesis and metabolic characteristics of type 2 diabetes in humans. We also investigated the possible mechanism by which chronic and acute exercise improves metabolism, and the phosphorylation and expression of components of AMP-activated protein kinase (AMPK) and downstream components of phosphatidylinositol 3-kinase (PI3K) signaling pathways in the soleus. As a result, blood glucose, triglyceride, total cholesterol, and free fatty acid were significantly increased, whereas insulin level progressively declined in diabetic rats. Interestingly, chronic and acute exercise reduced blood glucose, increased phosphorylation and expression of AMPKα1/2 and the isoforms AMPKα1 and AMPKα2, and decreased phosphorylation and expression of AMPK substrate, acetyl CoA carboxylase (ACC). Chronic exercise upregulated phosphorylation and expression of AMPK upstream kinase, LKB1. But acute exercise only increased LKB1 expression. In particular, exercise reversed the changes in protein kinase C (PKC)ζ/λ phosphorylation, and PKCζ phosphorylation and expression. Additionally, exercise also increased protein kinase B (PKB)/Akt1, Akt2 and GLUT4 expression, but AS160 protein expression was unchanged. Chronic exercise elevated Akt (Thr308) and (Ser473) and AS160 phosphorylation. Finally, we found that exercise increased peroxisome proliferator-activated receptor-γ coactivator 1 (PGC1) mRNA expression in the soleus of diabetic rats. These results indicate that both chronic and acute exercise influence the phosphorylation and expression of components of the AMPK and downstream to PIK3 (aPKC, Akt), and improve GLUT4 trafficking in skeletal muscle. These data help explain the mechanism how exercise regulates glucose homeostasis in diabetic rats. PMID:23272147

Reduction of vascular leakage by imatinib is associated with preserved microcirculatory perfusion and reduced renal injury markers in a rat model of cardiopulmonary bypass.

PubMed

Koning, N J; de Lange, F; van Meurs, M; Jongman, R M; Ahmed, Y; Schwarte, L A; van Nieuw Amerongen, G P; Vonk, A B A; Niessen, H W; Baufreton, C; Boer, C

2018-06-01

Cardiopulmonary bypass during cardiac surgery leads to impaired microcirculatory perfusion. We hypothesized that vascular leakage is an important contributor to microcirculatory dysfunction. Imatinib, a tyrosine kinase inhibitor, has been shown to reduce vascular leakage in septic mice. We investigated whether prevention of vascular leakage using imatinib preserves microcirculatory perfusion and reduces organ injury markers in a rat model of cardiopulmonary bypass. Male Wistar rats underwent cardiopulmonary bypass after treatment with imatinib or vehicle (n=8 per group). Cremaster muscle microcirculatory perfusion and quadriceps microvascular oxygen saturation were measured using intravital microscopy and reflectance spectroscopy. Evans Blue extravasation was determined in separate experiments. Organ injury markers were determined in plasma, intestine, kidney, and lungs. The onset of cardiopulmonary bypass decreased the number of perfused microvessels by 40% in the control group [9.4 (8.6-10.6) to 5.7 (4.8-6.2) per microscope field; P<0.001 vs baseline], whereas this reduction was not seen in the imatinib group. In the control group, the number of perfused capillaries remained low throughout the experiment, whilst perfusion remained normal after imatinib administration. Microvascular oxygen saturation was less impaired after imatinib treatment compared with controls. Imatinib reduced vascular leakage and decreased fluid resuscitation compared with control [3 (3-6) vs 12 ml (7-16); P=0.024]. Plasma neutrophil-gelatinase-associated-lipocalin concentrations were reduced by imatinib. Prevention of endothelial barrier dysfunction using imatinib preserved microcirculatory perfusion and oxygenation during and after cardiopulmonary bypass. Moreover, imatinib-induced protection of endothelial barrier integrity reduced fluid-resuscitation requirements and attenuated renal and pulmonary injury markers. Copyright © 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Human apolipoprotein B transgenic SHR/NDmcr-cp rats show exacerbated kidney dysfunction

PubMed Central

ASAHINA, Makoto; SHIMIZU, Fumi; OHTA, Masayuki; TAKEYAMA, Michiyasu; TOZAWA, Ryuichi

2015-01-01

Nephropathy frequently co-occurs with metabolic syndrome in humans. Metabolic syndrome is a cluster of metabolic diseases including obesity, diabetes, hypertension, and dyslipidemia, and some previous studies revealed that dyslipidemia contributes to the progression of kidney dysfunction. To establish a new nephropathy model with metabolic syndrome, we produced human apolipoprotein B (apoB) transgenic (Tg.) SHR/NDmcr-cp (SHR-cp/cp) rats, in which dyslipidemia is exacerbated more than in an established metabolic syndrome model, SHR-cp/cp rats. Human apoB Tg. SHR-cp/cp rats showed obesity, hyperinsulinemia, hypertension, and severe hyperlipidemia. They also exhibited exacerbated early-onset proteinuria, accompanied by increased kidney injury and increased oxidative and inflammatory markers. Histological analyses revealed the characteristic features of human apoB Tg. SHR-cp/cp rats including prominent glomerulosclerosis with lipid accumulation. Our newly established human apoB Tg. SHR-cp/cp rat could be a useful model for the nephropathy in metabolic syndrome and for understanding the interaction between dyslipidemia and renal dysfunction in metabolic syndrome. PMID:25912321

Human apolipoprotein B transgenic SHR/NDmcr-cp rats show exacerbated kidney dysfunction.

PubMed

Asahina, Makoto; Shimizu, Fumi; Ohta, Masayuki; Takeyama, Michiyasu; Tozawa, Ryuichi

2015-01-01

Nephropathy frequently co-occurs with metabolic syndrome in humans. Metabolic syndrome is a cluster of metabolic diseases including obesity, diabetes, hypertension, and dyslipidemia, and some previous studies revealed that dyslipidemia contributes to the progression of kidney dysfunction. To establish a new nephropathy model with metabolic syndrome, we produced human apolipoprotein B (apoB) transgenic (Tg.) SHR/NDmcr-cp (SHR-cp/cp) rats, in which dyslipidemia is exacerbated more than in an established metabolic syndrome model, SHR-cp/cp rats. Human apoB Tg. SHR-cp/cp rats showed obesity, hyperinsulinemia, hypertension, and severe hyperlipidemia. They also exhibited exacerbated early-onset proteinuria, accompanied by increased kidney injury and increased oxidative and inflammatory markers. Histological analyses revealed the characteristic features of human apoB Tg. SHR-cp/cp rats including prominent glomerulosclerosis with lipid accumulation. Our newly established human apoB Tg. SHR-cp/cp rat could be a useful model for the nephropathy in metabolic syndrome and for understanding the interaction between dyslipidemia and renal dysfunction in metabolic syndrome.

PHARMACOLOGIC PROBING OF AMPHOTERICIN B-INDUCED RENAL DYSFUNCTION IN THE NEONATAL RAT

EPA Science Inventory

Pharmacologic Probing of Amphotericin B-Induced Renal Dysfunction in the Neonatal Rat. Gray, J.A., and Kavlock, R.J. (1988). Toxicol. Appl. Pharmacol. 93, 360-368. Acetazolamide, furosemide, chlorothiazide, and amiloride pharmacologic agents that act primarily in the proximal tub...

Effect of ginger, Paullinia cupana, muira puama and l- citrulline, singly or in combination, on modulation of the inducible nitric oxide- NO-cGMP pathway in rat penile smooth muscle cells.

PubMed

Ferrini, Monica G; Garcia, Eduardo; Abraham, Andrea; Artaza, Jorge N; Nguyen, Sabine; Rajfer, Jacob

2018-06-01

COMP-4 is a natural compound-based dietary supplement consisting of the combination of ginger, Paullinia cupana, muira puama and l-citrulline, which when given long-term has been shown in the aged rat to a) upregulate iNOS in the penile smooth muscle cells (SMC), b) reverse the corporal SMC apoptosis and fibrosis associated with corporal veno-occlusive dysfunction (CVOD), and c) improve resulting erectile function. To elucidate the mechanism of how COMP-4 and its individual components modulate the iNOS-cGMP pathway, an in vitro study was conducted using a rat corporal primary SMC culture to determine its effect on NOS, soluble guanylate cyclase (sGC), cGMP and the phosphodiesterase 5 enzyme (PDE5). Primary SMC cultures using the explant technique were initiated by cutting small pieces of corporal tissue from 8 week old Sprague-Dawley rats. The SMC were grown in Dulbecco media with 20% fetal calf serum. The SMC were then incubated with or without COMP-4 (0.69 mg/ml) or its ingredients alone (ginger: 0.225 mg/ml; muira puama, Paullinia cupana and l-citrulline each at 0.9 mg/ml) for up to 24 h mRNA and protein were extracted and used for the determination of NOS, sGC and PDE5 content. cGMP content was determined by ELISA. L-NIL (4 μM) was used as an inhibitor of iNOS activity. Compared to the control values, COMP-4 upregulated expression of cGMP by 85%, induced a 42 fold increase in sGC as well as a 15 fold increase in both iNOS protein and mRNA content while it decreased both PDE5 mRNA and protein content each by about 50%. L-NIL completely inhibited the effect of COMP-4 on cGMP production. When compared with each of the individual four components of COMP-4, it appears that COMP-4 itself had the most profound effect in modulating each one the specific steps within the iNOS-cGMP pathway. This in vitro study demonstrates that COMP-4 is capable of activating the endogenous cellular iNOS-cGMP pathway within the CSM cells, which is theorized to be responsible for reducing the fibrosis and apoptosis as well as the CVOD observed in the aging rat penis. Further studies will be necessary in order to determine whether supplementation of COMP-4 on a daily basis may be beneficial in halting or reversing this aging related erectile dysfunction in the clinical setting. Copyright © 2018 Elsevier Inc. All rights reserved.

[Metabolic processes in rat skeletal muscle after a flight on the Kosmos-936 biosatellite].

PubMed

Nosova, E A; Veresotskaia, N A; Kolchina, E V; Kurkina, L M; Belitskaia, R A

1981-01-01

The study of skeletal muscles of rats flown on Cosmos-936 demonstrated different metabolic reactions in muscle fibers of different function and type to weightlessness and Earth gravity. The data obtained gave evidence that artificial gravity may considerably prevent metabolic changes in muscles developing in response to specific effects of weightlessness.

Effect of anabolic steroids on skeletal muscle mass during hindlimb suspension

NASA Technical Reports Server (NTRS)

Tsika, R. W.; Herrick, R. E.; Baldwin, K. M.

1987-01-01

The effect of treatment with an anabolic steroid (nandrolone decanoate) on the muscle mass of plantaris and soleus of a rats in hindlimb suspension, and on the isomyosin expression in these muscles, was investigated in young female rats divided into four groups: normal control (NC), normal steroid (NS), normal suspension (N-sus), and suspension steroid (sus-S). Steroid treatment of suspended animals (sus-S vs N-sus) was found to partially spare body weight and muscle weight, as well as myofibril content of plantaris (but not soleus), but did not modify the isomyosin pattern induced by suspension. In normal rats (NS vs NC), steroid treatment did enhance body weight and plantaris muscle weight; the treatment did not alter isomyosin expression in either muscle type.

Role of afferent input and mechanical load for size regulation of rat soleus muscle

NASA Astrophysics Data System (ADS)

Kawano, Fuminori; Matsuka, Yoshikazu; Oke, Yoshihiko; Higo, Yoko; Terada, Masahiro; Umemoto, Shiori; Kawabe, Naoko; Wang, Xiao Dong; Shinoda, Yo; Lan, Yong Bo; Fukuda, Hiroyuki; Ohmi, Shinobu; Ohira, Yoshinobu

2005-08-01

Effects of deafferentation on the phosphorylation of ribosomal protein S6 (S6), 27 kDa heat shock protein (HSP27) and extracellular signal-regulated kinase (ERK) 1/2 were studied in rat soleus muscle. Adult male Wistar rats were randomly separated into the pre- and post- experimental control, functionally overloaded (FO), sham-operated, deafferentated (DA), FO+DA, and hindlimb-unloaded (U) groups. The distal tendons of left plantaris and gastrocnemius muscles were transected in the FO rats. The left dorsal roots of the spinal cord at the L4-5 segmental levels were transected in the DA rats. The rats in U were tail-suspended. The sampling of the soleus muscle was performed 2 weeks after the treatments shown above. The cytoplasmic fraction of the soleus muscle homogenate was used for the quantitative analyses of the phosphorylation levels of S6, HSP27, and ERK 1/2. The phosphorylation levels of these proteins were up-regulated by FO. On the contrary, the phosphorylation of all of these proteins was down-regulated by U and DA. Further, the FO-related increase of the protein phosphorylation was inhibited by additional treatment with DA. These results indicated that the afferent feedback plays crucial roles in the intramuscular regulation of the soleus muscle mass.

Effect of electrical stimulation on beta-adrenergic receptor population and cyclic amp production in chicken and rat skeletal muscle cell cultures

NASA Technical Reports Server (NTRS)

Young, R. B.; Bridge, K. Y.; Strietzel, C. J.

2000-01-01

Expression of the beta-adrenergic receptor (betaAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the betaAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the betaAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the betaAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

Effect of Electrical Stimulation on Beta-Adrenergic Receptor Population and Cyclic AMP Production in Chicken and Rat Skeletal Muscle Cell Cultures

NASA Technical Reports Server (NTRS)

Young, Ronald B.; Bridge, Kristin Y.; Strietzel, Catherine J.

2000-01-01

Expression of the beta-adrenergic receptor (PAR) and its coupling to Adenosine 3'5' Cyclic Monophosphate (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the PAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture, were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the PAR population was not significantly affected by electrical stimulation; however, the ability, of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the PAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

Growth hormone, IGF-I, and exercise effects on non-weight-bearing fast muscles of hypophysectomized rats

NASA Technical Reports Server (NTRS)

Grossman, E. J.; Grindeland, R. E.; Roy, R. R.; Talmadge, R. J.; Evans, J.; Edgerton, V. R.

1997-01-01

The effects of growth hormone (GH) or insulin-like growth factor I (IGF-I) with or without exercise (ladder climbing) in countering the effects of unweighting on fast muscles of hypophysectomized rats during 10 days of hindlimb suspension were determined. Compared with untreated suspended rats, muscle weights were 16-29% larger in GH-treated and 5-15% larger in IGF-I-treated suspended rats. Exercise alone had no effect on muscle weights. Compared with ambulatory control, the medial gastrocnemius weight in suspended, exercised rats was larger after GH treatment and maintained with IGF-I treatment. The combination of GH or IGF-I plus exercise in suspended rats resulted in an increase in size of each predominant fiber type, i.e., types I, I + IIa and IIa + IIx, in the medial gastrocnemius compared with untreated suspended rats. Normal ambulation or exercise during suspension increased the proportion of fibers expressing embryonic myosin heavy chain in hypophysectomized rats. The phenotype of the medial gastrocnemius was minimally affected by GH, IGF-I, and/or exercise. These results show that there is an IGF-I, as well as a GH, and exercise interactive effect in maintaining medial gastrocnemius fiber size in suspended hypophysectomized rats.

Testosterone Deficiency Causes Endothelial Dysfunction via Elevation of Asymmetric Dimethylarginine and Oxidative Stress in Castrated Rats.

PubMed

Kataoka, Tomoya; Hotta, Yuji; Maeda, Yasuhiro; Kimura, Kazunori

2017-12-01

Testosterone is believed to mediate the penile erectile response by producing adequate nitric oxide; therefore, testosterone deficiency results in erectile dysfunction through decreased nitric oxide bioavailability. However, the mechanisms underlying endothelial dysfunction in testosterone deficiency remain unclear. To investigate the mechanism of endothelial dysfunction in a rat model of testosterone deficiency. Rats were distributed into 3 groups: castrated (Cast), castrated and supplemented with testosterone (Cast + T), and sham (Sham). In the Cast + T group, castrated rats were treated daily with subcutaneous testosterone (3 mg/kg daily) for 4 weeks; Sham and Cast rats received only the vehicle. Erectile function using intracavernosal pressure and mean arterial pressure measurements after electrical stimulation of the cavernous nerve, endothelial function using isometric tension, asymmetric dimethylarginine (ADMA) levels using ultra-performance liquid chromatography and tandem mass spectrometry, and inflammatory biomarker expression were performed 4 weeks after the operation. In the Cast group, the ratio of intracavernosal pressure to mean arterial pressure significantly decreased, acetylcholine-induced relaxation was lower, and serum ADMA, oxidative stress, and inflammation biomarker levels were significantly increased (P < .01). Testosterone injection significantly improved each of these parameters (P < .01). The present results provide scientific evidence of the effect of testosterone deficiency on erectile function and the effect of testosterone replacement therapy. This study provides evidence of the influence of testosterone deficiency on endothelial function by investigating ADMA and oxidative stress. A major limitation of this study is the lack of a direct link of increased ADMA by oxidative stress to inflammation. Testosterone deficiency increased not only ADMA levels but also oxidative stress and inflammation in castrated rats, which can cause damage to the corpus cavernosum, resulting in erectile dysfunction. Kataoka T, Hotta Y, Maeda Y, Kimura K. Testosterone Deficiency Causes Endothelial Dysfunction via Elevation of Asymmetric Dimethylarginine and Oxidative Stress in Castrated Rats. J Sex Med 2017;14:1540-1548. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Effect of a low-protein diet supplemented with ketoacids on skeletal muscle atrophy and autophagy in rats with type 2 diabetic nephropathy.

PubMed

Huang, Juan; Wang, Jialin; Gu, Lijie; Bao, Jinfang; Yin, Jun; Tang, Zhihuan; Wang, Ling; Yuan, Weijie

2013-01-01

A low-protein diet supplemented with ketoacids maintains nutritional status in patients with diabetic nephropathy. The activation of autophagy has been shown in the skeletal muscle of diabetic and uremic rats. This study aimed to determine whether a low-protein diet supplemented with ketoacids improves muscle atrophy and decreases the increased autophagy observed in rats with type 2 diabetic nephropathy. In this study, 24-week-old Goto-Kakizaki male rats were randomly divided into groups that received either a normal protein diet (NPD group), a low-protein diet (LPD group) or a low-protein diet supplemented with ketoacids (LPD+KA group) for 24 weeks. Age- and weight-matched Wistar rats served as control animals and received a normal protein diet (control group). We found that protein restriction attenuated proteinuria and decreased blood urea nitrogen and serum creatinine levels. Compared with the NPD and LPD groups, the LPD+KA group showed a delay in body weight loss, an attenuation in soleus muscle mass loss and a decrease of the mean cross-sectional area of soleus muscle fibers. The mRNA and protein expression of autophagy-related genes, such as Beclin-1, LC3B, Bnip3, p62 and Cathepsin L, were increased in the soleus muscle of GK rats fed with NPD compared to Wistar rats. Importantly, LPD resulted in a slight reduction in the expression of autophagy-related genes; however, these differences were not statistically significant. In addition, LPD+KA abolished the upregulation of autophagy-related gene expression. Furthermore, the activation of autophagy in the NPD and LPD groups was confirmed by the appearance of autophagosomes or autolysosomes using electron microscopy, when compared with the Control and LPD+KA groups. Our results showed that LPD+KA abolished the activation of autophagy in skeletal muscle and decreased muscle loss in rats with type 2 diabetic nephropathy.

Measurement of the trapezius muscle volume: A new assessment strategy of shoulder dysfunction after neck dissection for the treatment of head and neck cancers.

PubMed

Cho, Jae-Gu; Lee, Naree; Park, Min-Woo; Baek, Seung-Kuk; Kwon, Soon-Young; Jung, Kwang-Yoon; Woo, Jeong-Soo

2015-05-01

The purpose of this study was to determine the actual degree of shoulder muscle change and its relation to symptoms after neck dissection for head and neck cancers. Forty-two patients who underwent unilateral neck dissection were selected. Data obtained from each subject were trapezius muscle volume ratio and a Shoulder Disability Questionnaire (SDQ) score. Patients who had undergone neck dissection with spinal accessory nerve (SAN) preservation were compared with those who had received radical neck dissection. The preservation group was further separated into subgroups by the extent of neck dissection. Trapezius muscle volume ratio was higher and SDQ score was significantly lower in the SAN preservation group compared to the radical neck dissection group. However, the SAN preservation subgroups did not differ from each other. In addition, a good correlation between the muscle volume ratio and SDQ score was observed. With trapezius muscle volume ratio, clinicians may be able to diagnose shoulder dysfunction after neck dissection. Further research on the subject is warranted. This suggests a novel strategy for assessing the degree of shoulder dysfunction. © 2014 Wiley Periodicals, Inc.

The Measurement of Reversible Redox Dependent Post-translational Modifications and Their Regulation of Mitochondrial and Skeletal Muscle Function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kramer, Philip A.; Duan, Jicheng; Qian, Wei-Jun

Mitochondrial oxidative stress is a common feature of skeletal myopathies across multiple conditions; however, the mechanism by which it contributes to skeletal muscle dysfunction remains controversial. Oxidative damage to proteins, lipids, and DNA has received the most attention, yet an important role for reversible redox post-translational modifications (PTMs) in pathophysiology is emerging. The possibility that these PTMs can exert dynamic control of muscle function implicates them as a mechanism contributing to skeletal muscle dysfunction in chronic disease. Herein, we discuss the significance of thiol-based redox dependent modifications to mitochondrial, myofibrillar and excitation-contraction (EC) coupling proteins with an emphasis on howmore » these changes could alter skeletal muscle performance under chronically stressed conditions. A major barrier to a better mechanistic understanding of the role of reversible redox PTMs in muscle function is the technical challenges associated with accurately measuring the changes of site-specific redox PTMs. Here we will critically review current approaches with an emphasis on sample preparation artifacts, quantitation, and specificity. Despite these challenges, the ability to accurately quantify reversible redox PTMs is critical to understanding the mechanisms by which mitochondrial oxidative stress contributes to skeletal muscle dysfunction in chronic diseases.« less

LncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats mediated by P2X7 receptor in SCG.

PubMed

Wu, Bing; Zhang, Chunping; Zou, Lifang; Ma, Yucheng; Huang, Kangyu; Lv, Qiulan; Zhang, Xi; Wang, Shouyu; Xue, Yun; Yi, Zhihua; Jia, Tianyu; Zhao, Shanhong; Liu, Shuangmei; Xu, Hong; Li, Guilin; Liang, Shangdong

2016-05-01

Diabetic autonomic neuropathy includes the sympathetic ganglionic dysfunction. P2X7 receptor in superior cervical ganglia (SCG) participated in the pathological changes of cardiac dysfunction. Abnormal expression of long noncoding RNAs (lncRNAs) was reported to be involved in nervous system diseases. Our preliminary results obtained from rat lncRNA array profiling revealed that the expression of the uc.48+ was significantly increased in the rat SCG in response to diabetic sympathetic pathology. In this study, we found that lncRNAuc.48+ and P2X7 receptor in the SCG were increased in type 2 diabetic rats and were associated with the cardiac dysfunction. The uc.48+ small interference RNA (siRNA) improved the cardiac autonomic dysfunction and decreased the up-regulation P2X7 and the ratio of phosphorylated extracellular regulated protein kinases1/2 (p-ERK1/2) to ERK1/2 in SCG of type 2 diabetic rats. In conclusion, lncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats through regulating the expression of P2X7 and ERK signaling in SCG. Copyright © 2016 Elsevier B.V. All rights reserved.

Embryologic innervation of the rat laryngeal musculature--a model for investigation of recurrent laryngeal nerve reinnervation.

PubMed

Pitman, Michael J; Berzofsky, Craig E; Alli, Opeyemi; Sharma, Sansar

2013-12-01

Optimal management of vocal fold paralysis would entail recurrent laryngeal nerve (RLN) reinnervation resulting in normal vocal fold motion. Unfortunately, RLN reinnervation currently results in a nonfunctional vocal fold due to synkinetic reinnervation. Therapeutic interventions that guide regenerating axons back to the appropriate muscle would prevent synkinesis and restore vocal fold and glottal function. The initial step toward developing these therapies is the elucidation of the embryologic innervation of the larynx. This study aimed to identify the age of occurrence, timing, and pattern of embryologic innervation of the rat larynx, hypothesizing that differences in these parameters exist between distinct laryngeal muscles. Descriptive anatomic study. The larynx of rats aged embryologic day (E) 15, 16, 17, 19, and 21 were harvested and then sectioned. Two rats were used for each age. Sections were colabeled with neuronal class III β-tubulin polyclonal antibody to identify the presence of axons and alexa 488 conjugate α-bungarotoxin to identify the presence of motor endplates. The age at which axons and motor endplates were first present was noted. The position and pattern of the axons and motor endplates was recorded in relation to each other as well as the musculoskeletal anatomy of the larynx. The time at which axons appeared to innervate the medial thyroarytenoid (MTA) muscle, lateral thyroarytenoid (LTA) muscle, and the posterior cricoarytenoid (PCA) muscle was documented. Findings in the rat suggest the RLN reaches the larynx and begins branching by E15. Axons branch dorsally first and reach the PCA muscle before the other muscles. Branching toward the MTA muscle occurs only after axons have reached the LTA muscle. By E19, RLN axons have been guided to and selected their respective muscles with formation of neuromuscular junctions (NMJs) in the PCA, LTA and MTA muscles, though the formation of NMJs in the MTA muscle was comparatively delayed. This study describes the embryologic innervation of the rat larynx and suggests that there are distinct differences in the age of occurrence, timing, and pattern of innervation of the PCA, LTA, and MTA muscles of the rat. These findings lay the foundation for studies investigating the role of guidance cues in RLN axon guidance and the utility of these cues in the treatment of RLN injury via the stimulation of functional, nonsynkinetic reinnervation. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Changes in skeletal muscle and tendon structure and function following genetic inactivation of myostatin in rats

PubMed Central

Mendias, Christopher L; Lynch, Evan B; Gumucio, Jonathan P; Flood, Michael D; Rittman, Danielle S; Van Pelt, Douglas W; Roche, Stuart M; Davis, Carol S

2015-01-01

Myostatin is a negative regulator of skeletal muscle and tendon mass. Myostatin deficiency has been well studied in mice, but limited data are available on how myostatin regulates the structure and function of muscles and tendons of larger animals. We hypothesized that, in comparison to wild-type (MSTN+/+) rats, rats in which zinc finger nucleases were used to genetically inactivate myostatin (MSTNΔ/Δ) would exhibit an increase in muscle mass and total force production, a reduction in specific force, an accumulation of type II fibres and a decrease and stiffening of connective tissue. Overall, the muscle and tendon phenotype of myostatin-deficient rats was markedly different from that of myostatin-deficient mice, which have impaired contractility and pathological changes to fibres and their extracellular matrix. Extensor digitorum longus and soleus muscles of MSTNΔ/Δ rats demonstrated 20–33% increases in mass, 35–45% increases in fibre number, 20–57% increases in isometric force and no differences in specific force. The insulin-like growth factor-1 pathway was activated to a greater extent in MSTNΔ/Δ muscles, but no substantial differences in atrophy-related genes were observed. Tendons of MSTNΔ/Δ rats had a 20% reduction in peak strain, with no differences in mass, peak stress or stiffness. The general morphology and gene expression patterns were similar between tendons of both genotypes. This large rodent model of myostatin deficiency did not have the negative consequences to muscle fibres and extracellular matrix observed in mouse models, and suggests that the greatest impact of myostatin in the regulation of muscle mass may not be to induce atrophy directly, but rather to block hypertrophy signalling. PMID:25640143

Single molecular image of cytosolic free Ca2+ of skeletal muscle cells in rats pre- and post-exercise-induced fatigue

NASA Astrophysics Data System (ADS)

Liu, Yi; Zhang, Heming; Zhao, Yanping; Liu, Zhiming

2009-08-01

A growing body of literature indicated the cytosolic free Ca2+ concentration of skeletal muscle cells changes significantly during exercise-induced fatigue. But it is confusing whether cytosolic free Ca2+ concentration increase or decrease. Furthermore, current researches mainly adopt muscle tissue homogenate as experiment material, but the studies based on cellular and subcellular level is seldom. This study is aimed to establish rat skeletal muscle cell model of exercise-induced fatigue, and confirm the change of cytosolic free Ca2+ concentration of skeletal muscle cells in rats preand post- exercise-induced fatigue. In this research, six male Wistar rats were randomly divided into two groups: control group (n=3) and exercise-induced fatigue group (n=3). The former group were allowed to freely move and the latter were forced to loaded swimming to exhaustive. Three days later, all the rats were sacrificed, the muscle tissue from the same site of skeletal muscle were taken out and digested to cells. After primary culture of the two kinds of skeletal muscle cells from tissue, a fluorescent dye-Fluo-3 AM was used to label the cytosolic free Ca2+. The fluorescent of Ca2+ was recorded by confocal laser scanning microscopy. The results indicated that, the Ca2+ fluorescence intensity of cells from the rat of exercise-induced fatigue group was significantly higher than those in control group. In conclusion, cytosolic free Ca2+ concentration of skeletal muscle cells has a close relation with exercise-induced fatigue, and the increase of cytosolic free Ca2+ concentration may be one of the important factors of exercise-induced fatigue.

Formoterol attenuates increased oxidative stress and myosin protein loss in respiratory and limb muscles of cancer cachectic rats

PubMed Central

Salazar-Degracia, Anna; Busquets, Sílvia; Argilés, Josep M.; López-Soriano, Francisco J.

2017-01-01

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Therapeutic options are still scarce. We hypothesized that cachexia-induced muscle oxidative stress may be attenuated in response to treatment with beta2-adrenoceptor-selective agonist formoterol in rats. In diaphragm and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with formoterol (0.3 mg/kg body weight/day for seven days, daily subcutaneous injection), redox balance (protein oxidation and nitration and antioxidants) and muscle proteins (1-dimensional immunoblots), carbonylated proteins (2-dimensional immunoblots), inflammatory cells (immunohistochemistry), and mitochondrial respiratory chain (MRC) complex activities were explored. In the gastrocnemius, but not the diaphragm, of cancer cachectic rats compared to the controls, protein oxidation and nitration levels were increased, several functional and structural proteins were carbonylated, and in both study muscles, myosin content was reduced, inflammatory cell counts were greater, while no significant differences were seen in MRC complex activities (I, II, and IV). Treatment of cachectic rats with formoterol attenuated all the events in both respiratory and limb muscles. In this in vivo model of cancer-cachectic rats, the diaphragm is more resistant to oxidative stress. Formoterol treatment attenuated the rise in oxidative stress in the limb muscles, inflammatory cell infiltration, and the loss of myosin content seen in both study muscles, whereas no effects were observed in the MRC complex activities. These findings have therapeutic implications as they demonstrate beneficial effects of the beta2 agonist through decreased protein oxidation and inflammation in cachectic muscles, especially the gastrocnemius. PMID:29255650

Dissociation between PGC-1alpha and GLUT-4 expression in skeletal muscle of rats fed a high-fat diet.

PubMed

Higashida, Kazuhiko; Higuchi, Mitsuru; Terada, Shin

2009-12-01

It has recently been reported that a 4-wk high-fat diet gradually increases skeletal muscle peroxisome proliferator activated receptor (PPAR) gamma coactivator-1alpha (PGC-1alpha) protein content, which has been suggested to regulate GLUT-4 gene transcription. However, it has not been reported that a high-fat diet enhances GLUT-4 mRNA expression and protein content in skeletal muscle, suggesting that an increase in PGC-1alpha protein content is not sufficient to induce muscle GLUT-4 biogenesis in a high-fat fed animal. Therefore, we first evaluated the relationship between PGC-1alpha and GLUT-4 expression in skeletal muscle of rats fed a high-fat diet for 4 wk. The PGC-1alpha protein content in rat epitrochlearis muscle significantly increased by twofold after the 4-wk high-fat diet feeding. However, the high-fat diet had no effect on GLUT-4 protein content and induced a 30% decrease in GLUT-4 mRNA expression in rat skeletal muscle (p<0.05). To clarify the mechanism by which a high-fat diet downregulates GLUT-4 mRNA expression, we next examined the effect of PPARdelta activation, which is known to occur in response to a high-fat diet, on GLUT-4 mRNA expression in L6 myotubes. Incubation with 500 nM GW501516 (PPARdelta activator) for 24 h significantly decreased GLUT-4 mRNA in L6 myotubes. Taken together, these findings suggest that a high-fat diet downregulates GLUT-4 mRNA, possibly through the activation of PPARdelta, despite an increase in PGC-1alpha protein content in rat skeletal muscle, and that a posttranscriptional regulatory mechanism maintains GLUT-4 protein content in skeletal muscle of rats fed a high-fat diet.

Branched-chain amino acid-rich diet improves skeletal muscle wasting caused by cigarette smoke in rats.

PubMed

Tomoda, Koichi; Kubo, Kaoru; Hino, Kazuo; Kondoh, Yasunori; Nishii, Yasue; Koyama, Noriko; Yamamoto, Yoshifumi; Yoshikawa, Masanori; Kimura, Hiroshi

2014-04-01

Cigarette smoke induces skeletal muscle wasting by a mechanism not yet fully elucidated. Branched-chain amino acids (BCAA) in the skeletal muscles are useful energy sources during exercise or systemic stresses. We investigated the relationship between skeletal muscle wasting caused by cigarette smoke and changes in BCAA levels in the plasma and skeletal muscles of rats. Furthermore, the effects of BCAA-rich diet on muscle wasting caused by cigarette smoke were also investigated. Wistar Kyoto (WKY) rats that were fed with a control or a BCAA-rich diet were exposed to cigarette smoke for four weeks. After the exposure, the skeletal muscle weight and BCAA levels in plasma and the skeletal muscles were measured. Cigarette smoke significantly decreased the skeletal muscle weight and BCAA levels in both plasma and skeletal muscles, while a BCAA-rich diet increased the skeletal muscle weight and BCAA levels in both plasma and skeletal muscles that had decreased by cigarette smoke exposure. In conclusion, skeletal muscle wasting caused by cigarette smoke was related to the decrease of BCAA levels in the skeletal muscles, while a BCAA-rich diet may improve cases of cigarette smoke-induced skeletal muscle wasting.

Immobilization rapidly induces thioredoxin-interacting protein (TXNIP) gene expression together with insulin resistance in rat skeletal muscle.

PubMed

Kawamoto, Emi; Tamakoshi, Keigo; Ra, Song-Gyu; Masuda, Hiroyuki; Kawanaka, Kentaro

2018-05-24

Acute short-duration of disuse induces the development of insulin resistance for glucose uptake in rodent skeletal muscle. Since thioredoxin-interacting protein (TXNIP) has been implicated in the downregulation of insulin signaling and glucose uptake, we examined the possibility that muscle disuse rapidly induces insulin resistance via increased TXNIP mRNA and protein expression. Male Wistar rats were subjected to unilateral 6-hr hindlimb immobilization by plaster cast. At the end of this period, the soleus muscles from both immobilized and contralateral non-immobilized hindlimbs were excised and examined. The 6-hr immobilization resulted in an increase in TXNIP mRNA and protein expressions together with a decrease in insulin-stimulated 2-deoxyglucose uptake in the rat soleus muscle. Additionally, in the rats sacrificed 6 hr after the plaster cast removal, TXNIP protein expression and insulin-stimulated glucose uptake in the immobilized muscle had both been restored to a normal level. Various interventions (pretreatment with transcription inhibitor actinomycin D or AMPK activator AICAR) also suppressed the increase in TXNIP protein expression in 6-hr-immobilized muscle together with partial prevention of insulin resistance for glucose uptake. These results suggested the possibility that increased TXNIP protein expression in immobilized rat soleus muscles was associated with the rapid induction of insulin resistance for glucose uptake in that tissue.

Naringin ameliorates endothelial dysfunction in fructose-fed rats.

PubMed

Malakul, Wachirawadee; Pengnet, Sirinat; Kumchoom, Chanon; Tunsophon, Sakara

2018-03-01

High fructose consumption is associated with metabolic disorders including hyperglycemia and dyslipidemia, in addition to endothelial dysfunction. Naringin, a flavonoid present in citrus fruit, has been reported to exhibit lipid lowering, antioxidant, and cardiovascular protective properties. Therefore, the present study investigated the effect of naringin on fructose-induced endothelial dysfunction in rats and its underlying mechanisms. Male Sprague-Dawley rats were given 10% fructose in drinking water for 12 weeks, whereas control rats were fed drinking water alone. Naringin (100 mg/kg) was orally administered to fructose fed rats during the last 4 weeks of the study. Following 12 weeks, blood samples were collected for measurement of blood glucose, serum lipid profile and total nitrate/nitrite (NOx). Vascular function was assessed by isometric tension recording. Aortic expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), and nitrotyrosine were evaluated by western blot analysis. Fructose feeding induced increased levels of blood glucose, total cholesterol, triglyceride, and low density lipoprotein. In rat aortae, fructose reduced acethycholine-induced vasorelaxation, without affecting sodium nitroprusside-induced vasorelaxation. Treatment of fructose-fed rats with naringin restored fructose-induced metabolic alterations and endothelial dysfunction. Fructose-fed rats also exhibited decreased serum NOx level, reduced eNOS and p-eNOS protein expression, and enhanced nitrotyrosine expression in aortae. These alterations were improved by naringin treatment. The results of the present study suggested that naringin treatment preserves endothelium-dependent relaxation in aortae from fructose fed rats. This effect is primarily mediated through an enhanced NO bioavailability via increased eNOS activity and decreased NO inactivated to peroxynitrite in aortae.

Muscle Fatigue Affects the Interpolated Twitch Technique When Assessed Using Electrically-Induced Contractions in Human and Rat Muscles.

PubMed

Neyroud, Daria; Cheng, Arthur J; Bourdillon, Nicolas; Kayser, Bengt; Place, Nicolas; Westerblad, Håkan

2016-01-01

The interpolated twitch technique (ITT) is the gold standard to assess voluntary activation and central fatigue. Yet, its validity has been questioned. Here we studied how peripheral fatigue can affect the ITT. Repeated contractions at submaximal frequencies were produced by supramaximal electrical stimulations of the human adductor pollicis muscle in vivo and of isolated rat soleus fiber bundles; an extra stimulation pulse was given during contractions to induce a superimposed twitch. Human muscles fatigued by repeated 30-Hz stimulation trains (3 s on-1 s off) showed an ~80% reduction in the superimposed twitch force accompanied by a severely reduced EMG response (M-wave amplitude), which implies action potential failure. Subsequent experiments combined a less intense stimulation protocol (1.5 s on-3 s off) with ischemia to cause muscle fatigue, but which preserved M-wave amplitude. However, the superimposed twitch force still decreased markedly more than the potentiated twitch force; with ITT this would reflect increased "voluntary activation." In contrast, the superimposed twitch force was relatively spared when a similar protocol was performed in rat soleus bundles. Force relaxation was slowed by >150% in fatigued human muscles, whereas it was unchanged in rat soleus bundles. Accordingly, results similar to those in the human muscle were obtained when relaxation was slowed by cooling the rat soleus muscles. In conclusion, our data demonstrate that muscle fatigue can confound the quantification of central fatigue using the ITT.

The efficiency of botulinum toxin type A for the treatment of masseter muscle pain in patients with temporomandibular joint dysfunction and tension-type headache.

PubMed

Pihut, Malgorzata; Ferendiuk, Ewa; Szewczyk, Michal; Kasprzyk, Katarzyna; Wieckiewicz, Mieszko

2016-01-01

Temporomandibular joint dysfunction are often accompanied by symptoms of headache such as tension-type headache which is the most frequent spontaneous primary headache. Masseter muscle pain is commonly reported in this group. The purpose of the study was to assess the efficiency of intramuscular botulinum toxin type A injections for treating masseter muscle pain in patients with temporomandibular joint dysfunction and tension-type headache. This prospective outcome study consisted of 42 subjects of both genders aged 19-48 years diagnosed with masseter muscle pain related to temporomandibular joint dysfunction and tension-type headache. The subjects were treated by the intramuscular injection of 21 U (mice units) of botulinum toxin type A (Botox, Allergan) in the area of the greatest cross-section surface of both masseter bellies. Pain intensity was evaluated using visual analogue scale (VAS) and verbal numerical rating scale (VNRS) 1 week before the treatment and 24 weeks after the treatment. The obtained data were analyzed using the Wilcoxon matched pairs test (p ≤ 0,005). The results of this study showed a decrease in the number of referred pain episodes including a decrease in pain in the temporal region bilaterally, a reduction of analgesic drugs intake as well as a decrease in reported values of VAS and VNRS after injections (p = 0,000). The intramuscular botulinum toxin type A injections have been an efficient method of treatment for masseter muscle pain in patients with temporomandibular joint dysfunction and tension-type headache.

Increased adipogenic conversion of muscle satellite cells in obese Zucker rats.

PubMed

Scarda, A; Franzin, C; Milan, G; Sanna, M; Dal Prà, C; Pagano, C; Boldrin, L; Piccoli, M; Trevellin, E; Granzotto, M; Gamba, P; Federspil, G; De Coppi, P; Vettor, R

2010-08-01

Visceral and intermuscular adipose tissue (IMAT) depots account for most obesity-related metabolic and cardiovascular complications. Muscle satellite cells (SCs) are mesenchymal stem cells giving rise to myotubes and also to adipocytes, suggesting their possible contribution to IMAT origin and expansion. We investigated the myogenic differentiation of SCs and the adipogenic potential of both preadipocytes and SCs from genetically obese Zucker rats (fa/fa), focusing on the role of Wnt signaling in these differentiation processes. SCs were isolated by single-fiber technique from flexor digitorum brevis muscle and preadipocytes were extracted from subcutaneous adipose tissue (AT). Morphological features and gene expression profile were evaluated during in vitro myogenesis and adipogenesis. Wingless-type MMTV integration site family member 10b (Wnt10b) expression was quantified by quantitative PCR in skeletal muscle and AT. We did not observe any difference in the proliferation rate and in the myogenic differentiation of SCs from obese and lean rats. However, a decreased insulin-induced glucose uptake was present in myotubes originating from fa/fa rats. Under adipogenic conditions, preadipocytes and SCs of obese animals displayed an enhanced adipogenesis. Wnt10b expression was reduced in obese rats in both muscle and AT. Our data suggest that the increase in different fat depots including IMAT and the reduced muscle insulin sensitivity, the major phenotypical alteration of obese Zucker rats, could be ascribed to an intrinsic defect, either genetically determined or acquired, still present in both muscle and fat precursors. The involvement of Wnt10b as a regulator of both adipogenesis and muscle-to-fat conversion is suggested.

Effects of elevated temperature on protein breakdown in muscles from septic rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hall-Angeras, M.A.; Angeras, U.H.; Hasselgren, P.O.

Elevated temperature has been proposed to contribute to accelerated muscle protein degradation during fever and sepsis. The present study examined the effect of increased temperature in vitro on protein turnover in skeletal muscles from septic and control rats. Sepsis was induced by cecal ligation and puncture (CLP); control rats were sham operated. After 16 h, the extensor digitorum longus (EDL) and soleus (SOL) muscles were incubated at 37 or 40 degrees C. Protein synthesis was determined by measuring incorporation of (14C)phenylalanine into protein. Total and myofibrillar protein breakdown was assessed from release of tyrosine and 3-methylhistidine (3-MH), respectively. Total proteinmore » breakdown was increased at 40 degrees C by 15% in EDL and by 29% in SOL from control rats, whereas 3-MH release was not affected. In muscles from septic rats, total and myofibrillar protein breakdown was increased by 22 and 30%, respectively, at 40 degrees C in EDL but was not altered in SOL. Protein synthesis was unaffected by high temperature both in septic and nonseptic muscles. The present results suggest that high temperature is not the primary mechanism of increased muscle protein breakdown in sepsis because the typical response to sepsis, i.e., a predominant increase in myofibrillar protein breakdown, was not induced by elevated temperature in normal muscle. It is possible, however, that increased temperature may potentiate protein breakdown that is already stimulated by sepsis because elevated temperature increased both total and myofibrillar protein breakdown in EDL from septic rats.« less

Passive stiffness of rat skeletal muscle undernourished during fetal development

PubMed Central

Toscano, Ana Elisa; Ferraz, Karla Mônica; de Castro, Raul Manhães; Canon, Francis

2010-01-01

OBJECTIVES: The aim of the study was to investigate the effect of fetal undernutrition on the passive mechanical properties of skeletal muscle of weaned and young adult rats. INTRODUCTION: A poor nutrition supply during fetal development affects physiological functions of the fetus. From a mechanical point of view, skeletal muscle can be also characterized by its resistance to passive stretch. METHODS: Male Wistar rats were divided into two groups according to their mother's diet during pregnancy: a control group (mothers fed a 17% protein diet) and an isocaloric low‐protein group (mothers fed a 7.8% protein diet). At birth, all mothers received a standardized meal ad libitum. At the age of 25 and 90 days, the soleus muscle and extensor digitorum longus (EDL) muscles were removed in order to test the passive mechanical properties. A first mechanical test consisted of an incremental stepwise extension test using fast velocity stretching (500 mm/s) enabling us to measure, for each extension stepwise, the dynamic stress (σd) and the steady stress (σs). A second test consisted of a slow velocity stretch in order to calculate normalized stiffness and tangent modulus from the stress–strain relationship. RESULTS: The results for the mechanical properties showed an important increase in passive stiffness in both the soleus and EDL muscles in weaned rat. In contrast, no modification was observed in young adult rats. CONCLUSIONS: The increase in passive stiffness in skeletal muscle of weaned rat submitted to intrauterine undernutrition it is most likely due to changes in muscle passive stiffness. PMID:21340228

Endurance exercise training and high-fat diet differentially affect composition of diacylglycerol molecular species in rat skeletal muscle.

PubMed

Kawanishi, Noriaki; Takagi, Kana; Lee, Hyeon-Cheol; Nakano, Daiki; Okuno, Toshiaki; Yokomizo, Takehiko; Machida, Shuichi

2018-06-01

Insulin resistance of peripheral muscle is implicated in the etiology of metabolic syndrome in obesity. Although accumulation of glycerolipids, such as triacylglycerol and diacylglycerol (DAG), in muscle contributes to insulin resistance in obese individuals, endurance-trained athletes also have higher glycerolipid levels but normal insulin sensitivity. We hypothesized that the difference in insulin sensitivity of skeletal muscle between athletes and obese individuals stems from changes in fatty acid composition of accumulated lipids. Here, we evaluated the effects of intense endurance exercise and high-fat diet (HFD) on the accumulation and composition of lipid molecular species in rat skeletal muscle using a lipidomic approach. Sprague-Dawley female rats were randomly assigned to three groups and received either normal diet (ND) in sedentary conditions, ND plus endurance exercise training, or HFD in sedentary conditions. Rats were fed ND or HFD between 4 and 12 wk of age. Rats in the exercise group ran on a treadmill for 120 min/day, 5 days/wk, for 8 wk. Soleus muscle lipidomic profiles were obtained using liquid chromatography/tandem mass spectrometry. Total DAG levels, particularly those of palmitoleate-containing species, were increased in muscle by exercise training. However, whereas the total DAG level in the muscle was also increased by HFD, the levels of DAG molecular species containing palmitoleate were decreased by HFD. The concentration of phosphatidylethanolamine molecular species containing palmitoleate was increased by exercise but decreased by HFD. Our results indicate that although DAG accumulation was similar levels in trained and sedentary obese rats, specific changes in molecular species containing palmitoleate were opposite.

Ganglioside GM3 content in skeletal muscles is increased in type 2 but decreased in type 1 diabetes rat models: Implications of glycosphingolipid metabolism in pathophysiology of diabetes.

PubMed

Bozic, Josko; Markotic, Anita; Cikes-Culic, Vedrana; Novak, Anela; Borovac, Josip A; Vucemilovic, Hrvoje; Trgo, Gorana; Ticinovic Kurir, Tina

2018-02-01

Ganglioside GM3 is found in the plasma membrane, where its accumulation attenuates insulin receptor signaling. Considering the role of skeletal muscles in insulin-stimulated glucose uptake, the aim of the present study was to determine the expression of GM3 and its precursors in skeletal muscles of rat models of type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). Diabetes was induced in male Sprague-Dawley rats by streptozotocin injection (55 mg/kg, i.p., for T1DM induction; 35 mg/kg, i.p., for T2DM induction), followed by feeding of rats with either a normal pellet diet (T1DM) or a high-fat diet (T2DM). Rats were killed 2 weeks after diabetes induction and samples of skeletal muscle were collected. Frozen quadriceps muscle sections were stained with a primary antibody against GM3 (Neu5Ac) and visualized using a secondary antibody coupled with Texas Red. The muscle content of ganglioside GM3 and its precursors was analyzed by high-performance thin-layer chromatography (HPTLC) followed by GM3 immunostaining. Muscle GM3 content was significantly higher in T2DM compared with control rats (P < 0.001). Furthermore, levels of the GM3 precursors ceramide, glucosylceramide, and lactosylceramide were significantly higher in T2DM compared with control rats (P < 0.05), whereas ceramide content was significantly lower in T1DM rats (P < 0.05). The intensity of the GM3 band on HPTLC was significantly higher in T2DM rats (P < 0.001) and significantly lower in T1DM rats (P < 0.05) compared with control. The expression patterns of GM3 ganglioside and its precursors in diabetic rats suggest that the role of glycosphingolipid metabolism may differ between T2DM and T1DM. © 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Psychological Stress Induces Temporary Masticatory Muscle Mechanical Sensitivity in Rats

PubMed Central

Huang, Fei; Zhang, Min; Chen, Yong-Jin; Li, Qiang; Wu, An-Zhen

2011-01-01

To explore the relationship between psychological stress and masticatory muscle pain, we created a communication stress animal model to determine whether psychological stress could induce increased mechanical sensitivity in masticatory muscles and to study the changes of mechanical nociceptive thresholds after stress removal. Forty-eight male Sprague-Dawley rats were divided into a control group (CON), a foot-shocked group (FS, including 3 subgroups recorded as FS-1, FS-2, and FS-3), a psychological stress group (PS), and a drug treatment group (DT). PS and DT rats were confined in a communication box for one hour a day to observe the psychological responses of neighboring FS rats.Measurements of the mechanical nociceptive thresholds of the bilateral temporal and masseter muscles showed a stimulus-response relationship between psychological stress and muscle mechanical sensitivity. The DT rats, who received a diazepam injection, showed almost the same mechanical sensitivity of the masticatory muscles to that of the control in response to psychological stress. Fourteen days after the psychological stressor was removed, the mechanical nociceptive thresholds returned to normal. These findings suggest that psychological stress is directly related to masticatory muscle pain. Removal of the stressor could be a useful method for relieving mechanical sensitivity increase induced by psychological stress. PMID:21331360

Mechanisms underlying hypothermia-induced cardiac contractile dysfunction.

PubMed

Han, Young-Soo; Tveita, Torkjel; Prakash, Y S; Sieck, Gary C

2010-03-01

Rewarming patients after profound hypothermia may result in acute heart failure and high mortality (50-80%). However, the underlying pathophysiological mechanisms are largely unknown. We characterized cardiac contractile function in the temperature range of 15-30 degrees C by measuring the intracellular Ca(2+) concentration ([Ca(2+)](i)) and twitch force in intact left ventricular rat papillary muscles. Muscle preparations were loaded with fura-2 AM and electrically stimulated during cooling at 15 degrees C for 1.5 h before being rewarmed to the baseline temperature of 30 degrees C. After hypothermia/rewarming, peak twitch force decreased by 30-40%, but [Ca(2+)](i) was not significantly altered. In addition, we assessed the maximal Ca(2+)-activated force (F(max)) and Ca(2+) sensitivity of force in skinned papillary muscle fibers. F(max) was decreased by approximately 30%, whereas the pCa required for 50% of F(max) was reduced by approximately 0.14. In rewarmed papillary muscle, both total cardiac troponin I (cTnI) phosphorylation and PKA-mediated cTnI phosphorylation at Ser23/24 were significantly increased compared with controls. We conclude that after hypothermia/rewarming, myocardial contractility is significantly reduced, as evidenced by reduced twitch force and F(max). The reduced myocardial contractility is attributed to decreased Ca(2+) sensitivity of force rather than [Ca(2+)](i) itself, resulting from increased cTnI phosphorylation.

Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity.

PubMed

Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

2015-12-01

Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. © 2015 Authors; published by Portland Press Limited.

Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity

PubMed Central

Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W.; Barrett, Eugene J.; Cao, Wenhong

2015-01-01

Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. PMID:26265791

Loss of strength capacity is associated with mortality, but resistance exercise training promotes only modest effects during cachexia progression.

PubMed

das Neves, Willian; Alves, Christiano Robles Rodrigues; de Almeida, Ney Robson; Guimarães, Fátima Lúcia Rodrigues; Ramires, Paulo Rizzo; Brum, Patricia Chakur; Lancha, Antonio Herbert

2016-10-15

Resistance exercise training (RET) has been adopted as non-pharmacological anti-catabolic strategy. However, the role of RET to counteract cancer cachexia is still speculative. This study aimed to verify whether short-term RET would counteract skeletal muscle wasting in a severe cancer cachexia rat model. Wistar rats were randomly allocated into four experimental groups; 1) untrained control rats (control), 2) rats submitted to RET (control+RET), 3) untrained rats injected with Walker 256 tumor cells in the bone marrow (tumor) and 4) rats injected with Walker 256 tumor cells in the bone marrow and submitted to RET (tumor+RET). Tumor group displayed skeletal muscle atrophy fifteen days post tumor cells injection as assessed by plantaris (-20.5%) and EDL (-20.0%) muscle mass. EDL atrophy was confirmed showing 43.8% decline in the fiber cross sectional area. Even though RET increased the lactate dehydrogenase protein content and fully restored phosphorylated form of 4EBP-1 to the control levels in skeletal muscle, it failed to rescue muscle morphology in tumor-bearing rats. Indeed, RET did not mitigated loss of muscle function, anorexia, tumor growth or mortality rate. However, loss of strength capacity (assessed by 1-RM test performance) demonstrated a negative correlation with rats' survival (p=0.02; r=0.40), suggesting that loss of strength capacity might predict cancer mortality. These results demonstrated that bone marrow injection of Walker 256 tumor cells in rats induces cancer cachexia, strength capacity is associated with cancer survival and short-term RET promotes only modest effects during cachexia progression. Copyright © 2016 Elsevier Inc. All rights reserved.

Androgen-estrogen synergy in rat levator ani muscle Glucose-6-phosphate dehydrogenase

NASA Technical Reports Server (NTRS)

Max, S. R.

1984-01-01

The effects of castration and hormone administration on the activity of glucose-6-phosphate dehydrogenase in the rat levator ani muscle were studied. Castration caused a decrease in enzyme activity and in wet weight of the levator ani muscle. Chronic administration of testosterone propionate increased glucose-6-phosphate dehydrogenase activity in the levator ani muscle of castrated rats; the magnitude of the recovery of enzyme activity was related to the length of time of exposure to testosterone propionate after castration as well as to the length of time the animals were castrated. The longer the period of castration before exposure to testosterone propionate, the greater the effect. This result may be related to previously reported castration-mediated increases in androgen receptor binding in muscle. Dihydrotestosterone was less effective than testosterone propionate in enhancing glucose-6-phosphate dehydrogenase activity in the levator ani muscle from castrated rats; estradiol-17-beta alone was ineffective. Combined treatment with estradiol-17-beta and dihydrotestosterone, however, was as effective as testosterone alone. Thus, androgens and estrogens may exert synergistic effects on levator ani muscle.

A possible role for endogenous glucocorticoids in orchiectomy-induced atrophy of the rat levator ani muscle - Studies with RU 38486, a potent and selective antiglucocorticoid

NASA Technical Reports Server (NTRS)

Konagaya, Masaaki; Max, Stephen R.

1986-01-01

RU38486, a potent and selective antiglucocorticoid, was employed to study a possible role for endogenous glucocorticoids in atrophy of the levator ani muscle secondary to castration of male rats. RU38486 was shown to block (3H) triamcinolone acetonide binding to cytosol from levator ani muscle. Daily oral administration of RU38486 to castrated rats partially prevented atrophy of the levator ani muscle, as well as a decrease in RNA concentration. In a control group receiving RU38486 alone, the levator ani underwent significant 20 percent hypertrophy. Administration of exogenous dexamethasone also caused pronounced atrophy of the levator ani muscle. This atrophy was prevented, to a significant degree, by simultaneous oral administration of Ru38486. It is concluded that endogenous glucocorticoids, the actions of which are blocked by RU38486, may be involved in regulation of the mass of the levator ani muscle in intact rats.

A possible role for endogenous glucocorticoids in orchiectomy-induced atrophy of the rat levator ani muscle: Studies with RU38486, a potent and selective antiglucocorticoid

NASA Technical Reports Server (NTRS)

Konagaya, M.; Max, S. R.

1985-01-01

RU38486, a potent and selective antiglucocorticoid, was employed to study a possible role for endogenous glucocorticoids in atrophy of the levator ani muscle secondary to castration of male rats. RU38486 was shown to block (3H) triamcinolone acetonide binding to cytosol from levator ani muscle. Daily oral administration of RU38486 to castrated rats partially prevented atrophy of the levator ani muscle, as well as a decrease in RNA concentration. In a control group receiving RU38486 alone, the levator ani underwent significant (20%) hypertrophy. Administration of exogenous dexamethasone also caused pronounced atrophy of the levator ani muscle. This atrophy was prevented, to a significant degree, by simultaneous oral administration of RU38486. It is concluded that endogenous glucocorticoids, the actions of which are blocked by RU38486, may be involved in regulation of the mass of the levator ani muscle in intact rats.

Changes of contractile responses due to simulated weightlessness in rat soleus muscle

NASA Astrophysics Data System (ADS)

Elkhammari, A.; Noireaud, J.; Léoty, C.

1994-08-01

Some contractile and electrophysiological properties of muscle fibers isolated from the slow-twitch soleus (SOL) and fast-twitch extensor digitorum longus (EDL) muscles of rats were compared with those measured in SOL muscles from suspended rats. In suspendede SOL (21 days of tail-suspension) membrane potential (Em), intracellular sodium activity (aiNa) and the slope of the relationship between Em and log [K]o were typical of fast-twitch muscles. The relation between the maximal amplitude of K-contractures vs Em was steeper for control SOL than for EDL and suspended SOL muscles. After suspension, in SOL muscles the contractile threshold and the inactivation curves for K-contractures were shifted to more positive Em. Repriming of K-contractures was unaffected by suspencion. The exposure of isolated fibers to perchlorate (ClO4-)-containing (6-40 mM) solutions resulted ina similar concentration-dependent shift to more negative Em of activation curves for EDL and suspended SOL muscles. On exposure to a Na-free TEA solution, SOL from control and suspended rats, in contrast to EDL muscles, generated slow contractile responses. Suspended SOL showed a reduced sensitivity to the contracture-producing effect of caffeine compared to control muscles. These results suggested that the modification observed due to suspension could be encounted by changes in the characteristics of muscle fibers from slow to fast-twitch type.

Mechanisms underlying the losartan treatment-induced improvement in the endothelial dysfunction seen in mesenteric arteries from type 2 diabetic rats.

PubMed

Matsumoto, Takayuki; Ishida, Keiko; Nakayama, Naoaki; Taguchi, Kumiko; Kobayashi, Tsuneo; Kamata, Katsuo

2010-09-01

It is well known that type 2 diabetes mellitus is frequently associated with vascular dysfunction and an elevated systemic blood pressure, yet the underlying mechanisms are not completely understood. We previously reported that in mesenteric arteries from established type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats, which exhibit endothelial dysfunction, there is an imbalance between endothelium-derived vasodilators [namely, nitric oxide (NO) and hyperpolarizing factor (EDHF)] and vasoconstrictors [contracting factors (EDCFs) such as cyclooxygenase (COX)-derived prostanoids]. Here, we investigated whether the angiotensin II receptor antagonist losartan might improve endothelial dysfunction in OLETF rats at the established stage of diabetes. In mesenteric arteries isolated from OLETF rats [vs. those from age-matched control Long-Evans Tokushima Otsuka (LETO) rats]: (1) the acetylcholine (ACh)-induced relaxation was impaired, (2) the NO- and EDHF-mediated relaxations were reduced, (3) the ACh-induced EDCF-mediated contraction and the production of prostanoids were increased, and (4) superoxide generation was increased. After such OLETF rats had received losartan (25 mg/kg/day p.o. for 4 weeks), their isolated mesenteric arteries exhibited: (1) improvements in ACh-induced NO- and EDHF-mediated relaxations, (2) reduced EDCF- and arachidonic acid-induced contractions, (3) suppressed production of prostanoids, (4) reduced PGE(2)-mediated contraction, and (5) reduced superoxide generation. Within the timescale studied here, losartan did not change the protein expressions of endothelial NO synthase, COX1, or COX2 in mesenteric arteries from either OLETF or LETO rats. Losartan thus normalizes vascular dysfunction in this type 2 diabetic model, and the above effects may contribute to the reduction of adverse cardiovascular events seen in diabetic patients treated with angiotensin II receptor blockers. Copyright 2010 Elsevier Ltd. All rights reserved.

Working underground: Respiratory adaptations in the blind mole rat

PubMed Central

Widmer, Hans R.; Hoppeler, Hans; Nevo, Eviatar; Taylor, C. Richard; Weibel, Ewald R.

1997-01-01

Mole rats (Spalax ehrenbergi superspecies) perform the heavy work of digging their subterranean burrows in Israel under highly hypoxic/hypercapnic conditions. Unlike most other mammals, they can achieve high levels of metabolic rate under these conditions, while their metabolic rate at low work rates is depressed. We explored, by comparing mole rats with white rats, whether and how this is related to adaptations in the design of the respiratory system, which determines the transfer of O2 from the lung to muscle mitochondria. At the same body mass, mole rats were found to have a significantly smaller total skeletal muscle mass than ordinary white rats (−22%). In contrast, the fractional volume of muscle mitochondria was larger by 46%. As a consequence, both species had the same total amount of mitochondria and achieved, under normoxia, the same V̇O2max. Whereas the O2 transport capacity of the blood was not different, we found a larger capillary density (+31%) in the mole rat muscle, resulting in a reduced diffusion distance to mitochondria. The structural pulmonary diffusing capacity for O2 was greater in the mole rat (+44%), thus facilitating O2 uptake in hypoxia. We conclude that structural adaptations in lung and muscle tissue improve O2 diffusion conditions and serve to maintain high metabolic rates in hypoxia but have no consequences for achieving V̇O2max under normoxic conditions. PMID:9050905

Diaphragm Dysfunction in Mechanically Ventilated Patients.

PubMed

Dot, Irene; Pérez-Teran, Purificación; Samper, Manuel-Andrés; Masclans, Joan-Ramon

2017-03-01

Muscle involvement is found in most critical patients admitted to the intensive care unit (ICU). Diaphragmatic muscle alteration, initially included in this category, has been differentiated in recent years, and a specific type of muscular dysfunction has been shown to occur in patients undergoing mechanical ventilation. We found this muscle dysfunction to appear in this subgroup of patients shortly after the start of mechanical ventilation, observing it to be mainly associated with certain control modes, and also with sepsis and/or multi-organ failure. Although the specific etiology of process is unknown, the muscle presents oxidative stress and mitochondrial changes. These cause changes in protein turnover, resulting in atrophy and impaired contractility, and leading to impaired functionality. The term 'ventilator-induced diaphragm dysfunction' was first coined by Vassilakopoulos et al. in 2004, and this phenomenon, along with injury cause by over-distention of the lung and barotrauma, represents a challenge in the daily life of ventilated patients. Diaphragmatic dysfunction affects prognosis by delaying extubation, prolonging hospital stay, and impairing the quality of life of these patients in the years following hospital discharge. Ultrasound, a non-invasive technique that is readily available in most ICUs, could be used to diagnose this condition promptly, thus preventing delays in starting rehabilitation and positively influencing prognosis in these patients. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

Postinjury Exercise and Platelet-Rich Plasma Therapies Improve Skeletal Muscle Healing in Rats But Are Not Synergistic When Combined.

PubMed

Contreras-Muñoz, Paola; Torrella, Joan Ramon; Serres, Xavier; Rizo-Roca, David; De la Varga, Meritxell; Viscor, Ginés; Martínez-Ibáñez, Vicente; Peiró, José Luis; Järvinen, Tero A H; Rodas, Gil; Marotta, Mario

2017-07-01

Skeletal muscle injuries are the most common sports-related injury and a major concern in sports medicine. The effect of platelet-rich plasma (PRP) injections on muscle healing is still poorly understood, and current data are inconclusive. To evaluate the effects of an ultrasound-guided intramuscular PRP injection, administered 24 hours after injury, and/or posttraumatic daily exercise training for 2 weeks on skeletal muscle healing in a recently established rat model of skeletal muscle injury that highly mimics the muscle trauma seen in human athletes. Controlled laboratory study. A total of 40 rats were assigned to 5 groups. Injured rats (medial gastrocnemius injury) received a single PRP injection (PRP group), daily exercise training (Exer group), or a combination of a single PRP injection and daily exercise training (PRP-Exer group). Untreated and intramuscular saline-injected animals were used as controls. Muscle force was determined 2 weeks after muscle injury, and muscles were harvested and evaluated by means of histological assessment and immunofluorescence microscopy. Both PRP (exhibiting 4.8-fold higher platelet concentration than whole blood) and exercise training improved muscle strength (maximum tetanus force, TetF) in approximately 18%, 20%, and 30% of rats in the PRP, PRP-Exer, and Exer groups, respectively. Specific markers of muscle regeneration (developmental myosin heavy chain, dMHC) and scar formation (collagen I) demonstrated the beneficial effect of the tested therapies in accelerating the muscle healing process in rats. PRP and exercise treatments stimulated the growth of newly formed regenerating muscle fibers (1.5-, 2-, and 2.5-fold increase in myofiber cross-sectional area in PRP, PRP-Exer, and Exer groups, respectively) and reduced scar formation in injured skeletal muscle (20%, 34%, and 41% of reduction in PRP, PRP-Exer, and Exer groups, respectively). Exercise-treated muscles (PRP-Exer and Exer groups) had significantly reduced percentage of dMHC-positive regenerating fibers (35% and 47% decrease in dMHC expression, respectively), indicating that exercise therapies accelerated the muscle healing process witnessed by the more rapid replacement of the embryonic-developmental myosin isoform by mature muscle myosin isoforms. Intramuscular PRP injection and, especially, treadmill exercise improve histological outcome and force recovery of the injured skeletal muscle in a rat injury model that imitates sports-related muscle injuries in athletes. However, there was not a synergistic effect when both treatments were combined, suggesting that PRP does not add any beneficial effect to exercise-based therapy in the treatment of injured skeletal muscle. This study demonstrates the efficacy of an early active rehabilitation protocol or single intramuscular PRP injection on muscle recovery. The data also reveal that the outcome of the early active rehabilitation is adversely affected by the PRP injection when the two therapies are combined, and this could explain why PRP therapies have failed in randomized clinical trials where the athletes have adhered to postinjection rehabilitation protocols based on the principle of early, active mobilization.

Effects of exercise training on circulating and skeletal muscle renin-angiotensin system in chronic heart failure rats.

PubMed

Gomes-Santos, Igor Lucas; Fernandes, Tiago; Couto, Gisele Kruger; Ferreira-Filho, Julio César Ayres; Salemi, Vera Maria Cury; Fernandes, Fernanda Barrinha; Casarini, Dulce Elena; Brum, Patricia Chakur; Rossoni, Luciana Venturini; de Oliveira, Edilamar Menezes; Negrao, Carlos Eduardo

2014-01-01

Accumulated evidence shows that the ACE-AngII-AT1 axis of the renin-angiotensin system (RAS) is markedly activated in chronic heart failure (CHF). Recent studies provide information that Angiotensin (Ang)-(1-7), a metabolite of AngII, counteracts the effects of AngII. However, this balance between AngII and Ang-(1-7) is still little understood in CHF. We investigated the effects of exercise training on circulating and skeletal muscle RAS in the ischemic model of CHF. Male Wistar rats underwent left coronary artery ligation or a Sham operation. They were divided into four groups: 1) Sedentary Sham (Sham-S), 2) exercise-trained Sham (Sham-Ex), sedentary CHF (CHF-S), and exercise-trained CHF (CHF-Ex). Angiotensin concentrations and ACE and ACE2 activity in the circulation and skeletal muscle (soleus and plantaris) were quantified. Skeletal muscle ACE and ACE2 protein expression, and AT1, AT2, and Mas receptor gene expression were also evaluated. CHF reduced ACE2 serum activity. Exercise training restored ACE2 and reduced ACE activity in CHF. Exercise training reduced plasma AngII concentration in both Sham and CHF rats and increased the Ang-(1-7)/AngII ratio in CHF rats. CHF and exercise training did not change skeletal muscle ACE and ACE2 activity and protein expression. CHF increased AngII levels in both soleus and plantaris muscle, and exercise training normalized them. Exercise training increased Ang-(1-7) in the plantaris muscle of CHF rats. The AT1 receptor was only increased in the soleus muscle of CHF rats, and exercise training normalized it. Exercise training increased the expression of the Mas receptor in the soleus muscle of both exercise-trained groups, and normalized it in plantaris muscle. Exercise training causes a shift in RAS towards the Ang-(1-7)-Mas axis in skeletal muscle, which can be influenced by skeletal muscle metabolic characteristics. The changes in RAS circulation do not necessarily reflect the changes occurring in the RAS of skeletal muscle.

Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy.

PubMed

Larcher, Thibaut; Lafoux, Aude; Tesson, Laurent; Remy, Séverine; Thepenier, Virginie; François, Virginie; Le Guiner, Caroline; Goubin, Helicia; Dutilleul, Maéva; Guigand, Lydie; Toumaniantz, Gilles; De Cian, Anne; Boix, Charlotte; Renaud, Jean-Baptiste; Cherel, Yan; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio; Huchet, Corinne

2014-01-01

A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.

Neuromuscular junction formation between human stem-cell-derived motoneurons and rat skeletal muscle in a defined system.

PubMed

Guo, Xiufang; Das, Mainak; Rumsey, John; Gonzalez, Mercedes; Stancescu, Maria; Hickman, James

2010-12-01

To date, the coculture of motoneurons (MNs) and skeletal muscle in a defined in vitro system has only been described in one study and that was between rat MNs and rat skeletal muscle. No in vitro studies have demonstrated human MN to rat muscle synapse formation, although numerous studies have attempted to implant human stem cells into rat models to determine if they could be of therapeutic use in disease or spinal injury models, although with little evidence of neuromuscular junction (NMJ) formation. In this report, MNs differentiated from human spinal cord stem cells, together with rat skeletal myotubes, were used to build a coculture system to demonstrate that NMJ formation between human MNs and rat skeletal muscles is possible. The culture was characterized by morphology, immunocytochemistry, and electrophysiology, while NMJ formation was demonstrated by immunocytochemistry and videography. This defined system provides a highly controlled reproducible model for studying the formation, regulation, maintenance, and repair of NMJs. The in vitro coculture system developed here will be an important model system to study NMJ development, the physiological and functional mechanism of synaptic transmission, and NMJ- or synapse-related disorders such as amyotrophic lateral sclerosis, as well as for drug screening and therapy design.

Effects of continuous low-carbohydrate diet after long-term exercise on GLUT-4 protein content in rat skeletal muscle.

PubMed

Kubota, M; Koshinaka, K; Kawata, Y; Koike, T; Oshida, Y

2008-01-01

Stimulation of AMPK and decreased glycogen levels in skeletal muscle have a deep involvement in enhanced insulin action and GLUT-4 protein content after exercise training. The present study examined the chronic effects of a continuous low-carbohydrate diet after long-term exercise on GLUT-4 protein content, glycogen content, AMPK, and insulin signaling in skeletal muscle. Rats were divided randomly into four groups: normal chow diet sedentary (N-Sed), low carbohydrate diet sedentary (L-Sed), normal chow diet exercise (N-Ex), and low carbohydrate diet exercise (L-Ex) groups. Rats in the exercise groups (N-Ex and L-Ex) were exercised by swimming for 6 hours/day in two 3-hour bouts separated by 45 minutes of rest. The 10-day exercise training resulted in a significant increase in the GLUT-4 protein content (p<0.01). Additionally, the GLUT-4 protein content in L-Ex rats was increased by 29% above that in N-Ex rats (p<0.01). Finally, the glycogen content in skeletal muscle of L-Ex rats was decreased compared with that of N-Ex rats. Taken together, we suggest that the maintenance of glycogen depletion after exercise by continuous low carbohydrate diet results in the increment of the GLUT-4 protein content in skeletal muscle.

Exercise alters myostatin protein expression in sedentary and exercised streptozotocin-diabetic rats.

PubMed

Bassi, Daniela; Bueno, Patricia de Godoy; Nonaka, Keico Okino; Selistre-Araujo, Heloisa Sobreiro; Leal, Angela Merice de Oliveira

2015-04-01

The aim of this study was to analyze the effect of exercise on the pattern of muscle myostatin (MSTN) protein expression in two important metabolic disorders, i.e., obesity and diabetes mellitus. MSTN, is a negative regulator of skeletal muscle mass. We evaluated the effect of exercise on MSTN protein expression in diabetes mellitus and high fat diet-induced obesity. MSTN protein expression in gastrocnemius muscle was analyzed by Western Blot. P < 0.05 was assumed. Exercise induced a significant decrease in glycemia in both diabetic and obese animals. The expression of precursor and processed protein forms of MSTN and the weight of gastrocnemius muscle did not vary in sedentary or exercised obese animals. Diabetes reduced gastrocnemius muscle weight in sedentary animals. However, gastrocnemius muscle weight increased in diabetic exercised animals. Both the precursor and processed forms of muscle MSTN protein were significantly higher in sedentary diabetic rats than in control rats. The precursor form was significantly lower in diabetic exercised animals than in diabetic sedentary animals. However, the processed form did not change. These results demonstrate that exercise can modulate the muscle expression of MSTN protein in diabetic rats and suggest that MSTN may be involved in energy homeostasis.

Mechanism linking glycogen concentration and glycogenolytic rate in perfused contracting rat skeletal muscle.

PubMed Central

Hespel, P; Richter, E A

1992-01-01

The influence of differences in glycogen concentration on glycogen breakdown and on phosphorylase activity was investigated in perfused contracting rat skeletal muscle. The rats were preconditioned by a combination of swimming exercise and diet (carbohydrate-free or carbohydrate-rich) in order to obtain four sub-groups of rats with varying resting muscle glycogen concentrations (range 10-60 mumol/g wet wt.). Pre-contraction muscle glycogen concentration was closely positively correlated with glycogen breakdown over 15 min of intermittent short tetanic contractions (r = 0.75; P less than 0.001; n = 56) at the same tension development and oxygen uptake. Additional studies in supercompensated and glycogen-depleted hindquarters during electrical stimulation for 20 s or 2 min revealed that the difference in glycogenolytic rate was found at the beginning rather than at the end of the contraction period. Phosphorylase alpha activity was approximately twice as high (P less than 0.001) in supercompensated muscles as in glycogen-depleted muscles after 20 s as well as after 2 min of contractions. It is concluded that glycogen concentration is an important determinant of phosphorylase activity in contracting skeletal muscle, and probably via this mechanism a regulator of glycogenolytic rate during muscle contraction. PMID:1622395

Proteomics Analysis Identifies Molecular Targets Related to Diabetes Mellitus-associated Bladder Dysfunction *S⃞

PubMed Central

Yohannes, Elizabeth; Chang, Jinsook; Christ, George J.; Davies, Kelvin P.; Chance, Mark R.

2008-01-01

Protein expression profiles in rat bladder smooth muscle were compared between animal models of streptozotocin-induced diabetes mellitus (STZ-DM) and age-matched controls at 1 week and 2 months after induction of hyperglycemia with STZ treatment. At each time point, protein samples from four STZ-DM and four age-matched control rat bladder tissues were prepared independently and analyzed together across multiple DIGE gels using a pooled internal standard sample to quantify expression changes with statistical confidence. A total of 100 spots were determined to be significantly changing among the four experimental groups. A subsequent mass spectrometry analysis of the 100 spots identified a total of 56 unique proteins. Of the proteins identified by two-dimensional DIGE/MS, 10 exhibited significant changes 1 week after STZ-induced hyperglycemia, whereas the rest showed differential expression after 2 months. A network analysis of these proteins using MetaCore™ suggested induction of transcriptional factors that are too low to be detected by two-dimensional DIGE and identified an enriched cluster of down-regulated proteins that are involved in cell adhesion, cell shape control, and motility, including vinculin, intermediate filaments, Ppp2r1a, and extracellular matrix proteins. The proteins that were up-regulated include proteins involved in muscle contraction (e.g. Mrlcb and Ly-GDI), in glycolysis (e.g. α-enolase and Taldo1), in mRNA processing (e.g. heterogeneous nuclear ribonucleoprotein A2/B1), in inflammatory response (e.g. S100A9, Annexin 1, and apoA-I), and in chromosome segregation and migration (e.g. Tuba1 and Vil2). Our results suggest that the development of diabetes-related complications in this model involves the down-regulation of structural and extracellular matrix proteins in smooth muscle that are essential for normal muscle contraction and relaxation but also induces proteins that are associated with cell proliferation and inflammation that may account for some of the functional deficits known to occur in diabetic complications of bladder. PMID:18337374

Protection of rat skeletal muscle fibers by either L-carnitine or coenzyme Q10 against statins toxicity mediated by mitochondrial reactive oxygen generation

PubMed Central

La Guardia, P. G.; Alberici, L. C.; Ravagnani, F. G.; Catharino, R. R.; Vercesi, A. E.

2013-01-01

Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1–40 μM) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 μM) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 μM simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 μM mevalonate or 10 μM coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 μM) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. In all cases the damage to these complexes, presumably at the level of 4Fe-4S clusters, is prevented by L-carnitine. PMID:23720630

Intracerebral transplants of primary muscle cells: a potential 'platform' for transgene expression in the brain

NASA Technical Reports Server (NTRS)

Jiao, S.; Schultz, E.; Wolff, J. A.

1992-01-01

After the transplantation of rat primary muscle cells into the caudate or cortex of recipient rats, the muscle cells were able to persist for at least 6 months. Muscle cells transfected with expression plasmids prior to transplantation were able to express reporter genes in the brains for at least 2 months. These results suggest that muscle cells might be a useful 'platform' for transgene expression in the brain.

Differential effects of peroxynitrite on contractile protein properties in fast- and slow-twitch skeletal muscle fibers of rat.

PubMed

Dutka, T L; Mollica, J P; Lamb, G D

2011-03-01

Oxidative modification of contractile proteins is thought to be a key factor in muscle weakness observed in many pathophysiological conditions. In particular, peroxynitrite (ONOO(-)), a potent short-lived oxidant, is a likely candidate responsible for this contractile dysfunction. In this study ONOO(-) or 3-morpholinosydnonimine (Sin-1, a ONOO(-) donor) was applied to rat skinned muscle fibers to characterize the effects on contractile properties. Both ONOO(-) and Sin-1 exposure markedly reduced maximum force in slow-twitch fibers but had much less effect in fast-twitch fibers. The rate of isometric force development was also reduced without change in the number of active cross bridges. Sin-1 exposure caused a disproportionately large decrease in Ca(2+) sensitivity, evidently due to coproduction of superoxide, as it was prevented by Tempol, a superoxide dismutase mimetic. The decline in maximum force with Sin-1 and ONOO(-) treatments could be partially reversed by DTT, provided it was applied before the fiber was activated. Reversal by DTT indicates that the decrease in maximum force was due at least in part to oxidation of cysteine residues. Ascorbate caused similar reversal, further suggesting that the cysteine residues had undergone S-nitrosylation. The reduction in Ca(2+) sensitivity, however, was not reversed by either DTT or ascorbate. Western blot analysis showed cross-linking of myosin heavy chain (MHC) I, appearing as larger protein complexes after ONOO(-) exposure. The findings suggest that ONOO(-) initially decreases maximum force primarily by oxidation of cysteine residues on the myosin heads, and that the accompanying decrease in Ca(2+) sensitivity is likely due to other, less reversible actions of hydroxyl or related radicals.

Age-related changes in functional NANC innervation with VIP and substance P in the jejunum of Lewis rats.

PubMed

Kasparek, Michael S; Fatima, Javairiah; Iqbal, Corey W; Duenes, Judith A; Sarr, Michael G

2009-12-03

Age-related changes in non-adrenergic, non-cholinergic (NANC) neurotransmission might contribute to differences in gastrointestinal motility. Our aim was to determine age-related changes in functional innervation with vasoactive intestinal polypeptide (VIP) and substance P (Sub P) in rat jejunum. We hypothesized that maturation causes changes in neurotransmission with these two neuropeptides. Longitudinal and circular jejunal muscle strips from young (3 months) and middle-aged (15 months) rats (total: 24 rats) were studied; the response to exogenous VIP and Sub P and the effect of their endogenous release from the enteric nervous system during electrical field stimulation (EFS) were evaluated. In longitudinal muscle, response to exogenous VIP and endogenously released VIP during EFS were increased in middle-aged rats, while the effect of endogenously released Sub P was decreased. In the circular muscle, the response to endogenously released VIP was increased in middle-aged rats, while the effects of exogenous VIP and endogenously released Sub P were unchanged. Response to exogenous Sub P was unaffected by maturation in both muscle layers. Spontaneous contractile activity was increased in the longitudinal and circular muscle of the older rats. In the jejunum of middle-aged rats, participation of VIP in functional NANC innervation was increased, while functional innervation with Sub P was decreased. These changes in the balance of inhibitory and excitatory neurotransmission occur during the year of maturation in rats and demonstrate an age-dependant plasticity of neuromuscular bowel function.

Enhanced skeletal muscle insulin sensitivity in year-old rats adapted to hypergravity

NASA Technical Reports Server (NTRS)

Mondon, C. E.; Dolkas, C. B.; Oyama, J.

1981-01-01

Rats induced into a hypermetabolic state by exposure to chronic (7 mo) centrifugation at 4.15 g exhibited increased glucose uptake at lower plasma insulin levels than weight-matched control animals following oral glucose administration. In order to determine the insulin sensitivity of specific tissues, the effect of exogenous insulin on glucose uptake by isolated perfused livers and hindlim skeletal muscle from rats adapted to chronic centrifugation for one year was compared with perfused tissue from 2.5 mo-old noncentrifuged control animals of equal body weight. Metabolic glucose clearance by skeletal muscle from hypergravic rats did not prove significantly greater than control muscle when perfused in the absence of insulin (10.6 vs 8.1 microliters/min-g-muscle), but was twice as fast (23.0 vs 9.5) at perfusate insulin levels of 35 micro-U/ml. Conversely, glucose uptake by hypergravic livers was significantly decreased (P is less than 0.001) compared with control livers (10.3 vs 27.8) at perfusate insulin levels of 40 micro-U/ml. Results suggest that skeletal muscle rather than liver is primarily responsible for the enhanced sensitivity to insulin and the increased energy expenditure observed in rats subjected to hypergravity.

Role of mast cells in bronchial contraction in nonallergic obstructive lung pathology.

PubMed

Kuzubova, Nataliya A; Lebedeva, Elena S; Titova, Olga N; Fedin, Anatoliy N; Dvorakovskaya, Ivetta V

2017-01-01

The role of mast cells in contractile bronchial smooth muscle activity has been evaluated in a model of chronic obstructive pulmonary disease induced in rats that were intermittently exposed to nitrogen dioxide (NO 2 ) for 60 days. Starting from the 31st day, one group of rats inhaled sodium cromoglycate before exposure to NO 2 to stabilize mast cell membranes. The second group (control) was not treated. Isometric smooth muscle contraction was analysed in isolated bronchial samples in response to nerve and smooth muscle stimulation. Histological analysis revealed large numbers of mast cells in lung tissue of COPD model rats. The inhibition of mast cell degranulation by sodium cromoglycate prevented the development of nerve-stimulated bronchial smooth muscle hyperactivity in COPD model rats. Histamine or adenosine-induced hyperactivity on nerve stimulation was also inhibited by sodium cromoglycate in bronchial smooth muscle in both control and COPD model rats. This suggests that the mechanism of contractile activity enhancement of bronchial wall smooth muscle cells may be mediated through the activation of resident mast cells transmembrane adenosine receptors resulting in their partial degranulation, with the released histamine acting upon histamine H1-receptors which trigger reflex pathways via intramural ganglion neurons.

Role of mast cells in bronchial contraction in nonallergic obstructive lung pathology

PubMed Central

Kuzubova, Nataliya A.; Lebedeva, Elena S.; Titova, Olga N.; Fedin, Anatoliy N.; Dvorakovskaya, Ivetta V.

2017-01-01

Abstract The role of mast cells in contractile bronchial smooth muscle activity has been evaluated in a model of chronic obstructive pulmonary disease induced in rats that were intermittently exposed to nitrogen dioxide (NO2) for 60 days. Starting from the 31st day, one group of rats inhaled sodium cromoglycate before exposure to NO2 to stabilize mast cell membranes. The second group (control) was not treated. Isometric smooth muscle contraction was analysed in isolated bronchial samples in response to nerve and smooth muscle stimulation. Histological analysis revealed large numbers of mast cells in lung tissue of COPD model rats. The inhibition of mast cell degranulation by sodium cromoglycate prevented the development of nerve-stimulated bronchial smooth muscle hyperactivity in COPD model rats. Histamine or adenosine-induced hyperactivity on nerve stimulation was also inhibited by sodium cromoglycate in bronchial smooth muscle in both control and COPD model rats. This suggests that the mechanism of contractile activity enhancement of bronchial wall smooth muscle cells may be mediated through the activation of resident mast cells transmembrane adenosine receptors resulting in their partial degranulation, with the released histamine acting upon histamine H1-receptors which trigger reflex pathways via intramural ganglion neurons. PMID:28867718

Maltitol inhibits small intestinal glucose absorption and increases insulin mediated muscle glucose uptake ex vivo but not in normal and type 2 diabetic rats.

PubMed

Chukwuma, Chika Ifeanyi; Ibrahim, Mohammed Auwal; Islam, Md Shahidul

2017-02-01

This study investigated the effects of maltitol on intestinal glucose absorption and muscle glucose uptake using ex vivo and in vivo experimental models. The ex vivo experiment was conducted in isolated jejunum and psoas muscle from normal rats. The in vivo study investigated the effects of a single bolus dose of maltitol on gastric emptying, intestinal glucose absorption and digesta transit in normal and type 2 diabetic rats. Maltitol inhibited glucose absorption in isolated rat jejunum and increased glucose uptake in isolated rat psoas muscle in the presence of insulin but not in the absence of insulin. In contrast, maltitol did not significantly (p > 0.05) alter small intestinal glucose absorption or blood glucose levels as well as gastric emptying and digesta transit in normal or type 2 diabetic rats. The results suggest that maltitol may not be a suitable dietary supplement for anti-diabetic food and food products to improve glycemic control.

Thymic involution in the suspended rat model for weightlessness - Decreased glucocorticoid receptor concentration

NASA Technical Reports Server (NTRS)

Steffen, J. M.; Musacchia, X. J.

1984-01-01

Hindlimb muscle atrophy, thymic involution and adrenal hypertrophy in rats during spaceflight can be simulated using suspension models. Skeletal muscle and thymus are sensitive to gluco-corticoids (GC), and previous studies have demonstrated that muscle atrophy in suspended rats is associated with increased GC receptor concentration. The objectives were to confirm thymic involution during suspension, and determine if involution correlated with increased GC receptor concentration. Seven days of antiorthostatic (AO) suspension of rats produced a significant (P less than 0.001) reduction in thymic wet weight not associated with an alteration of percent water content. GC receptor concentration (pmol/mg protein) decreased 20 percent (P less than 0.025) in thymus glands from 7 day AO suspended rats. Suspension, therefore, is associated with involution of the thymus, but this is not dependent upon AO positioning. Thymus GC receptor concentrations were depressed in 7-day suspended rats, in contrast with previous observations on skeletal muscle, suggesting that different mechanisms may underlie these responses.

Effect of salbutamol on innervated and denervated rat soleus muscle.

PubMed

Soić-Vranić, T; Bobinac, D; Bajek, S; Jerković, R; Malnar-Dragojević, D; Nikolić, M

2005-12-01

The objective of the present investigation was to perform a 14-day time-course study of treatment with salbutamol, a beta2 adrenoceptor agonist, on rat soleus muscle in order to assess fiber type selectivity in the hypertrophic response and fiber type composition. Male Wistar rats were divided into four groups: control (N = 10), treated with salbutamol (N = 30), denervated (N = 30), and treated with salbutamol after denervation (N = 30). Salbutamol was injected intraperitoneally in the rats of the 2nd and 4th groups at a concentration of 0.3 mg/kg twice a day for 2 weeks. The muscles were denervated using the crush method with pean. The animals were sacrificed 3, 6, 9, 12, and 14 days after treatment. Frozen cross-sections of soleus muscle were stained for myosin ATPase, pH 9.4. Cross-sectional area and percent of muscle fibers were analyzed morphometrically by computerized image analysis. Treatment with salbutamol induced hypertrophy of all fiber types and a higher percentage of type II fibers (21%) in the healthy rat soleus muscle. Denervation caused marked atrophy of all fibers and conversion from type I to type II muscle fibers. Denervated muscles treated with salbutamol showed a significantly larger cross-sectional area of type I muscle fibers, 28.2% compared to the denervated untreated muscle. Moreover, the number of type I fibers was increased. These results indicate that administration of salbutamol is able to induce changes in cross-sectional area and fiber type distribution in the early phase of treatment. Since denervation-induced atrophy and conversion from type I to type II fibers were improved by salbutamol treatment we propose that salbutamol, like other beta2 adrenoceptor agonists, may have a therapeutic potential in improving the condition of skeletal muscle after denervation.

Tensor veli palatini electromyography for monitoring Eustachian tube rehabilitation in otitis media.

PubMed

Picciotti, P M; Della Marca, G; D'Alatri, L; Lucidi, D; Rigante, M; Scarano, E

2017-05-01

The pathogenesis of otitis media is related to Eustachian tube dysfunction. The tensor veli palatini muscle actively opens the Eustachian tube and promotes middle-ear ventilation. This study describes a technique for paratubal electromyography that uses a surface, non-invasive electrode able to record tensor veli palatini muscle activity during swallowing. Twenty otitis media patients and 10 healthy patients underwent tensor veli palatini electromyography. Activity of this muscle before and after Eustachian tube rehabilitation was also assessed. In 78.5 per cent of patients, the electromyography duration phase and/or amplitude were reduced in the affected side. The muscle action potential was impaired in all patients who underwent Eustachian tube rehabilitation. This study confirmed that Eustachian tube muscle dysfunction has a role in otitis media pathogenesis and showed that muscle activity increases after Eustachian tube rehabilitation therapy.

Lithium Visibility in Rat Brain and Muscle in Vivoby 7Li NMR Imaging

NASA Astrophysics Data System (ADS)

Komoroski, Richard A.; Pearce, John M.; Newton, Joseph E. O.

1998-07-01

The apparent concentration of lithium (Li)in vivowas determined for several regions in the brain and muscle of rats by7Li NMR imaging at 4.7 T with inclusion of an external standard of known concentration and visibility. The average apparent concentrations were 10.1 mM for muscle, and 4.2-5.3 mM for various brain regions under the dosing conditions used. The results were compared to concentrations determinedin vitroby high-resolution7Li NMR spectroscopy of extracts of brain and muscle tissue from the same rats. The comparison provided estimates of the7Li NMR visibility of the Li cation in each tissue region. Although there was considerable scatter of the calculated visibilities among the five rats studied, the results suggested essentially full visibility (96%) for Li in muscle, and somewhat reduced visibility (74-93%) in the various brain regions.

Morphometric analysis of rat muscle fibers following space flight and hypogravity

NASA Technical Reports Server (NTRS)

Chui, L. A.; Castleman, K. R.

1982-01-01

The effect of hypogravity on striate muscles, containing both fast twitch glycolytic and slow twitch oxidative fibers, was studied in rats aboard two Cosmos biosatellites. Results of a computer-assisted image analysis of extensor digitorum muscles from five rats, exposed to 18.5 days of hypogravity and processed for the alkaline ATPase reaction, showed a reduction of the mean fiber diameter (41.32 + or - 0.55 microns), compared to synchronous (46.32 + or - 0.55 microns) and vivarium (49 + or - 0.5 microns) controls. A further experiment studied the ratio of fast to slow twitch fibers in 25 rats exposed to 18.5 days of hypogravity and analyzed at four different periods of recovery following the space flight. Using the previous techniques, the gastrocnemius muscle showed a reduction of the total muscle fiber area in square microns and a reduction in the percentage of slow fibers of flight animals compared to the control animals.

Isoflavin-β modifies muscle oxidative stress and prevents a thyrotoxicosis-induced loss of muscle mass in rats.

PubMed

Marinello, Poliana C; Bernardes, Sara S; Guarnier, Flávia A; Da Silva, Thamara N X; Borges, Fernando H; Lopes, Natália M D; Simão, Andréa N C; Armani, André; Cecchini, Rubens; Cecchini, Alessandra L

2017-11-01

We sought to verify whether isoflavin-beta (Iso-β), a mixture of isoflavones with antioxidant properties, could prevent thyrotoxicosis-induced loss of muscle mass and the participation of oxidative stress (OS) in the mechanisms of this prevention. Two experimental periods of thyrotoxicosis induction were used in Wistar rats: 3 and 5 days to assess Iso-β effects before and after thyrotoxicosis-induced muscle wasting. After euthanasia, peritoneal fat and gastrocnemius muscle were collected, weighed, and muscle OS was assessed. Iso-β prevented the loss of gastrocnemius mass in thyrotoxic rats through the prevention of muscle OS generation during thyrotoxicosis, increasing muscle total antioxidant capacity and decreasing mitochondrial cytochrome c oxidase activity, lipid peroxidation, and protein carbonyl content. Iso-β decreased oxidative modification of proteins, which is known to exert a major role during proteolysis induction and is present in thyrotoxic myopathy, highlighting the potential action of Iso-β in this complication of the disease. Muscle Nerve 56: 975-981, 2017. © 2016 Wiley Periodicals, Inc.

Kir2.1 regulates rat smooth muscle cell proliferation, migration, and post-injury carotid neointimal formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qiao, Yong; Tang, Chengchun, E-mail: tangchengchun@medmail.com.cn; Wang, Qingjie

Phenotype switching of vascular smooth muscle cells (VSMC) from the contractile type to the synthetic type is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty. Inward rectifier K{sup +} channel 2.1 (Kir2.1) has been identified in VSMC. However, whether it plays a functional role in regulating cellular transformation remains obscure. In this study, we evaluated the role of Kir2.1 on VSMC proliferation, migration, phenotype switching, and post-injury carotid neointimal formation. Kir2.1 knockdown significantly suppressed platelet-derived growth factor BB-stimulated rat vascular smooth muscle cells (rat-VSMC) proliferation and migration. Deficiency in Kir2.1 contributed to the restoration of smoothmore » muscle α-actin, smooth muscle 22α, and calponin and to a reduction in osteopontin expression in rat-VSMC. Moreover, the in vivo study showed that rat-VSMC switched to proliferative phenotypes and that knockdown of Kir2.1 significantly inhibited neointimal formation after rat carotid injury. Kir2.1 may be a potential therapeutic target in the treatment of cardiovascular diseases, such as atherosclerosis and restenosis following percutaneous coronary intervention.« less

Low molecular weight guluronate prevents TNF-α-induced oxidative damage and mitochondrial dysfunction in C2C12 skeletal muscle cells.

PubMed

Dun, Yun-lou; Zhou, Xiao-lin; Guan, Hua-shi; Yu, Guang-li; Li, Chun-xia; Hu, Ting; Zhao, Xia; Cheng, Xiao-lei; He, Xiao-xi; Hao, Jie-jie

2015-09-01

Muscle wasting is associated with a variety of chronic or inflammatory disorders. Evidence suggests that inflammatory cytokines play a vital role in muscle inflammatory pathology and this may result in oxidative damage and mitochondrial dysfunction in skeletal muscle. In our study, we used microwave degradation to prepare a water-soluble low molecular weight guluronate (LMG) of 3000 Da from Fucus vesiculosus obtained from Canada, the Atlantic Ocean. We demonstrated the structural characteristics, using HPLC, FTIR and NMR of LMG and investigated its effects on oxidative damage and mitochondrial dysfunction in C2C12 skeletal muscle cells induced by tumor necrosis factor alpha (TNF-α), a cell inflammatory cytokine. The results indicated that LMG could alleviate mitochondrial reactive oxygen species (ROS) production, increase the activities of antioxidant enzymes (GSH and SOD), promote mitochondrial membrane potential (MMP) and upregulate the expression of mitochondrial respiratory chain protein in TNF-α-induced C2C12 cells. LMG supplement also increased the mitochondrial DNA copy number and mitochondrial biogenesis related genes in TNF-α-induced C2C12 cells. LMG may exert these protective effects through the nuclear factor kappa B (NF-κB) signaling pathway. These suggest that LMG is capable of protecting TNF-α-induced C2C12 cells against oxidative damage and mitochondrial dysfunction.

Sustained glucagon-like peptide 1 expression from encapsulated transduced cells to treat obese diabetic rats.

PubMed

Moralejo, Daniel; Yanay, Ofer; Kernan, Kelly; Bailey, Adam; Lernmark, Ake; Osborne, William

2011-04-01

Obesity and type 2 diabetes (T2D) are two prevalent chronic diseases that have become a major public health concern in industrialized countries. T2D is characterized by hyperglycemia and islet beta cell dysfunction. Glucagon-like peptide 1 (GLP-1) promotes β cell proliferation and neogenesis and has a potent insulinotropic effect. Leptin receptor deficient male rats are obese and diabetic and provide a model of T2D. We hypothesized that their treatment by sustained expression of GLP-1 using encapsulated cells may prevent or delay diabetes onset. Vascular smooth muscle cells (VSMC) retrovirally transduced to secrete GLP-1 were seeded into TheraCyte(TM) encapsulation devices, implanted subcutaneously and rats were monitored for diabetes. Rats that received cell implants showed mean plasma GLP-1 level of 119.3 ± 10.2pM that was significantly elevated over control values of 32.4 ± 2.9pM (P<0.001). GLP-1 treated rats had mean insulin levels of 45.9 ± 2.3ng/ml that were significantly increased over control levels of 7.3±1.5ng/ml (P<0.001). In rats treated before diabetes onset elevations in blood glucose were delayed and rats treated after onset became normoglycemic and showed improved glucose tolerance tests. Untreated diabetic rats possess abnormal islet structures characterized by enlarged islets with α-cell infiltration and multifocal vacuolization. GLP-1 treatment induced normalization of islet structures including a mantle of α-cells and increased islet mass. These data suggest that encapsulated transduced cells may offer a potential long term treatment of patients. Copyright © 2010 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Sustained glucagon-like peptide 1 expression from encapsulated transduced cells to treat obese diabetic rats

PubMed Central

Moralejo, Daniel; Yanay, Ofer; Kernan, Kelly; Bailey, Adam; Lernmark, Ake; Osborne, William

2011-01-01

Obesity and type 2 diabetes (T2D) are two prevalent chronic diseases that have become a major public health concern in industrialized countries. T2D is characterized by hyperglycemia and islet beta cell dysfunction. Glucagon-like peptide 1 (GLP-1) promotes β cell proliferation and neogenesis and has a potent insulinotropic effect. Leptin receptor deficient male rats are obese and diabetic and provide a model of T2D. We hypothesized that their treatment by sustained expression of GLP-1 using encapsulated cells may prevent or delay diabetes onset. Vascular smooth muscle cells (VSMC) retrovirally transduced to secrete GLP-1 were seeded into TheraCyteTM encapsulation devices, implanted subcutaneously and rats monitored for diabetes. Rats that received cell implants showed mean plasma GLP-1 level of 119.3±10.2 pM that was significantly elevated over control values of 32.4±2.9 pM (P<0.001). GLP-1 treated rats had mean insulin levels of 45.9±2.3 ng/ml that were significantly increased over control levels of 7.3±1.5 ng/ml (P<0.001). In rats treated before diabetes onset elevations in blood glucose were delayed and rats treated after onset became normoglycemic and showed improved glucose tolerance tests. Untreated diabetic rats possess abnormal islet structures characterized by enlarged islets with β-cell infiltration and multifocal vacuolization. GLP-1 treatment induced normalization of islet structures including a mantle of β-cells and increased islet mass. These data suggest encapsulated transduced cells may offer a potential long term treatment of patients. PMID:21216666

Neuromuscular electric stimulation in patellofemoral dysfunction: literature review

PubMed Central

dos Santos, Ricardo Lucas; Souza, Márcia Leal São Pedro; dos Santos, Fernanda Andrade

2013-01-01

Patellofemoral dysfunction is a fairly common deficiency among young individuals that primarily affects females and may be characterized by pain, swelling and retropatellar crepitation. The purpose of this review of literature from the period between 2005 and 2011 was to systematize knowledge in relation to the increase in quadriceps muscle strength and pain relief in patients with patellofemoral dysfunction, using neuromuscular electrical stimulation and resistance exercises. The inclusion criteria were intervention articles from the past six years, in English, Spanish and Portuguese, which used muscle strengthening and neuromuscular electrical stimulation for rehabilitation obtained through searches in the electronic databases Medline and Lilacs and in the Bireme library. The bibliographic search yielded 28 references, of which nine were excluded in accordance with the aims and inclusion criteria while 16 articles were selected for reading of the abstracts and subsequent analysis. Mediumfrequency Neuromuscular Electrical Stimulation (NMES) can be used in association with resistance exercises as an adjuvant in the treatment of patellofemoral dysfunction (PFD), both to achieve muscle rebalance and for pain relief. PMID:24453645

Botulinum toxin injection causes hyper-reflexia and increased muscle stiffness of the triceps surae muscle in the rat

PubMed Central

Pingel, Jessica; Wienecke, Jacob; Lorentzen, Jakob

2016-01-01

Botulinum toxin is used with the intention of diminishing spasticity and reducing the risk of development of contractures. Here, we investigated changes in muscle stiffness caused by reflex activity or elastic muscle properties following botulinum toxin injection in the triceps surae muscle in rats. Forty-four rats received injection of botulinum toxin in the left triceps surae muscle. Control measurements were performed on the noninjected contralateral side in all rats. Acute experiments were performed, 1, 2, 4, and 8 wk following injection. The triceps surae muscle was dissected free, and the Achilles tendon was cut and attached to a muscle puller. The resistance of the muscle to stretches of different amplitudes and velocities was systematically investigated. Reflex-mediated torque was normalized to the maximal muscle force evoked by supramaximal stimulation of the tibial nerve. Botulinum toxin injection caused severe atrophy of the triceps surae muscle at all time points. The force generated by stretch reflex activity was also strongly diminished but not to the same extent as the maximal muscle force at 2 and 4 wk, signifying a relative reflex hyperexcitability. Passive muscle stiffness was unaltered at 1 wk but increased at 2, 4, and 8 wk (P < 0.01). These data demonstrate that botulinum toxin causes a relative increase in reflex stiffness, which is likely caused by compensatory neuroplastic changes. The stiffness of elastic elements in the muscles also increased. The data are not consistent with the ideas that botulinum toxin is an efficient antispastic medication or that it may prevent development of contractures. PMID:27628204

Potential clinical translation of juvenile rodent inactivity models to study the onset of childhood obesity

PubMed Central

Roberts, Michael D.; Company, Joseph M.; Brown, Jacob D.; Toedebusch, Ryan G.; Padilla, Jaume; Jenkins, Nathan T.; Laughlin, M. Harold

2012-01-01

According to the latest data from the Center for Disease Control and Prevention 17%, or 12.5 million, of children and adolescents aged 2–19 years in the United States are obese. Physical inactivity is designated as one of the actual causes of US deaths and undoubtedly contributes to the obesity epidemic in children and adults. Examining the effects of inactivity on physiological homeostasis during youth is crucial given that 58% of children between the ages 6–11 yr old fail to obtain the recommended 60 min/day of physical activity and 92% of adolescents fail to achieve this goal [Troiano et al. Med Sci Sports Exerc. 40, 2008]. Nonetheless, invasive mechanistic studies in children linking diminished physical activity with metabolic maladies are lacking for obvious ethical reasons. The rodent wheel lock (WL) model was adopted by our laboratory and others to study how different organ systems of juvenile rats respond to a cessation of daily physical activity. Our WL model houses rats in cages equipped with voluntary running wheels starting at 28 days of age. After a certain period of voluntary running (3 to 6 wk), the wheels are locked, thus preventing the rats' primary source of physical activity. The studies discussed herein suggest that obesity-associated maladies including skeletal muscle insulin resistance, hypothalamic leptin resistance, fatty acid oxidation impairments in skeletal muscle and adipose tissue, nonalcoholic fatty liver disease, and endothelial dysfunction are initiated in juvenile animals that are restrained from voluntary exercise via WL. The use of the juvenile rodent WL or other inactivity models will continue to provide a powerful clinical translational tool that can be used for primordial prevention of human childhood obesity. PMID:22696577

Myocardial short-range force responses increase with age in F344 rats

PubMed Central

Mitov, Mihail I.; Holbrook, Anastasia M.; Campbell, Kenneth S.

2009-01-01

The mechanical properties of triton-permeabilized ventricular preparations isolated from 4, 18 and 24-month-old F344 rats were analyzed to provide information about the molecular mechanisms that lead to age-related increases in diastolic myocardial stiffness in these animals. Passive stiffness (measured in solutions with minimal free Ca2+) did not change with age. This implies that the aging-associated dysfunction is not due to changes in titin or collagen molecules. Ca2+-activated preparations exhibited a characteristic short-range force response: force rose rapidly until the muscle reached its elastic limit and less rapidly thereafter. The elastic limit increased from 0.43 ± 0.01 % l0 (where l0 is the initial muscle length) in preparations from 4-month-old animals to 0.49 ± 0.01 % l0 in preparations from 24-month-old rats (p<0.001, ANOVA). Relative short-range force was defined as the maximum force produced during the short-range response normalized to the prevailing tension. This parameter increased from 0.110 ± 0.002 to 0.142 ± 0.002 over the same age-span (p<0.001, ANOVA). Analytical gel electrophoresis showed that the maximum stiffness of the preparations during the short-range response and the relative short-range force increased (p=0.031 and p=0.005 respectively) with the relative content of slow β myosin heavy chain molecules. Elastic limit values did not correlate with myosin isoform content. Simulations based on these results suggest that attached β myosin heavy chain cross-bridges are stiffer than links formed by α myosin heads. In conclusion, elevated content of stiffer β myosin heavy chain molecules may contribute to aging-associated increases in myocardial stiffness. PMID:19007786

Transcription of G-protein coupled receptors in corporal smooth muscle is regulated by sialorphin (an endogenous neutral endopeptidase inhibitor)

PubMed Central

Tong, Yuehong; Tiplitsky, Scott I.; Tar, Moses; Melman, Arnold; Davies, Kelvin P.

2009-01-01

Purpose Several reports have suggested the rat Vcsa1 gene is down-regulated in models of erectile dysfunction (ED). Vcsa’s protein product, sialorphin, is an endogenous neutral endopeptidase (NEP), and its down-regulation could result in prolonged activation of G-protein activated signaling pathways by their peptide agonists. We investigated if down- regulation of Vcsa1 could result in adaptive change in the expression of G-protein coupled receptors (GPCR). Materials and Methods Gene expression in cultured rat corporal smooth muscle cells (CSM) following treatment with siRNA directed against Vcsa1 or the NEP gene was analyzed using microarray and quantitative RT-PCR. In rats Vcsa1 is one of the most down-regulated genes following bilateral transection of the cavernosal nerves. Using that animal model, we also investigated whether the down-regulation of Vcsa1 is accompanied by similar changes in gene expression observed in the CSM cells where Vcsa1 was knocked-down in vitro. Results Microarray analysis and quantitative RT-PCR demonstrated that CSM cells treated in vitro with siRNA against Vcsa1 resulted in up-regulation of GPCR as a functional group. In contrast, treatment of CSM cells that lowered NEP activity resulted in decreases in GPCR expression. These results suggest that the peptide product of Vcsa1, sialorphin, can effect GPCR expression by acting on NEP. In animals with bilaterally transected cavernous nerves the reduced expression of Vcsa1 is accompanied by increased GPCR expression in cavernosal tissue. Conclusions These experiments suggest that the mechanism by which Vcsa1 modulates erectile function is partly mediated through changes in GPCR expression. PMID:18554633

Potential clinical translation of juvenile rodent inactivity models to study the onset of childhood obesity.

PubMed

Roberts, Michael D; Company, Joseph M; Brown, Jacob D; Toedebusch, Ryan G; Padilla, Jaume; Jenkins, Nathan T; Laughlin, M Harold; Booth, Frank W

2012-08-01

According to the latest data from the Center for Disease Control and Prevention 17%, or 12.5 million, of children and adolescents aged 2-19 years in the United States are obese. Physical inactivity is designated as one of the actual causes of US deaths and undoubtedly contributes to the obesity epidemic in children and adults. Examining the effects of inactivity on physiological homeostasis during youth is crucial given that 58% of children between the ages 6-11 yr old fail to obtain the recommended 60 min/day of physical activity and 92% of adolescents fail to achieve this goal [Troiano et al. Med Sci Sports Exerc. 40, 2008]. Nonetheless, invasive mechanistic studies in children linking diminished physical activity with metabolic maladies are lacking for obvious ethical reasons. The rodent wheel lock (WL) model was adopted by our laboratory and others to study how different organ systems of juvenile rats respond to a cessation of daily physical activity. Our WL model houses rats in cages equipped with voluntary running wheels starting at 28 days of age. After a certain period of voluntary running (3 to 6 wk), the wheels are locked, thus preventing the rats' primary source of physical activity. The studies discussed herein suggest that obesity-associated maladies including skeletal muscle insulin resistance, hypothalamic leptin resistance, fatty acid oxidation impairments in skeletal muscle and adipose tissue, nonalcoholic fatty liver disease, and endothelial dysfunction are initiated in juvenile animals that are restrained from voluntary exercise via WL. The use of the juvenile rodent WL or other inactivity models will continue to provide a powerful clinical translational tool that can be used for primordial prevention of human childhood obesity.

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

PubMed Central

Golomb, Beatrice A.; Evans, Marcella A.

2009-01-01

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 (CYP)3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many non-muscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity. PMID:19159124

Different responses in soleus muscle fibers of Wistar and Wistar Hannover rats to hindlimb unloading

NASA Astrophysics Data System (ADS)

Wang, Xiaodong; Kawano, Fuminori; Terada, Masahiro; Matsuoka, Yoshikazu; Shinoda, Yo; Ishihara, Akihiko; Ohira, Yoshinobu

2005-08-01

Effects of 16 days of hindlimb suspension on the characteristics of single soleus muscle fibers were compared between male Wistar and Wistar Hannover rats (5 weeks old). The greater effects of unloading were noted in Wistar Hannover rats. The unloading-related reductions of muscle weight and fiber cross-sectional area vs. the pre-suspension levels were greater than Wistar rats. The percent of fibers expressing pure type I myosin heavy chain (MHC) was decreased and that of type I+II MHC fibers was increased, the magnitudes of these changes were greater than Wistar rats. Total number of myonuclei in control situation was greater in Wistar Hannover rats, but the more numbers of myonuclei were decreased following unloading. Responses of myonuclear domain levels were similar. The numbers of both quiescent and mitotic active satellite cells in control situation were greater in Wistar rats. But the magnitude of the unloading- related decrease was identical for Wistar Hannover and Wistar rats. Although the level of heat shock protein 27 (HSP27) expression in Wistar rats was decreased by unloading, de novo appearance of HSP27 was noted in Wistar Hannover rats. It is suggested that greater responses of soleus muscle fibers of Wistar Hannover than Wistar rats may be related to the different expression of protein, although the precise mechanism is still unclear.

Soluble Milk Protein Supplementation with Moderate Physical Activity Improves Locomotion Function in Aging Rats.

PubMed

Lafoux, Aude; Baudry, Charlotte; Bonhomme, Cécile; Le Ruyet, Pascale; Huchet, Corinne

2016-01-01

Aging is associated with a loss of muscle mass and functional capacity. Present study was designed to compare the impact of specific dairy proteins on muscular function with or without a low-intensity physical activity program on a treadmill in an aged rat model. We investigated the effects of nutritional supplementation, five days a week over a 2-month period with a slow digestible protein, casein or fast digestible proteins, whey or soluble milk protein, on strength and locomotor parameters in sedentary or active aged Wistar RjHan rats (17-19 months of age). An extensive gait analysis was performed before and after protein supplementation. After two months of protein administration and activity program, muscle force was evaluated using a grip test, spontaneous activity using an open-field and muscular mass by specific muscle sampling. When aged rats were supplemented with proteins without exercise, only minor effects of different diets on muscle mass and locomotion were observed: higher muscle mass in the casein group and improvement of stride frequencies with soluble milk protein. By contrast, supplementation with soluble milk protein just after physical activity was more effective at improving overall skeletal muscle function in old rats compared to casein. For active old rats supplemented with soluble milk protein, an increase in locomotor activity in the open field and an enhancement of static and dynamic gait parameters compared to active groups supplemented with casein or whey were observed without any differences in muscle mass and forelimb strength. These results suggest that consumption of soluble milk protein as a bolus immediately after a low intensity physical activity may be a suitable nutritional intervention to prevent decline in locomotion in aged rats and strengthen the interest to analyze the longitudinal aspect of locomotion in aged rodents.

Exercise training and return to a well-balanced diet activate the neuregulin 1/ErbB pathway in skeletal muscle of obese rats

PubMed Central

Ennequin, Gaël; Boisseau, Nathalie; Caillaud, Kevin; Chavanelle, Vivien; Gerbaix, Maude; Metz, Lore; Etienne, Monique; Walrand, Stéphane; Masgrau, Aurélie; Guillet, Christelle; Courteix, Daniel; Niu, Airu; Li, Yi-Ping; Capel, Fréderic; Sirvent, Pascal

2015-01-01

Some studies suggest that the signalling pathway of neuregulin 1 (NRG1), a protein involved in the regulation of skeletal muscle metabolism, could be altered by nutritional and exercise interventions. We hypothesized that diet-induced obesity could lead to alterations of the NRG1 signalling pathway and that chronic exercise could improve NRG1 signalling in rat skeletal muscle. To test this hypothesis, male Wistar rats received a high fat/high sucrose (HF/HS) diet for 16 weeks. At the end of this period, NRG1 and ErbB expression/activity in skeletal muscle was assessed. The obese rats then continued the HF/HS diet or were switched to a well-balanced diet. Moreover, in both groups, half of the animals also performed low intensity treadmill exercise training. After another 8 weeks, NRG1 and ErbB expression/activity in skeletal muscle were tested again. The 16 week HF/HS diet induced obesity, but did not significantly affect the NRG1/ErbB signalling pathway in rat skeletal muscle. Conversely, after the switch to a well-balanced diet, NRG1 cleavage ratio and ErbB4 amount were increased. Chronic exercise training also promoted NRG1 cleavage, resulting in increased ErbB4 phosphorylation. This result was associated with increased protein expression and phosphorylation ratio of the metalloprotease ADAM17, which is involved in NRG1 shedding. Similarly, in vitro stretch-induced activation of ADAM17 in rat myoblasts induced NRG1 cleavage and ErbB4 activation. These results show that low intensity endurance training and well-balanced diet activate the NRG1-ErbB4 pathway, possibly via the metalloprotease ADAM17, in skeletal muscle of diet-induced obese rats. PMID:25820551

Soluble Milk Protein Supplementation with Moderate Physical Activity Improves Locomotion Function in Aging Rats

PubMed Central

Lafoux, Aude; Baudry, Charlotte; Bonhomme, Cécile; Le Ruyet, Pascale; Huchet, Corinne

2016-01-01

Aging is associated with a loss of muscle mass and functional capacity. Present study was designed to compare the impact of specific dairy proteins on muscular function with or without a low-intensity physical activity program on a treadmill in an aged rat model. We investigated the effects of nutritional supplementation, five days a week over a 2-month period with a slow digestible protein, casein or fast digestible proteins, whey or soluble milk protein, on strength and locomotor parameters in sedentary or active aged Wistar RjHan rats (17–19 months of age). An extensive gait analysis was performed before and after protein supplementation. After two months of protein administration and activity program, muscle force was evaluated using a grip test, spontaneous activity using an open-field and muscular mass by specific muscle sampling. When aged rats were supplemented with proteins without exercise, only minor effects of different diets on muscle mass and locomotion were observed: higher muscle mass in the casein group and improvement of stride frequencies with soluble milk protein. By contrast, supplementation with soluble milk protein just after physical activity was more effective at improving overall skeletal muscle function in old rats compared to casein. For active old rats supplemented with soluble milk protein, an increase in locomotor activity in the open field and an enhancement of static and dynamic gait parameters compared to active groups supplemented with casein or whey were observed without any differences in muscle mass and forelimb strength. These results suggest that consumption of soluble milk protein as a bolus immediately after a low intensity physical activity may be a suitable nutritional intervention to prevent decline in locomotion in aged rats and strengthen the interest to analyze the longitudinal aspect of locomotion in aged rodents. PMID:27973615

[Morphohistochemical study of skeletal muscles in rats after experimental flight on "Kosmos-1887"].

PubMed

Il'ina-Kakueva, E I

1990-01-01

Morphometric and histochemical methods were used to examine the soleus, gastrocnemius (medial portion), quadriceps femoris (central portion) and biceps brachii muscles of Wistar SPF rats two days after the 13-day flight on Cosmos-1887. It was found that significant atrophy developed only in the soleus muscle. The space flight did not change the percentage content of slow (type I) and fast (type II) fibers in fast twitch muscles. During two days at 1 g the slow soleus muscle developed substantial circulation disorders, which led to interstitial edema and necrotic changes. The gastrocnemius muscle showed small foci containing necrotic myofibers. Two days after recovery no glycogen aggregates were seen in myofibers, which were previously observed in other rats examined 4--8 hours after flight. An initial stage of muscle readaptation to 1 g occurred, when NAD.H2-dehydrogenase activity was decreased.

Skeletal Muscle Satellite Cell Activation Following Cutaneous Burn in Rats

DTIC Science & Technology

2013-12-01

satellite cell activation and survival during oxidative stress. J Muscle Res Cell Motil 2011;32(2):99–109. [33] Rathbone CR, Booth FW, Lees SJ. Sirt1 ...Skeletal muscle satellite cell activation following cutaneous burn in rats Xiaowu Wu*, Thomas J. Walters, Christopher R. Rathbone Extremity Trauma...f o Article history: Accepted 15 October 2012 Keywords: Muscle precursor cell Thermal injury Atrophy Skeletal muscle Activation a b s t r a c t

Muscle glucose uptake in the rat after suspension with single hindlimb weight bearing

NASA Technical Reports Server (NTRS)

Stump, Craig S.; Woodman, Christopher R.; Fregosi, Ralph F.; Tipton, Charles M.

1993-01-01

An examination is conducted of the effect of nonweight-bearing conditions, and the systemic influences of simulated microgravity on rat hindlimb muscles. The results obtained suggest that the increases in hindlimb muscle glucose uptake and extracellular space associated with simulated microgravity persist with hindlimb weightbearing, despite the prevention of muscle atrophy. The mechanism (or mechanisms) responsible for these effects are currently unknown.

Exercise training improves the defective centrally mediated erectile responses in rats with type I diabetes.

PubMed

Zheng, Hong; Mayhan, William G; Patel, Kaushik P

2011-11-01

Erectile dysfunction is a serious and common complication of diabetes mellitus. Apart from the peripheral actions, central mechanisms are also responsible for the penile erection. The goal of the present study was to determine the impact of exercise training (ExT) on the centrally mediated erectile dysfunction in streptozotocin (STZ)-induced type I diabetic (T1D) rats. Male Sprague-Dawley rats were injected with STZ to induce diabetes mellitus. Three weeks after STZ or vehicle injections, rats were assigned to either ExT (treadmill running for 3-4 weeks) or sedentary groups to produce four experimental groups: control + sedentary, T1D + sedentary, control + ExT, and T1D + ExT. After 3-4 weeks ExT, central N-methyl-D-aspartic acid (NMDA) or sodium nitroprusside (SNP)-induced penile erectile responses were measured. Neuronal nitric oxide synthase (nNOS) expression in the paraventricular nucleus (PVN) of the hypothalamus was measured by using histochemistry, real time polymerase chain reaction (PCR) and Western blot approaches. In rats with T1D, ExT significantly improved the blunted erectile response, and the intracavernous pressure changes to NMDA (50 ng) microinjection within the PVN (T1D + ExT: 3.0 ± 0.6 penile erection/rat; T1D + sedentary: 0.5 ± 0.3 penile erection/rat within 20 minutes, P < 0.05). ExT improved erectile dysfunction induced by central administration of exogenous nitric oxide (NO) donor, SNP in T1D rats. Other behavior responses including yawning and stretching, induced by central NMDA and SNP microinjection were also significantly increased in T1D rats after ExT. Furthermore, we found that ExT restored the nNOS mRNA and protein expression in the PVN in T1D rats. These results suggest that ExT may have beneficial effects on the erectile dysfunction in diabetes through improvement of NO bioavailability within the PVN. Thus, ExT may be used as therapeutic modality to up-regulate nNOS within the PVN and improve the central component of the erectile dysfunction in diabetes mellitus. © 2011 International Society for Sexual Medicine.

Low-Load Resistance Training with Blood Flow Occlusion as a Countermeasure to Disuse Atrophy

NASA Technical Reports Server (NTRS)

Ploutz-Snyder, L. L.; Cook, S. B.

2009-01-01

Decreases in strength and neuromuscular function are observed following prolonged disuse. Exercise countermeasures to prevent muscle dysfunction during disuse typically involve high intensity resistance training. The purpose of the study is to evaluate the effectiveness of low-load resistance training with a blood flow occlusion to mitigate muscle loss and dysfunction during 30 days of unilateral lower limb suspension (ULLS).

Respiratory failure associated with hypoventilation in a patient with severe hypothyroidism

PubMed Central

Fukusumi, Munehisa; Iidaka, Toshiko; Mouri, Atsuto; Hamamoto, Yoichiro; Kamimura, Mitsuhiro

2014-01-01

A 70-year-old Japanese man was admitted to hospital because of decreased consciousness due to type II respiratory failure. Severe hypothyroidism was diagnosed and considered to be associated with hypoventilation due to respiratory muscle dysfunction and sleep apnea syndrome. His status was improved partially by replacement of thyroid hormone. Despite maintaining a euthyroid state, improvement of respiratory muscle dysfunction was incomplete. PMID:25473574

Estrogen modulation of the ethanol-evoked myocardial oxidative stress and dysfunction via DAPK3/Akt/ERK activation in male rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Mas, Mahmoud M., E-mail: mahelm@hotmail.com; Abdel-Rahman, Abdel A., E-mail: abdelrahmana@ecu.edu

Evidence suggests that male rats are protected against the hypotensive and myocardial depressant effects of ethanol compared with females. We investigated whether E{sub 2} modifies the myocardial and oxidative effects of ethanol in male rats. Conscious male rats received ethanol (0.5, 1 or 1.5 g/kg i.v.) 30-min after E{sub 2} (1 μg/kg i.v.) or its vehicle (saline), and hearts were collected at the conclusion of hemodynamic measurements for ex vivo molecular studies. Ethanol had no effect in vehicle-treated rats, but it caused dose-related reductions in LV developed pressure (LVDP), end-diastolic pressure (LVEDP), rate of rise in LV pressure (dP/dt{sub max})more » and systolic (SBP) and diastolic (DBP) blood pressures in E{sub 2}-pretreated rats. These effects were associated with elevated (i) indices of reactive oxygen species (ROS), (ii) malondialdehyde (MDA) protein adducts, and (iii) phosphorylated death-associated protein kinase-3 (DAPK3), Akt, and extracellular signal-regulated kinases (ERK1/2). Enhanced myocardial anti-oxidant enzymes (heme oxygenase-1, catalase and aldehyde dehydrogenase 2) activities were also demonstrated. In conclusion, E{sub 2} promotes ethanol-evoked myocardial oxidative stress and dysfunction in male rats. The present findings highlight the risk of developing myocardial dysfunction in men who consume alcohol while receiving E{sub 2} for specific medical conditions. - Highlights: • Ethanol lowers blood pressure and causes LV dysfunction in E{sub 2}-treated rats. • E{sub 2}/ethanol aggravates cardiac oxidative state via of DAPK3/Akt/ERK activation. • E{sub 2}/ethanol causes a feedback increase in cardiac HO-1, catalase and ALDH2. • Alcohol might increase risk of myocardial dysfunction in men treated with E{sub 2}.« less

T lymphocytes are not required for the development of fatty degeneration after rotator cuff tear

PubMed Central

Gumucio, J.; Flood, M.; Harning, J.; Phan, A.; Roche, S.; Lynch, E.; Bedi, A.; Mendias, C.

2014-01-01

Objectives Rotator cuff tears are among the most common and debilitating upper extremity injuries. Chronic cuff tears result in atrophy and an infiltration of fat into the muscle, a condition commonly referred to as ‘fatty degeneration’. While stem cell therapies hold promise for the treatment of cuff tears, a suitable immunodeficient animal model that could be used to study human or other xenograft-based therapies for the treatment of rotator cuff injuries had not previously been identified. Methods A full-thickness, massive supraspinatus and infraspinatus tear was induced in adult T-cell deficient rats. We hypothesised that, compared with controls, 28 days after inducing a tear we would observe a decrease in muscle force production, an accumulation of type IIB fibres, and an upregulation in the expression of genes involved with muscle atrophy, fibrosis and inflammation. Results Chronic cuff tears in nude rats resulted in a 30% to 40% decrease in muscle mass, a 23% reduction in production of muscle force, and an induction of genes that regulate atrophy, fibrosis, lipid accumulation, inflammation and macrophage recruitment. Marked large lipid droplet accumulation was also present. Conclusions The extent of degenerative changes in nude rats was similar to what was observed in T-cell competent rats. T cells may not play an important role in regulating muscle degeneration following chronic muscle unloading. The general similarities between nude and T-cell competent rats suggest the nude rat is likely an appropriate preclinical model for the study of xenografts that have the potential to enhance the treatment of chronically torn rotator cuff muscles. Cite this article: Bone Joint Res 2014;3:262–72. PMID:25185444

Transient gestational and neonatal hypothyroidism-induced specific changes in androgen receptor expression in skeletal and cardiac muscles of adult rat.

PubMed

Annapoorna, K; Anbalagan, J; Neelamohan, R; Vengatesh, G; Stanley, J; Amudha, G; Aruldhas, M M

2013-03-01

The present study aims to identify the association between androgen status and metabolic activity in skeletal and cardiac muscles of adult rats with transient gestational/neonatal-onset hypothyroidism. Pregnant and lactating rats were made hypothyroid by exposing to 0.05% methimazole in drinking water; gestational exposure was from embryonic day 9-14 (group II) or 21 (group III), lactational exposure was from postnatal day 1-14 (group IV) or 29 (group V). Serum was collected for hormone assay. Androgen receptor status, Glu-4 expression, and enzyme activities were assessed in the skeletal and cardiac muscles. Serum testosterone and estradiol levels decreased in adult rats of groups II and III, whereas testosterone remained normal but estradiol increased in group IV and V, when compared to coeval control. Androgen receptor ligand binding activity increased in both muscle phenotypes with a consistent increase in the expression level of its mRNA and protein expressions except in the forelimb of adult rats with transient hypothyroidism (group II-V). Glut-4 expression remained normal in skeletal and cardiac muscle of experimental rats. Specific activity of hexokinase and lactate dehydrogenase increased in both muscle phenotypes whereas, creatine kinase activity increased in skeletal muscles alone. It is concluded that transient gestational/lactational exposure to methimazole results in hypothyroidism during prepuberal life whereas it increases AR status and glycolytic activity in skeletal and cardiac muscles even at adulthood. Thus, the present study suggests that euthyroid status during prenatal and early postnatal life is essential to have optimal AR status and metabolic activity at adulthood. © Georg Thieme Verlag KG Stuttgart · New York.

Unexplained lower abdominal pain associated with sacroiliac joint dysfunction: report of 2 cases.

PubMed

Morimoto, Daijiro; Isu, Toyohiko; Kim, Kyongsong; Matsumoto, Ryoji; Isobe, Masanori

2011-01-01

A 25-year-old woman and a 31-year-old man presented with chronic lower back pain and unexplained lower abdominal pain. Both patients had groin tenderness at the medial border of the anterior superior iliac spine. The results of radiographical and physical examinations suggested sacroiliac joint dysfunction. Sacroiliac joint injection relieved their symptoms, including groin tenderness. In our experience, groin tenderness is highly specific for sacroiliac joint dysfunction. We speculate that spasm of the iliac muscle can cause groin pain and tenderness. Groin pain and a history of unexplained abdominal pain, with lower back pain, are symptoms that suggest sacroiliac joint dysfunction. Additionally, compression of the iliac muscle is a simple and useful maneuver; therefore, it can be used as a screening test for sacroiliac joint dysfunction, alongside other provocation tests.

Ureter smooth muscle cell orientation in rat is predominantly longitudinal.

PubMed

Spronck, Bart; Merken, Jort J; Reesink, Koen D; Kroon, Wilco; Delhaas, Tammo

2014-01-01

In ureter peristalsis, the orientation of the contracting smooth muscle cells is essential, yet current descriptions of orientation and composition of the smooth muscle layer in human as well as in rat ureter are inconsistent. The present study aims to improve quantification of smooth muscle orientation in rat ureters as a basis for mechanistic understanding of peristalsis. A crucial step in our approach is to use two-photon laser scanning microscopy and image analysis providing objective, quantitative data on smooth muscle cell orientation in intact ureters, avoiding the usual sectioning artifacts. In 36 rat ureter segments, originating from a proximal, middle or distal site and from a left or right ureter, we found close to the adventitia a well-defined longitudinal smooth muscle orientation. Towards the lamina propria, the orientation gradually became slightly more disperse, yet the main orientation remained longitudinal. We conclude that smooth muscle cell orientation in rat ureter is predominantly longitudinal, though the orientation gradually becomes more disperse towards the proprial side. These findings do not support identification of separate layers. The observed longitudinal orientation suggests that smooth muscle contraction would rather cause local shortening of the ureter, than cause luminal constriction. However, the net-like connective tissue of the ureter wall may translate local longitudinal shortening into co-local luminal constriction, facilitating peristalsis. Our quantitative, minimally invasive approach is a crucial step towards more mechanistic insight into ureter peristalsis, and may also be used to study smooth muscle cell orientation in other tube-like structures like gut and blood vessels.

Impact of Western and Mediterranean Diets and Vitamin D on Muscle Fibers of Sedentary Rats

PubMed Central

Purrello, Francesco

2018-01-01

Background: The metabolic syndrome is associated with sarcopenia. Decreased serum levels of Vitamin D (VitD) and insulin-like growth factor (IGF)-1 and their mutual relationship were also reported. We aimed to evaluate whether different dietary profiles, containing or not VitD, may exert different effects on muscle molecular morphology. Methods: Twenty-eight male rats were fed for 10 weeks in order to detect early defects induced by different dietary regimens: regular diet (R); regular diet with vitamin D supplementation (R-DS) and regular diet with vitamin D restriction (R-DR); high-fat butter-based diets (HFB-DS and HFB-DR) with 41% energy from fat; high-fat extra-virgin olive oil-based diets (HFEVO-DS and HFEVO-DR) with 41% energy from fat. IL-1β, insulin-like growth factor (IGF)1, Dickkopf-1 (DKK-1), and VitD-receptor (VDR) expressions were evaluated by immunohistochemistry. Muscle fiber perimeter was measured by histology and morphometric analysis. Results: The muscle fibers of the HEVO-DS rats were hypertrophic, comparable to those of the R-DS rats. An inverse correlation existed between the dietary fat content and the perimeter of the muscle fibers (p < 0.01). In the HFB-DR rats, the muscle fibers appeared hypotrophic with an increase of IL-1β and a dramatic decrease of IGF-1 expression. Conclusions: High-fat western diet could impair muscle metabolism and lay the ground for subsequent muscle damage. VitD associated with a Mediterranean diet showed trophic action on the muscle fibers. PMID:29462978

Reduction-oxidation state and protein degradation in skeletal muscles of growing rats

NASA Technical Reports Server (NTRS)

Fagan, Julie M.; Tischler, Marc E.

1986-01-01

The relationship between the NAD redox state and protein degradation during growth was studied in isolated soleus and extensor digitorum longus muscles of 4- to 14-week-old rats. As muscle size increased with age, protein breakdown slowed and the muscles became progressively more reduced as shown by higher ratios of lactate/pyruvate in incubated and fresh-frozen muscle. Correlations were strong between redox state of protein degradation, and muscle mass, and between redox state and protein degradation. This relationship may be important in the slowing of muscle breakdown that occurs with age.

Bone Marrow Stromal Cells Generate Muscle Cells and Repair Muscle Degeneration

NASA Astrophysics Data System (ADS)

Dezawa, Mari; Ishikawa, Hiroto; Itokazu, Yutaka; Yoshihara, Tomoyuki; Hoshino, Mikio; Takeda, Shin-ichi; Ide, Chizuka; Nabeshima, Yo-ichi

2005-07-01

Bone marrow stromal cells (MSCs) have great potential as therapeutic agents. We report a method for inducing skeletal muscle lineage cells from human and rat general adherent MSCs with an efficiency of 89%. Induced cells differentiated into muscle fibers upon transplantation into degenerated muscles of rats and mdx-nude mice. The induced population contained Pax7-positive cells that contributed to subsequent regeneration of muscle upon repetitive damage without additional transplantation of cells. These MSCs represent a more ready supply of myogenic cells than do the rare myogenic stem cells normally found in muscle and bone marrow.

Transcriptional profiling of rat skeletal muscle hypertrophy under restriction of blood flow.

PubMed

Xu, Shouyu; Liu, Xueyun; Chen, Zhenhuang; Li, Gaoquan; Chen, Qin; Zhou, Guoqing; Ma, Ruijie; Yao, Xinmiao; Huang, Xiao

2016-12-15

Blood flow restriction (BFR) under low-intensity resistance training (LIRT) can produce similar effects upon muscles to that of high-intensity resistance training (HIRT) while overcoming many of the restrictions to HIRT that occurs in a clinical setting. However, the potential molecular mechanisms of BFR induced muscle hypertrophy remain largely unknown. Here, using a BFR rat model, we aim to better elucidate the mechanisms regulating muscle hypertrophy as induced by BFR and reveal possible clinical therapeutic targets for atrophy cases. We performed genome wide screening with microarray analysis to identify unique differentially expressed genes during rat muscle hypertrophy. We then successfully separated the differentially expressed genes from BRF treated soleus samples by comparing the Affymetrix rat Genome U34 2.0 array with the control. Using qRT-PCR and immunohistochemistry (IHC) we also analyzed other related differentially expressed genes. Results suggested that muscle hypertrophy induced by BFR is essentially regulated by the rate of protein turnover. Specifically, PI3K/AKT and MAPK pathways act as positive regulators in controlling protein synthesis where ubiquitin-proteasome acts as a negative regulator. This represents the first general genome wide level investigation of the gene expression profile in the rat soleus after BFR treatment. This may aid our understanding of the molecular mechanisms regulating and controlling muscle hypertrophy and provide support to the BFR strategies aiming to prevent muscle atrophy in a clinical setting. Copyright © 2016 Elsevier B.V. All rights reserved.

Muscle Carnosine Concentration with the Co-Ingestion of Carbohydrate with β-alanine in Male Rats.

PubMed

Naderi, Alireza; Sadeghi, Mehdi; Sarshin, Amir; Imanipour, Vahid; Nazeri, Seyed Ali; Farkhayi, Fatemeh; Willems, Mark E T

2017-07-04

Muscle carnosine is an intracellular buffer. The intake of β-alanine, combined with carbohydrate and protein, enhanced carnosine loading in human muscle. The aim of the present study was to examine if muscle carnosine loading was enhanced by β-alanine intake and co-ingestion of glucose in male rats. Thirty-six male rats were divided into three groups and supplemented for four weeks: β-alanine (βA group, 1.8% β-alanine in drinking water), β-alanine and glucose (βAGL group, 1.8% β-alanine and 5% glucose in drinking water), and control (C group, drinking water). During the supplementation period, rats were exercised (20 m·min -1 , 10 min·day -1 , 4 days·week -1 for 4 weeks). Muscle carnosine concentration was quantified in soleus (n = 12) and rectus femoris (n = 6) muscles using high-performance liquid chromatography. In soleus muscle, carnosine concentration was 2.24 ± 1.10, 6.12 ± 1.08, and 6.93 ± 2.56 mmol/kg dw for control, βA, and βAGL, respectively. In rectus femoris, carnosine concentration was 2.26 ± 1.31, 7.90 ± 1.66, and 8.59 ± 2.33 mmol/kg dw for control, βA, and βAGL respectively. In each muscle, βA and βAGL resulted in similar carnosine increases compared to the control. In conclusion, β-alanine intake for four weeks, either alone or with glucose co-ingestion, equally increased muscle carnosine content. It appears that the potential insulin response to fluid glucose intake does not affect muscle carnosine loading in male rats.

Effect of heat shock preconditioning on ROS scavenging activity in rat skeletal muscle after downhill running.

PubMed

Shima, Yosuke; Kitaoka, Katsuhiko; Yoshiki, Yumiko; Maruhashi, Yoshinobu; Tsuyama, Takeshi; Tomita, Katsuro

2008-10-01

The mechanisms of the protective effect conferred by heat shock preconditioning (HS) are currently unknown. The purpose of this study was to determine the effect of HS on muscle injury after downhill running and to address the mechanism of the effect. Female Wistar rats were assigned to three groups: HS, downhill running (E), and downhill running after heat shock preconditioning (HS + E). The HS and HS + E rats were placed in a heat chamber for 60 min (ambient temperature 42 +/- 1.0 degrees C) 48 h before downhill running. Reactive oxygen species (ROS) scavenging activity was determined by electron spin resonance (ESR), and heat shock protein 72 (HSP72) mRNA expression was measured in rat quadriceps femoris. Leukocyte infiltration and degenerated muscle fibers were determined histopathologically. ROS scavenging activity significantly increased at 3 days after HS (151 +/- 18%) and HSP72 mRNA expression increased immediately after HS (1750 +/- 1914%). No decrease in ROS scavenging activity was observed in the HS + E rats at 2 days after exercise compared with the E rats (102 +/- 9% vs. 79 +/- 5%). Degenerated muscle fibers in HS + E rats were significantly less than in E rats at 2, 3, and 7 days after exercise (0.8 +/- 1.0 vs. 2.8 +/- 1.6, 0.8 +/- 1.0 vs. 1.8 +/- 1.6, 0 vs. 0.3 +/- 0.6, respectively). These data demonstrated that HS can reduce muscle injury after downhill running, and this effect may be mediated by increased ROS scavenging activity. Furthermore, HS may protect the antioxidant defense system in skeletal muscle by enhancing the adaptive HSP72 mRNA response.

Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation

PubMed Central

Wu, Yao; Si, Feifei; Ji, Xiaojuan; Jiang, Kunfeng; Song, Sijie

2017-01-01

Background. This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods. Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results. The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions. The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281. PMID:28536695

Contractile properties of rat fast-twitch skeletal muscle during reinnervation - Effects of testosterone and castration

NASA Technical Reports Server (NTRS)

Yeagle, S. P.; Mayer, R. F.; Max, S. R.

1983-01-01

The peroneal nerve of subject rats were crushed 1 cm from the muscle in order to examine the isometric contractile properties of skeletal muscle in the recovery sequency during reinnervation of normal, castrated, and testosterone-treated rats. The particular muscle studied was the extensor digitorum longus, with functional reinnervation first observed 8-9 days after nerve crush. No evidence was found that either castration or testosterone injections altered the process of reinnervation after the nerve crush, with the conclusion being valid at the 0.05 p level. The most reliable index of reinnervation was found to be the twitch:tetanus ratio, a factor of use in future studies of the reinnervation of skeletal muscle.

Effects of chronic Akt/mTOR inhibition by rapamycin on mechanical overload-induced hypertrophy and myosin heavy chain transition in masseter muscle.

PubMed

Umeki, Daisuke; Ohnuki, Yoshiki; Mototani, Yasumasa; Shiozawa, Kouichi; Fujita, Takayuki; Nakamura, Yoshiki; Saeki, Yasutake; Okumura, Satoshi

2013-01-01

To examine the effects of the Akt/mammalian target of rapamycin (mTOR) pathway on masseter muscle hypertrophy and myosin heavy chain (MHC) transition in response to mechanical overload, we analyzed the effects of bite-opening (BO) on the hypertrophy and MHC composition of masseter muscle of BO-rats treated or not treated with rapamycin (RAPA), a selective mTOR inhibitor. The masseter muscle weight in BO-rats was significantly greater than that in controls, and this increase was attenuated by RAPA treatment. Expression of slow-twitch MHC isoforms was significantly increased in BO-rats with/without RAPA treatment, compared with controls, but the magnitude of the increase was much smaller in RAPA-treated BO-rats. Phosphorylation of p44/42 MAPK (ERK1/2), which preserves fast-twitch MHC isoforms in skeletal muscle, was significantly decreased in BO-rats, but the decrease was abrogated by RAPA treatment. Calcineurin signaling is known to be important for masseter muscle hypertrophy and fast-to-slow MHC isoform transition, but expression of known calcineurin activity modulators was unaffected by RAPA treatment. Taken together, these results indicate that the Akt/mTOR pathway is involved in both development of masseter muscle hypertrophy and fast-to-slow MHC isoform transition in response to mechanical overload with inhibition of the ERK1/2 pathway and operates independently of the calcineurin pathway.

Dynamic contrast-enhanced magnetic resonance imaging of the sarcopenic muscle

PubMed Central

Nicolato, Elena; Farace, Paolo; Asperio, Roberto M; Marzola, Pasquina; Lunati, Ernesto; Sbarbati, Andrea; Osculati, Francesco

2002-01-01

Background Studies about capillarity of the aged muscle provided conflicting results and no data are currently available about the magnetic resonance imaging (MRI) in vivo characteristics of the microvascular bed in aged rats. We have studied age-related modifications of the skeletal muscle by in vivo T2-relaxometry and dynamic contrast-enhanced magnetic resonance imaging (CE-MRI) at high field intensity (4.7 T). The aim of the work was to test the hypothesis that the ageing process involves microvessels in skeletal muscle. Methods The study was performed in 4-month-old (n = 6) and 20-month-old (n = 6) rats. Results At MRI examination, the relaxation time T2 of the gastrocnemius muscle showed no significant difference between these two groups. The kinetic of contrast penetration in the tissue showed that in 4-month-old rats the enhancement values of the signal intensity at different time-points were significantly higher than those found in senescent rats. Conclusion The reported finding suggests that there is a modification of the microcirculatory function in skeletal muscle of aged rats. This work also demonstrates that CE-MRI allows for an in vivo quantification of the multiple biological processes involving the skeletal muscle during aging. Therefore, CE-MRI could represent a further tool for the follow up of tissue modification and therapeutic intervention both in patients with sarcopenia and in experimental models of this pathology. PMID:12049675

Global muscle dysfunction as a risk factor of readmission to hospital due to COPD exacerbations.

PubMed

Vilaró, Jordi; Ramirez-Sarmiento, Alba; Martínez-Llorens, Juana M A; Mendoza, Teresa; Alvarez, Miguel; Sánchez-Cayado, Natalia; Vega, Angeles; Gimeno, Elena; Coronell, Carlos; Gea, Joaquim; Roca, Josep; Orozco-Levi, Mauricio

2010-12-01

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with several modifiable (sedentary life-style, smoking, malnutrition, hypoxemia) and non-modifiable (age, co-morbidities, severity of pulmonary function, respiratory infections) risk factors. We hypothesise that most of these risk factors may have a converging and deleterious effects on both respiratory and peripheral muscle function in COPD patients. A multicentre study was carried out in 121 COPD patients (92% males, 63 ± 11 yr, FEV(1), 49 ± 17%pred). Assessments included anthropometrics, lung function, body composition using bioelectrical impedance analysis (BIA), and global muscle function (peripheral muscle (dominant and non-dominant hand grip strength, HGS), inspiratory (PI(max)), and expiratory (PE(max)) muscle strength). GOLD stage, clinical status (stable vs. non-stable) and both current and past hospital admissions due to COPD exacerbations were included as covariates in the analyses. Respiratory and peripheral muscle weakness were observed in all subsets of patients. Muscle weakness, was significantly associated with both current and past hospitalisations. Patients with history of multiple admissions showed increased global muscle weakness after adjusting by FEV(1) (PE(max), OR = 6.8, p < 0.01; PI(max), OR = 2.9, p < 0.05; HGSd, OR = 2.4, and HGSnd, OR = 2.6, p = 0.05). Moreover, a significant increase in both respiratory and peripheral muscle weakness, after adjusting by FEV(1), was associated with current acute exacerbations. Muscle dysfunction, adjusted by GOLD stage, is associated with an increased risk of hospital admissions due to acute episodes of exacerbation of the disease. Current exacerbations further deteriorate muscle dysfunction. Copyright © 2010 Elsevier Ltd. All rights reserved.

Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis

PubMed Central

Lowes, D. A.; Webster, N. R.; Murphy, M. P.; Galley, H. F.

2013-01-01

Background Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage. Methods Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines. Results MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001). Conclusions Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis. PMID:23381720

Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression

PubMed Central

Pierno, S; Camerino, GM; Cippone, V; Rolland, J-F; Desaphy, J-F; De Luca, A; Liantonio, A; Bianco, G; Kunic, JD; George, AL; Camerino, D Conte

2009-01-01

Background and purpose: Statins and fibrates can produce mild to life-threatening skeletal muscle damage. Resting chloride channel conductance (gCl), carried by the ClC-1 channel, is reduced in muscles of rats chronically treated with fluvastatin, atorvastatin or fenofibrate, along with increased resting cytosolic calcium in statin-treated rats. A high gCl, controlled by the Ca2+-dependent protein kinase C (PKC), maintains sarcolemma electrical stability and its reduction alters muscle function. Here, we investigated how statins and fenofibrate impaired gCl. Experimental approach: In rats treated with fluvastatin, atorvastatin or fenofibrate, we examined the involvement of PKC in gCl reduction by the two intracellular microelectrodes technique and ClC-1 mRNA level by quantitative real time-polymerase chain reaction. Direct drug effects were tested by patch clamp analysis on human ClC-1 channels expressed in human embryonic kidney (HEK) 293 cells. Key results: Chelerythrine, a PKC inhibitor, applied in vitro on muscle dissected from atorvastatin-treated rats fully restored gCl, suggesting the involvement of this enzyme in statin action. Chelerythrine partially restored gCl in muscles from fluvastatin-treated rats but not in those from fenofibrate-treated rats, implying additional mechanisms for gCl impairment. Accordingly, a decrease of ClC-1 channel mRNA was found in both fluvastatin-and fenofibrate-treated rat muscles. Fenofibric acid, the in vivo metabolite of fenofibrate, but not fluvastatin, rapidly reduced chloride currents in HEK 293 cells. Conclusions and implications: Our data suggest multiple mechanisms underlie the effect of statins and fenofibrate on ClC-1 channel conductance. While statins promote Ca2+-mediated PKC activation, fenofibrate directly inhibits ClC-1 channels and both fluvastatin and fenofibrate impair expression of mRNA for ClC-1. PMID:19220292

Unveiling the Metabolic Changes on Muscle Cell Metabolism Underlying p-Phenylenediamine Toxicity

PubMed Central

Marín de Mas, Igor; Marín, Silvia; Pachón, Gisela; Rodríguez-Prados, Juan C.; Vizán, Pedro; Centelles, Josep J.; Tauler, Romà; Azqueta, Amaya; Selivanov, Vitaly; López de Ceraín, Adela; Cascante, Marta

2017-01-01

Rhabdomyolysis is a disorder characterized by acute damage of the sarcolemma of the skeletal muscle leading to release of potentially toxic muscle cell components into the circulation, most notably creatine phosphokinase (CK) and myoglobulin, and is frequently accompanied by myoglobinuria. In the present work, we evaluated the toxicity of p-phenylenediamine (PPD), a main component of hair dyes which is reported to induce rhabdomyolysis. We studied the metabolic effect of this compound in vivo with Wistar rats and in vitro with C2C12 muscle cells. To this aim we have combined multi-omic experimental measurements with computational approaches using model-driven methods. The integrative study presented here has unveiled the metabolic disorders associated to PPD exposure that may underlay the aberrant metabolism observed in rhabdomyolys disease. Animals treated with lower doses of PPD (10 and 20 mg/kg) showed depressed activity and myoglobinuria after 10 h of treatment. We measured the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) in rats after 24, 48, and 72 h of PPD exposure. At all times, treatment with PPD at higher doses (40 and 60 mg/kg) showed an increase of AST and ALT, and also an increase of lactate dehydrogenase (LDH) and CK after 24 h. Blood packed cell volume and hemoglobin levels, as well as organs weight at 48 and 72 h, were also measured. No significant differences were observed in these parameters under any condition. PPD induce cell cycle arrest in S phase and apoptosis (40% or early apoptotic cells) on mus musculus mouse C2C12 cells after 24 h of treatment. Incubation of mus musculus mouse C2C12 cells with [1,2-13C2]-glucose during 24 h, subsequent quantification of 13C isotopologues distribution in key metabolites of glucose metabolic network and a computational fluxomic analysis using in-house developed software (Isodyn) showed that PPD is inhibiting glycolysis, non-oxidative pentose phosphate pathway, glycogen turnover, and ATPAse reaction leading to a reduction in ATP synthesis. These findings unveil the glucose metabolism collapse, which is consistent with a decrease in cell viability observed in PPD-treated C2C12 cells and with the myoglubinuria and other effects observed in Wistar Rats treated with PPD. These findings shed new light on muscle dysfunction associated to PPD exposure, opening new avenues for cost-effective therapies in Rhabdomyolysis disease. PMID:28321398

Loss of the Endothelial Glycocalyx Links Albuminuria and Vascular Dysfunction

PubMed Central

Ferguson, Joanne K.; Burford, James L.; Gevorgyan, Haykanush; Nakano, Daisuke; Harper, Steven J.; Bates, David O.; Peti-Peterdi, Janos

2012-01-01

Patients with albuminuria and CKD frequently have vascular dysfunction but the underlying mechanisms remain unclear. Because the endothelial surface layer, a meshwork of surface-bound and loosely adherent glycosaminoglycans and proteoglycans, modulates vascular function, its loss could contribute to both renal and systemic vascular dysfunction in proteinuric CKD. Using Munich-Wistar-Fromter (MWF) rats as a model of spontaneous albuminuric CKD, multiphoton fluorescence imaging and single-vessel physiology measurements revealed that old MWF rats exhibited widespread loss of the endothelial surface layer in parallel with defects in microvascular permeability to both water and albumin, in both continuous mesenteric microvessels and fenestrated glomerular microvessels. In contrast to young MWF rats, enzymatic disruption of the endothelial surface layer in old MWF rats resulted in neither additional loss of the layer nor additional changes in permeability. Intravenous injection of wheat germ agglutinin lectin and its adsorption onto the endothelial surface layer significantly improved glomerular albumin permeability. Taken together, these results suggest that widespread loss of the endothelial surface layer links albuminuric kidney disease with systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease. PMID:22797190

Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans.

PubMed

Gouspillou, Gilles; Sgarioto, Nicolas; Kapchinsky, Sophia; Purves-Smith, Fennigje; Norris, Brandon; Pion, Charlotte H; Barbat-Artigas, Sébastien; Lemieux, Francois; Taivassalo, Tanja; Morais, José A; Aubertin-Leheudre, Mylène; Hepple, Russell T

2014-04-01

Mitochondrial dysfunction is implicated in skeletal muscle atrophy and dysfunction with aging, with strong support for an increased mitochondrial-mediated apoptosis in sedentary rodent models. Whether this applies to aged human muscle is unknown, nor is it clear whether these changes are caused by sedentary behavior. Thus, we examined mitochondrial function [respiration, reactive oxygen species (ROS) emission, and calcium retention capacity (CRC)] in permeabilized myofibers obtained from vastus lateralis muscle biopsies of healthy physically active young (23.7±2.7 yr; mean±SD) and older (71.2±4.9 yr) men. Although mitochondrial ROS and maximal respiratory capacity were unaffected, the acceptor control ratio was reduced by 18% with aging, suggesting mild uncoupling of oxidative phosphorylation. CRC was reduced by 50% with aging, indicating sensitization of the mitochondrial permeability transition pore (mPTP) to apoptosis. Consistent with the mPTP sensitization, older muscles showed a 3-fold greater fraction of endonuclease G (a mitochondrial proapoptotic factor)-positive myonuclei. Aged muscles also had lower mitophagic potential, based on a 43% reduction in Parkin to the voltage-dependent anion channel (VDAC) protein ratio. Collectively, these results show that mitochondrial-mediated apoptotic signaling is increased in older human muscle and suggest that accumulation of dysfunctional mitochondria with exaggerated apoptotic sensitivity is due to impaired mitophagy.

Sex steroids do not affect muscle weight, oxidative metabolism or cytosolic androgen reception binding of functionally overloaded rat Plantaris muscles

NASA Technical Reports Server (NTRS)

Max, S. R.; Rance, N.

1983-01-01

The effects of sex steroids on muscle weight and oxidative capacity of rat planaris muscles subjected to functional overload by removal of synergistic muscles were investigated. Ten weeks after bilateral synergist removal, plantaris muscles were significantly hypertrophic compared with unoperated controls. After this period, the ability of the muscles to oxide three substrates of oxidative metabolism was assessed. Experimental procedures are discussed and results are presented herein. Results suggest a lack of beneficial effect of sex hormone status on the process of hypertrophy and on biochemical changes in overloaded muscle. Such findings are not consistent with the idea of synergistic effects of sex steroids and muscle usage.

Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia.

PubMed

Ábrigo, Johanna; Elorza, Alvaro A; Riedel, Claudia A; Vilos, Cristian; Simon, Felipe; Cabrera, Daniel; Estrada, Lisbell; Cabello-Verrugio, Claudio

2018-01-01

Skeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia.

Soy β-conglycinin improves glucose uptake in skeletal muscle and ameliorates hepatic insulin resistance in Goto-Kakizaki rats.

PubMed

Tachibana, Nobuhiko; Yamashita, Yoko; Nagata, Mayuko; Wanezaki, Satoshi; Ashida, Hitoshi; Horio, Fumihiko; Kohno, Mitsutaka

2014-02-01

Although the underlying mechanism is unclear, β-conglycinin (βCG), the major component of soy proteins, regulates blood glucose levels. Here, we hypothesized that consumption of βCG would normalize blood glucose levels by ameliorating insulin resistance and stimulating glucose uptake in skeletal muscles. To test our hypothesis, we investigated the antidiabetic action of βCG in spontaneously diabetic Goto-Kakizaki (GK) rats. Our results revealed that plasma adiponectin levels and adiponectin receptor 1 messenger RNA expression in skeletal muscle were higher in βCG-fed rats than in casein-fed rats. Phosphorylation of adenosine monophosphate-activated protein kinase (AMP kinase) but not phosphatidylinositol-3 kinase was activated in βCG-fed GK rats. Subsequently, βCG increased translocation of glucose transporter 4 to the plasma membrane. Unlike the results in skeletal muscle, the increase in adiponectin receptor 1 did not lead to AMP kinase activation in the liver of βCG-fed rats. The down-regulation of sterol regulatory element-binding factor 1, which is induced by low insulin levels, promoted the increase in hepatic insulin receptor substrate 2 expression. Based on these findings, we concluded that consumption of soy βCG improves glucose uptake in skeletal muscle via AMP kinase activation and ameliorates hepatic insulin resistance and that these actions may help normalize blood glucose levels in GK rats. Copyright © 2014 Elsevier Inc. All rights reserved.

Myostatin propeptide gene delivery by gene gun ameliorates muscle atrophy in a rat model of botulinum toxin-induced nerve denervation.

PubMed

Tsai, Sen-Wei; Tung, Yu-Tang; Chen, Hsiao-Ling; Yang, Shang-Hsun; Liu, Chia-Yi; Lu, Michelle; Pai, Hui-Jing; Lin, Chi-Chen; Chen, Chuan-Mu

2016-02-01

Muscle atrophy is a common symptom after nerve denervation. Myostatin propeptide, a precursor of myostatin, has been documented to improve muscle growth. However, the mechanism underlying the muscle atrophy attenuation effects of myostatin propeptide in muscles and the changes in gene expression are not well established. We investigated the possible underlying mechanisms associated with myostatin propeptide gene delivery by gene gun in a rat denervation muscle atrophy model, and evaluated gene expression patterns. In a rat botulinum toxin-induced nerve denervation muscle atrophy model, we evaluated the effects of wild-type (MSPP) and mutant-type (MSPPD75A) of myostatin propeptide gene delivery, and observed changes in gene activation associated with the neuromuscular junction, muscle and nerve. Muscle mass and muscle fiber size was moderately increased in myostatin propeptide treated muscles (p<0.05). And enhancement of the gene expression of the muscle regulatory factors, neurite outgrowth factors (IGF-1, GAP43) and acetylcholine receptors was observed. Our results demonstrate that myostatin propeptide gene delivery, especially the mutant-type of MSPPD75A, attenuates muscle atrophy through myogenic regulatory factors and acetylcholine receptor regulation. Our data concluded that myostatin propeptide gene therapy may be a promising treatment for nerve denervation induced muscle atrophy. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of orally administered OP-1206 alpha-CD with loxoprofen-Na on walking dysfunction in the rat neuropathic intermittent claudication model.

PubMed

Nakai, Katsuhiko; Takenobu, Yoshifumi; Takimizu, Hideyuki; Akimaru, Shinji; Ito, Hidenori; Maegawa, Hitoshi; Marsala, Martin; Katsube, Nobuo

2003-10-01

An orally active prostaglandin E1 analogue, OP-1206 alpha-CD improves walking dysfunction in the rat spinal stenosis model. Loxoprofen-Na, a non-steroidal anti-inflammatory drug, is used to relieve chronic pain in patients with lumbar spinal canal stenosis. To determine whether the OP-1206 alpha-CD in combination with loxoprofen-Na could induce a greater therapeutical effect on walking dysfunction and spinal cord blood flow (SCBF) than OP-1206 alpha-CD treatment alone after chronic spinal stenosis in the rat. Spinal stenosis was induced by placing two pieces of silicon rubber strips in the lumbar (L4 and L6) epidural space of rats. After surgery, walking function was measured using a treadmill apparatus and SCBF was measured using a laser-Doppler flow meter. Drugs were administered orally twice a day for 11 days from the day 3 post-surgery. OP-1206 alpha-CD elicited a significant improvement of walking dysfunction on days 7 and 14 post-surgery and significantly increased spinal cord blood flow on day 15, whereas walking dysfunction and SCBF of rats treated with loxoprofen-Na alone remained unchanged. Combined treatment of OP-1206 alpha-CD with loxoprofen-Na did not provide additive therapeutical effect. These results suggest that a significant improvement seen after OP-1206 alpha-CD treatment is primarily mediated by improvement of the local spinal cord blood flow. This effect is not ameliorated or potentiated by a combined treatment with loxoprofen-Na.

Effects of hindlimb unloading on neuromuscular development of neonatal rats

NASA Technical Reports Server (NTRS)

Huckstorf, B. L.; Slocum, G. R.; Bain, J. L.; Reiser, P. M.; Sedlak, F. R.; Wong-Riley, M. T.; Riley, D. A.

2000-01-01

We hypothesized that hindlimb suspension unloading of 8-day-old neonatal rats would disrupt the normal development of muscle fiber types and the motor innervation of the antigravity (weightbearing) soleus muscles but not extensor digitorum longus (EDL) muscles. Five rats were suspended 4.5 h and returned 1.5 h to the dam for nursing on a 24 h cycle for 9 days. To control for isolation from the dam, the remaining five littermates were removed on the same schedule but not suspended. Another litter of 10 rats housed in the same room provided a vivarium control. Fibers were typed by myofibrillar ATPase histochemistry and immunostaining for embryonic, slow, fast IIA and fast IIB isomyosins. The percentage of multiple innervation and the complexity of singly-innervated motor terminal endings were assessed in silver/cholinesterase stained sections. Unique to the soleus, unloading accelerated production of fast IIA myosin, delayed expression of slow myosin and retarded increases in standardized muscle weight and fiber size. Loss of multiple innervation was not delayed. However, fewer than normal motor nerve endings achieved complexity. Suspended rats continued unloaded hindlimb movements. These findings suggest that motor neurons resolve multiple innervation through nerve impulse activity, whereas the postsynaptic element (muscle fiber) controls endplate size, which regulates motor terminal arborization. Unexpectedly, in the EDL of unloaded rats, transition from embryonic to fast myosin expression was retarded. Suspension-related foot drop, which stretches and chronically loads EDL, may have prevented fast fiber differentiation. These results demonstrate that neuromuscular development of both weightbearing and non-weightbearing muscles in rats is dependent upon and modulated by hindlimb loading.

Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis.

PubMed

Nardelli, Paul; Vincent, Jacob A; Powers, Randall; Cope, Tim C; Rich, Mark M

2016-08-01

The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced motor neuron excitability for weeks after resolution of sepsis. To assess whether additional contributions from myopathy, neuropathy and defects in neuromuscular transmission contributed to the reduction in force generation, we measured whole-muscle force production in response to electrical stimulation of the muscle nerve. We found no abnormality in force generation that would suggest the presence of myopathy, neuropathy or defective neuromuscular transmission. These data suggest disruption of repetitive firing of motor neurons is an important contributor to weakness induced by sepsis in rats and raise the possibility that reduced motor neuron excitability contributes to disability that persists after resolution of sepsis. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of the beta2 agonist formoterol on atrophy signaling, autophagy, and muscle phenotype in respiratory and limb muscles of rats with cancer-induced cachexia.

PubMed

Salazar-Degracia, Anna; Busquets, Sílvia; Argilés, Josep M; Bargalló-Gispert, Núria; López-Soriano, Francisco J; Barreiro, Esther

2018-06-01

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Beta-adrenoceptors attenuate muscle wasting. We hypothesized that specific muscle atrophy signaling pathways and altered metabolism may be attenuated in cancer cachectic animals receiving treatment with the beta 2 agonist formoterol. In diaphragm and gastrocnemius of tumor-bearing rats (intraperitoneal inoculum, 10 8 AH-130 Yoshida ascites hepatoma cells, 7-day study period) with and without treatment with formoterol (0.3 mg/kg body weight/day/7days, subcutaneous), atrophy signaling pathways (NF-κB, MAPK, FoxO), proteolytic markers (ligases, proteasome, ubiquitination), autophagy markers (p62, beclin-1, LC3), myostatin, apoptosis, muscle metabolism markers, and muscle structure features were analyzed (immunoblotting, immunohistochemistry). In diaphragm and gastrocnemius of cancer cachectic rats, fiber sizes were reduced, levels of structural alterations, atrophy signaling pathways, proteasome content, protein ubiquitination, autophagy, and myostatin were increased, while those of regenerative and metabolic markers (myoD, mTOR, AKT, and PGC-1alpha) were decreased. Formoterol treatment attenuated such alterations in both muscles. Muscle wasting in this rat model of cancer-induced cachexia was characterized by induction of significant structural alterations, atrophy signaling pathways, proteasome activity, apoptotic and autophagy markers, and myostatin, along with a significant decline in the expression of muscle regenerative and metabolic markers. Treatment of the cachectic rats with formoterol partly attenuated the structural alterations and atrophy signaling, while improving other molecular perturbations similarly in both respiratory and limb muscles. The results reported in this study have relevant therapeutic implications as they showed beneficial effects of the beta 2 agonist formoterol in the cachectic muscles through several key biological pathways. Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.