Respiratory muscle strength is not decreased in patients undergoing cardiac surgery.

PubMed

Urell, Charlotte; Emtner, Margareta; Hedenstrom, Hans; Westerdahl, Elisabeth

2016-03-31

Postoperative pulmonary impairments are significant complications after cardiac surgery. Decreased respiratory muscle strength could be one reason for impaired lung function in the postoperative period. The primary aim of this study was to describe respiratory muscle strength before and two months after cardiac surgery. A secondary aim was to describe possible associations between respiratory muscle strength and lung function. In this prospective observational study 36 adult cardiac surgery patients (67 ± 10 years) were studied. Respiratory muscle strength and lung function were measured before and two months after surgery. Pre- and postoperative respiratory muscle strength was in accordance with predicted values; MIP was 78 ± 24 cmH2O preoperatively and 73 ± 22 cmH2O at two months follow-up (p = 0.19). MEP was 122 ± 33 cmH2O preoperatively and 115 ± 38 cmH2O at two months follow-up (p = 0.18). Preoperative lung function was in accordance with predicted values, but was significantly decreased postoperatively. At two-months follow-up there was a moderate correlation between MIP and FEV1 (r = 0.43, p = 0.009). Respiratory muscle strength was not impaired, either before or two months after cardiac surgery. The reason for postoperative lung function alteration is not yet known. Interventions aimed at restore an optimal postoperative lung function should focus on other interventions then respiratory muscle strength training.

[Cardiac myopathy due to overt hypothyroidism].

PubMed

Harbeck, B; Berndt, M J; Lehnert, H

2014-03-01

A 51-year-old man presented with progressive tiredness, proximal muscle weakness, hair loss and weight gain for months. The patient showed mild pretibial myxedema and dry skin. Laboratory findings revealed strongly elevated cardiac enzymes as well as marked hypothyroidism. The electrocardiogram, echocardiography, abdominal sonography and chest X-ray were unremarkable. Thyroid ultrasound demonstrated features of Hashimoto thyroiditis. The findings supported the diagnosis of an overt hypothyroidism with myxedema and rhabdomyolysis. After starting levothyroxine and volume substitution laboratory parameters and clinical condition slowly normalized. Severe overt hypothyroidism may rarely present primarily as myopathy with myositis and cardiac involvement. © Georg Thieme Verlag KG Stuttgart · New York.

Muscle-derived stem cells isolated as non-adherent population give rise to cardiac, skeletal muscle and neural lineages.

PubMed

Arsic, Nikola; Mamaeva, Daria; Lamb, Ned J; Fernandez, Anne

2008-04-01

Stem cells with the ability to differentiate in specialized cell types can be extracted from a wide array of adult tissues including skeletal muscle. Here we have analyzed a population of cells isolated from skeletal muscle on the basis of their poor adherence on uncoated or collagen-coated dishes that show multi-lineage differentiation in vitro. When analysed under proliferative conditions, these cells express stem cell surface markers Sca-1 (65%) and Bcrp-1 (80%) but also MyoD (15%), Neuronal beta III-tubulin (25%), GFAP (30%) or Nkx2.5 (1%). Although capable of growing as non-attached spheres for months, when given an appropriate matrix, these cells adhere giving rise to skeletal muscle, neuronal and cardiac muscle cell lineages. A similar cell population could not be isolated from either bone marrow or cardiac tissue suggesting their specificity to skeletal muscle. When injected into damaged muscle, these non-adherent muscle-derived cells are retrieved expressing Pax7, in a sublaminar position characterizing satellite cells and participate in forming new myofibers. These data show that a non-adherent stem cell population can be specifically isolated and expanded from skeletal muscle and upon attachment to a matrix spontaneously differentiate into muscle, cardiac and neuronal lineages in vitro. Although competing with resident satellite cells, these cells are shown to significantly contribute to repair of injured muscle in vivo supporting that a similar muscle-derived non-adherent cell population from human muscle may be useful in treatment of neuromuscular disorders.

Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

PubMed Central

Breitbart, Astrid; Auger-Messier, Mannix; Molkentin, Jeffery D.

2011-01-01

A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future. PMID:21421824

In utero Undernutrition Programs Skeletal and Cardiac Muscle Metabolism.

PubMed

Beauchamp, Brittany; Harper, Mary-Ellen

2015-01-01

In utero undernutrition is associated with increased risk for insulin resistance, obesity, and cardiovascular disease during adult life. A common phenotype associated with low birth weight is reduced skeletal muscle mass. Given the central role of skeletal muscle in whole body metabolism, alterations in its mass as well as its metabolic characteristics may contribute to disease risk. This review highlights the metabolic alterations in cardiac and skeletal muscle associated with in utero undernutrition and low birth weight. These tissues have high metabolic demands and are known to be sites of major metabolic dysfunction in obesity, type 2 diabetes, and cardiovascular disease. Recent research demonstrates that mitochondrial energetics are decreased in skeletal and cardiac muscles of adult offspring from undernourished mothers. These effects apparently lead to the development of a thrifty phenotype, which may represent overall a compensatory mechanism programmed in utero to handle times of limited nutrient availability. However, in an environment characterized by food abundance, the effects are maladaptive and increase adulthood risks of metabolic disease.

Cardiac Muscle Studies with Rat Ventricular Strips

ERIC Educational Resources Information Center

Whitten, Bert K.; Faleschini, Richard J.

1977-01-01

Details undergraduate physiology laboratory experiments that demonstrate mechanical properties of cardiac muscle, using strips from the ventricle of a rat heart. Includes procedures for obtaining length-tension curves, demonstrating the role of calcium in excitation-contraction coupling, and showing effects of several cardiovascular drugs…

Effect of muscle length on cross-bridge kinetics in intact cardiac trabeculae at body temperature.

PubMed

Milani-Nejad, Nima; Xu, Ying; Davis, Jonathan P; Campbell, Kenneth S; Janssen, Paul M L

2013-01-01

Dynamic force generation in cardiac muscle, which determines cardiac pumping activity, depends on both the number of sarcomeric cross-bridges and on their cycling kinetics. The Frank-Starling mechanism dictates that cardiac force development increases with increasing cardiac muscle length (corresponding to increased ventricular volume). It is, however, unclear to what extent this increase in cardiac muscle length affects the rate of cross-bridge cycling. Previous studies using permeabilized cardiac preparations, sub-physiological temperatures, or both have obtained conflicting results. Here, we developed a protocol that allowed us to reliably and reproducibly measure the rate of tension redevelopment (k(tr); which depends on the rate of cross-bridge cycling) in intact trabeculae at body temperature. Using K(+) contractures to induce a tonic level of force, we showed the k(tr) was slower in rabbit muscle (which contains predominantly β myosin) than in rat muscle (which contains predominantly α myosin). Analyses of k(tr) in rat muscle at optimal length (L(opt)) and 90% of optimal length (L(90)) revealed that k(tr) was significantly slower at L(opt) (27.7 ± 3.3 and 27.8 ± 3.0 s(-1) in duplicate analyses) than at L(90) (45.1 ± 7.6 and 47.5 ± 9.2 s(-1)). We therefore show that k(tr) can be measured in intact rat and rabbit cardiac trabeculae, and that the k(tr) decreases when muscles are stretched to their optimal length under near-physiological conditions, indicating that the Frank-Starling mechanism not only increases force but also affects cross-bridge cycling kinetics.

In utero Undernutrition Programs Skeletal and Cardiac Muscle Metabolism

PubMed Central

Beauchamp, Brittany; Harper, Mary-Ellen

2016-01-01

In utero undernutrition is associated with increased risk for insulin resistance, obesity, and cardiovascular disease during adult life. A common phenotype associated with low birth weight is reduced skeletal muscle mass. Given the central role of skeletal muscle in whole body metabolism, alterations in its mass as well as its metabolic characteristics may contribute to disease risk. This review highlights the metabolic alterations in cardiac and skeletal muscle associated with in utero undernutrition and low birth weight. These tissues have high metabolic demands and are known to be sites of major metabolic dysfunction in obesity, type 2 diabetes, and cardiovascular disease. Recent research demonstrates that mitochondrial energetics are decreased in skeletal and cardiac muscles of adult offspring from undernourished mothers. These effects apparently lead to the development of a thrifty phenotype, which may represent overall a compensatory mechanism programmed in utero to handle times of limited nutrient availability. However, in an environment characterized by food abundance, the effects are maladaptive and increase adulthood risks of metabolic disease. PMID:26779032

Isoform variants of troponin in skeletal and cardiac muscle cells cultured with and without nerves.

PubMed

Toyota, N; Shimada, Y

1983-05-01

Immunofluorescence microscopy shows that cultured skeletal and cardiac muscle cells of chicken embryos exhibit the same stainabilities with antibodies against skeletal and cardiac troponin components as do those in embryos. Muscle cells of each type cultured with motor or sympathetic nerves or in medium containing the nerve extract exhibit the same reactivities as do those in adult animals. Cardiac muscle cells incubated in the nerve-conditioned medium also change the form of troponin components to the adult type. It appears that the differentiation of individual muscle fibers to specific types is induced by nerves, and especially by the neurohumoral effect.

Noncontact quantitative biomechanical characterization of cardiac muscle using shear wave imaging optical coherence tomography

PubMed Central

Wang, Shang; Lopez, Andrew L.; Morikawa, Yuka; Tao, Ge; Li, Jiasong; Larina, Irina V.; Martin, James F.; Larin, Kirill V.

2014-01-01

We report on a quantitative optical elastographic method based on shear wave imaging optical coherence tomography (SWI-OCT) for biomechanical characterization of cardiac muscle through noncontact elasticity measurement. The SWI-OCT system employs a focused air-puff device for localized loading of the cardiac muscle and utilizes phase-sensitive OCT to monitor the induced tissue deformation. Phase information from the optical interferometry is used to reconstruct 2-D depth-resolved shear wave propagation inside the muscle tissue. Cross-correlation of the displacement profiles at various spatial locations in the propagation direction is applied to measure the group velocity of the shear waves, based on which the Young’s modulus of tissue is quantified. The quantitative feature and measurement accuracy of this method is demonstrated from the experiments on tissue-mimicking phantoms with the verification using uniaxial compression test. The experiments are performed on ex vivo cardiac muscle tissue from mice with normal and genetically altered myocardium. Our results indicate this optical elastographic technique is useful as a noncontact tool to assist the cardiac muscle studies. PMID:25071943

Dmpk gene deletion or antisense knockdown does not compromise cardiac or skeletal muscle function in mice

PubMed Central

Carrell, Samuel T.; Carrell, Ellie M.; Auerbach, David; Pandey, Sanjay K.; Bennett, C. Frank; Dirksen, Robert T.; Thornton, Charles A.

2016-01-01

Myotonic dystrophy type 1 (DM1) is a genetic disorder in which dominant-active DM protein kinase (DMPK) transcripts accumulate in nuclear foci, leading to abnormal regulation of RNA processing. A leading approach to treat DM1 uses DMPK-targeting antisense oligonucleotides (ASOs) to reduce levels of toxic RNA. However, basal levels of DMPK protein are reduced by half in DM1 patients. This raises concern that intolerance for further DMPK loss may limit ASO therapy, especially since mice with Dmpk gene deletion reportedly show cardiac defects and skeletal myopathy. We re-examined cardiac and muscle function in mice with Dmpk gene deletion, and studied post-maturity knockdown using Dmpk-targeting ASOs in mice with heterozygous deletion. Contrary to previous reports, we found no effect of Dmpk gene deletion on cardiac or muscle function, when studied on two genetic backgrounds. In heterozygous knockouts, the administration of ASOs reduced Dmpk expression in cardiac and skeletal muscle by > 90%, yet survival, electrocardiogram intervals, cardiac ejection fraction and muscle strength remained normal. The imposition of cardiac stress by pressure overload, or muscle stress by myotonia, did not unmask a requirement for DMPK. Our results support the feasibility and safety of using ASOs for post-transcriptional silencing of DMPK in muscle and heart. PMID:27522499

A personal historic perspective on the role of chloride in skeletal and cardiac muscle.

PubMed

Hutter, Otto F

2017-03-01

During the early decades of the last century, skeletal muscle was held to be impermeable to chloride ions. This theory, based on shaky grounds, was famously falsified by Boyle and Conway in 1941. Two decades later and onwards, the larger part of the resting conductance of skeletal muscle was found to be due to chloride ions, sensitive to the chemical environment, and to be time-and-voltage dependent. So, much of the groundwork for the physiological role of chloride ions in skeletal muscle was laid before the game-changing discovery of chloride channels. The early history of the role of chloride in cardiac muscle, and work on the relative permeability to foreign anions of different muscles are also here covered from a personal perspective. © 2017 The Author. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Effect of oxidative insult on young and adult cardiac muscle cells in vitro.

PubMed

Nag, A C; Sreepathi, P; Lee, M L; Reddan, J R

1996-01-01

The effect of hydrogen peroxide on cultured neonatal and adult cardiac myocytes was investigated. On neonatal cardiac myocytes the effect was very pronounced at a low concentration (0.03 mM), whereas the adult cardiac myocytes were resistant to the same concentration of H2O2. Dividing neonatal cardiac myocytes were more susceptible to H2O2 insult than the non-dividing adult cardiac myocytes. At a concentration of 0.1 mM H2O2, the neonatal cardiac myocytes were significantly damaged compared with the adult cardiac myocytes. Cardiac muscle cells from neonatal and adult hearts at high density culture were more tolerant to the oxidative insult by H2O2 than cells in low density culture. The damaging effect of H2O2 was very selective on F-actin in neonatal and adult cardiac muscle cells. The effect of H2O2 on myosin, titin, alpha-actinin, desmin or tubulin was not pronounced. Microscopical studies suggested a more marked protection by catalase than by glutathione reductase in the neonatal cells.

Chronic losartan administration reduces mortality and preserves cardiac but not skeletal muscle function in dystrophic mice.

PubMed

Bish, Lawrence T; Yarchoan, Mark; Sleeper, Meg M; Gazzara, Jeffrey A; Morine, Kevin J; Acosta, Pedro; Barton, Elisabeth R; Sweeney, H Lee

2011-01-01

Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy. Angiotension receptor blockade (ARB) has excellent therapeutic potential in DMD based on recent data demonstrating attenuation of skeletal muscle disease progression during 6-9 months of therapy in the mdx mouse model of DMD. Since cardiac-related death is major cause of mortality in DMD, it is important to evaluate the effect of any novel treatment on the heart. Therefore, we evaluated the long-term impact of ARB on both the skeletal muscle and cardiac phenotype of the mdx mouse. Mdx mice received either losartan (0.6 g/L) (n = 8) or standard drinking water (n = 9) for two years, after which echocardiography was performed to assess cardiac function. Skeletal muscle weight, morphology, and function were assessed. Fibrosis was evaluated in the diaphragm and heart by Trichrome stain and by determination of tissue hydroxyproline content. By the study endpoint, 88% of treated mice were alive compared to only 44% of untreated (p = 0.05). No difference in skeletal muscle morphology, function, or fibrosis was noted in losartan-treated animals. Cardiac function was significantly preserved with losartan treatment, with a trend towards reduction in cardiac fibrosis. We saw no impact on the skeletal muscle disease progression, suggesting that other pathways that trigger fibrosis dominate over angiotensin II in skeletal muscle long term, unlike the situation in the heart. Our study suggests that ARB may be an important prophylactic treatment for DMD-associated cardiomyopathy, but will not impact skeletal muscle disease.

Age-related conversion of dystrophin-negative to -positive fiber segments of skeletal but not cardiac muscle fibers in heterozygote mdx mice.

PubMed

Karpati, G; Zubrzycka-Gaarn, E E; Carpenter, S; Bulman, D E; Ray, P N; Worton, R G

1990-03-01

Immunoreactive dystrophin was examined in muscle fibers of quadriceps, extraocular muscles and cardiac ventricular muscles of female heterozygote mdx mice at 10, 35 and 60 days of age, with microscopic immunoperoxidase method and by immunoblots. In quadriceps muscle fibers there was a marked gradual diminution of the dystrophin-negative fiber segments between age 10 and 60 days. We suggest that this was partly due to a spontaneous fusion of dystrophin-competent satellite cells into the dystrophin-negative fiber segments and partly to an expansion of the cytoplasmic domain of dystrophin expression related to the original myonuclei. In cardiac muscle that lacks satellite cells, there was persistence of a large number of dystrophin-negative fiber segments even at age 60 days and probably beyond. The findings of this study have implications for the detection of heterozygote female carriers of Duchenne muscular dystrophy (DMD) and for the possible therapy of DMD muscles by myoblast transfer.

Translating golden retriever muscular dystrophy microarray findings to novel biomarkers for cardiac/skeletal muscle function in Duchenne muscular dystrophy.

PubMed

Galindo, Cristi L; Soslow, Jonathan H; Brinkmeyer-Langford, Candice L; Gupte, Manisha; Smith, Holly M; Sengsayadeth, Seng; Sawyer, Douglas B; Benson, D Woodrow; Kornegay, Joe N; Markham, Larry W

2016-04-01

In Duchenne muscular dystrophy (DMD), abnormal cardiac function is typically preceded by a decade of skeletal muscle disease. Molecular reasons for differences in onset and progression of these muscle groups are unknown. Human biomarkers are lacking. We analyzed cardiac and skeletal muscle microarrays from normal and golden retriever muscular dystrophy (GRMD) dogs (ages 6, 12, or 47+ mo) to gain insight into muscle dysfunction and to identify putative DMD biomarkers. These biomarkers were then measured using human DMD blood samples. We identified GRMD candidate genes that might contribute to the disparity between cardiac and skeletal muscle disease, focusing on brain-derived neurotropic factor (BDNF) and osteopontin (OPN/SPP1, hereafter indicated as SPP1). BDNF was elevated in cardiac muscle of younger GRMD but was unaltered in skeletal muscle, while SPP1 was increased only in GRMD skeletal muscle. In human DMD, circulating levels of BDNF were inversely correlated with ventricular function and fibrosis, while SPP1 levels correlated with skeletal muscle function. These results highlight gene expression patterns that could account for differences in cardiac and skeletal disease in GRMD. Most notably, animal model-derived data were translated to DMD and support use of BDNF and SPP1 as biomarkers for cardiac and skeletal muscle involvement, respectively.

Changes of intracellular milieu with fatigue or hypoxia depress contraction of skinned rabbit skeletal and cardiac muscle.

PubMed Central

Godt, R E; Nosek, T M

1989-01-01

1. Maximal calcium-activated force (Fmax) and calcium sensitivity were markedly decreased in detergent-skinned fibres from skeletal and cardiac muscle by solutions that mimicked the total milieu changes associated with fatigue and hypoxia. Further experiments determined the relative contribution of each of the individual changes in milieu. 2. Both Ca2+ sensitivity and Fmax of skeletal and cardiac fibres were decreased with increased [H+] or inorganic phosphate (Pi). These effects were greater in cardiac muscle. 3. Decreasing MgATP over the range observed with fatigue and hypoxia (6.8-4.7 mM) had no effect on Fmax or Ca2+ sensitivity of either muscle type. 4. Decreasing phosphocreatine (PCr: 15-1 mM) increased Fmax but had little effect on Ca2+ sensitivity in both muscle types. In cardiac fibres, the effect on Fmax could be mimicked by inhibition of endogenous creatine kinase. 5. ADP (0.7 mM) increased Fmax and Ca2+ sensitivity, while AMP (0.06 mM) slightly increased Fmax but had no effect on Ca2+ sensitivity of either skeletal or cardiac fibres. 6. Creatine (25 mM) had no significant effect on either Ca2+ sensitivity or Fmax of skeletal and cardiac muscle fibres. At higher levels (50 mM), however, creatine depressed Fmax and slightly altered Ca2+ sensitivity. 7. Thiophosphorylation of myosin P light chains (phosphorylatable light chains of myosin) in rabbit psoas fibres had no effect on Ca2+ sensitivity, yet slightly but significantly increased Fmax under fatigue conditions. 8. Reducing the affinity for ATP hydrolysis (by adding ADP, AMP and creatine) over the range calculated for fatigue/hypoxia (60-45 kJ/mol) produced the enhancement in Fmax expected from added ADP and AMP in cardiac but not skeletal muscle, indicating that changes in affinity influence Fmax of skeletal muscle. Reducing affinity produced little change in Ca2+ sensitivity of skeletal muscle. In contrast, the change produced in cardiac muscle was greater than that expected from addition of ADP and

Capillarization in skeletal muscle of rats with cardiac hypertrophy.

PubMed

Degens, Hans; Anderson, Rebecca K; Alway, Stephen E

2002-02-01

Exercise intolerance during chronic heart failure (CHF) is localized mainly in skeletal muscle. A decreased capillarization may impair exchange of oxygen between capillaries and muscle tissue and in this way contribute to exercise intolerance. We assessed changes in capillary supply in plantaris and diaphragm muscles of a rat aorta-caval fistula (ACF) preparation, a volume overload model for CHF. An ACF was created under equithesin anesthesia. Plantaris and diaphragm muscles were removed 6 wk postsurgery and examined for myosin heavy chain (MyHC) content and capillary supply. Cardiac hypertrophy was 96% (P < 0.002) after ACF. The Type IIb MyHC content of the plantaris muscles increased (33.9 +/- 3.3 vs 49.8 +/- 3.8%; mean +/- SEM) at the expense of Type IIa MyHC (17.6 +/- 1.8 vs 11.2 +/- 1.7%) in ACF rats (P < 0.05). In the diaphragm, the number of Type I (32.1 +/- 2.3 vs 40.6 +/- 2.7%) and IIb fibers (40.6 +/- 1.9 vs 49.6 +/- 3.6%) increased at the expense of Type IIa fibers (26.8 +/- 2.5 vs 9.4 +/- 0.9%) (P < 0.05). The capillary number per fiber did not change, and this indicated that no capillary loss occurred with ACF. Also, the capillary density was maintained in the diaphragm and plantaris muscles of ACF rats. Furthermore, the coupling between fiber type, size, and metabolic type of surrounding fibers, with the capillary supply to a fiber, was maintained in rats with an ACF. The cardiac hypertrophy induced by volume overload seems adequate to prevent atrophy and changes in the microcirculation of limb and diaphragm muscles.

Length dependence of force generation exhibit similarities between rat cardiac myocytes and skeletal muscle fibres.

PubMed

Hanft, Laurin M; McDonald, Kerry S

2010-08-01

According to the Frank-Starling relationship, increased ventricular volume increases cardiac output, which helps match cardiac output to peripheral circulatory demand. The cellular basis for this relationship is in large part the myofilament length-tension relationship. Length-tension relationships in maximally calcium activated preparations are relatively shallow and similar between cardiac myocytes and skeletal muscle fibres. During twitch activations length-tension relationships become steeper in both cardiac and skeletal muscle; however, it remains unclear whether length dependence of tension differs between striated muscle cell types during submaximal activations. The purpose of this study was to compare sarcomere length-tension relationships and the sarcomere length dependence of force development between rat skinned left ventricular cardiac myocytes and fast-twitch and slow-twitch skeletal muscle fibres. Muscle cell preparations were calcium activated to yield 50% maximal force, after which isometric force and rate constants (k(tr)) of force development were measured over a range of sarcomere lengths. Myofilament length-tension relationships were considerably steeper in fast-twitch fibres compared to slow-twitch fibres. Interestingly, cardiac myocyte preparations exhibited two populations of length-tension relationships, one steeper than fast-twitch fibres and the other similar to slow-twitch fibres. Moreover, myocytes with shallow length-tension relationships were converted to steeper length-tension relationships by protein kinase A (PKA)-induced myofilament phosphorylation. Sarcomere length-k(tr) relationships were distinct between all three cell types and exhibited patterns markedly different from Ca(2+) activation-dependent k(tr) relationships. Overall, these findings indicate cardiac myocytes exhibit varied length-tension relationships and sarcomere length appears a dominant modulator of force development rates. Importantly, cardiac myocyte length

The Tropomyosin Binding Region of Cardiac Troponin T Modulates Crossbridge Recruitment Dynamics in Rat Cardiac Muscle Fibers

PubMed Central

Gollapudi, Sampath K.; Gallon, Clare E.; Chandra, Murali

2013-01-01

The cardiac muscle comprises dynamically interacting components that use allosteric/cooperative mechanisms to yield unique heart-specific properties. An essential protein in this allosteric/cooperative mechanism is cardiac muscle troponin T (cTnT), the central region (CR) and the T2 region of which differ significantly from those of fast skeletal muscle troponin T (fsTnT). To understand the biological significance of such sequence heterogeneity, we replaced the T1 or T2 domain of rat cTnT (RcT1 or RcT2) with its counterpart from rat fsTnT (RfsT1or RfsT2) to generate RfsT1-RcT2 and RcT1-RfsT2 recombinant proteins. In addition to contractile function measurements, dynamic features of RfsT1-RcT2 and RcT1-RfsT2 reconstituted rat cardiac muscle fibers were captured by fitting the recruitment-distortion model to force response of small amplitude (0.5%) muscle length changes. RfsT1-RcT2 fibers showed a ~40% decrease in tension and ~44% decrease in ATPase activity, but RcT1-RfsT2 fibers were unaffected. The magnitude of length-mediated increase in crossbridge recruitment (E0) decreased by ~33% and the speed of crossbridge recruitment (b) increased by ~100% in RfsT1-RcT2 fibers. Our data suggest the following: (1) the CR of cTnT modulates crossbridge recruitment dynamics; (2) the N-terminal end region of cTnT has a synergistic effect on the ability of CR to modulate crossbridge recruitment dynamics; (3) the T2 region is important for tuning the Ca2+ regulation of cardiac thin filaments. The combined effects of CR-Tm interactions and the modulating effect of the N-terminal end of cTnT on CR-Tm interactions may lead to the emergence of a unique property that tunes contractile dynamics to heart rates. PMID:23357173

Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis.

PubMed

Harel, Itamar; Maezawa, Yoshiro; Avraham, Roi; Rinon, Ariel; Ma, Hsiao-Yen; Cross, Joe W; Leviatan, Noam; Hegesh, Julius; Roy, Achira; Jacob-Hirsch, Jasmine; Rechavi, Gideon; Carvajal, Jaime; Tole, Shubha; Kioussi, Chrissa; Quaggin, Susan; Tzahor, Eldad

2012-11-13

The search for developmental mechanisms driving vertebrate organogenesis has paved the way toward a deeper understanding of birth defects. During embryogenesis, parts of the heart and craniofacial muscles arise from pharyngeal mesoderm (PM) progenitors. Here, we reveal a hierarchical regulatory network of a set of transcription factors expressed in the PM that initiates heart and craniofacial organogenesis. Genetic perturbation of this network in mice resulted in heart and craniofacial muscle defects, revealing robust cross-regulation between its members. We identified Lhx2 as a previously undescribed player during cardiac and pharyngeal muscle development. Lhx2 and Tcf21 genetically interact with Tbx1, the major determinant in the etiology of DiGeorge/velo-cardio-facial/22q11.2 deletion syndrome. Furthermore, knockout of these genes in the mouse recapitulates specific cardiac features of this syndrome. We suggest that PM-derived cardiogenesis and myogenesis are network properties rather than properties specific to individual PM members. These findings shed new light on the developmental underpinnings of congenital defects.

SYNTHETIC STRANDS OF CARDIAC MUSCLE

PubMed Central

Purdy, Joyce E.; Lieberman, Melvyn; Roggeveen, Anne E.; Kirk, R. Gary

1972-01-01

Spontaneously active bundles of cardiac muscle (synthetic strands) were prepared from isolated cells of 11–13-day old embryonic chick hearts which were disaggregated with trypsin. Linear orientation of the cells was obtained by plating them on agar-coated culture dishes in which either grooves were cut in the agar film or a thin line of palladium was deposited over the agar. The influence of cell-to-cell and cell-to-substrate interactions was observed with time lapse cinematography and the formation of the synthetic strand was shown to involve both random and guided cell movements, enlargement of aggregates by accretion and coalescence, and the compact linear arrangement of cells along paths of preferential adhesion. Electron microscope investigations of these strands showed that a dispersed population of heart cells organized into an inner core of muscle cells and an outer sheath of fibroblast-like cells. The muscle cells contained well-developed, but widely spaced myofibrils, a developing sarcoplasmic reticulum associated in part with the myofibrils and in part with the sarcolemma, an abundance of nonmembrane bound ribosomes and glycogen, and a prominent Golgi complex. Numerous specialized contacts were observed between the muscle cells in the strand, e.g., fasciae adherentes, desmosomes, and nexuses. A distinct type of muscle cell characterized by its pale appearance was regularly observed in the strand and was noted to be similar to Purkinje cells described in the adult avian conduction system and in developing chick myocardium. The present findings were compared with other observations of the developing myocardium, in situ, and it was concluded that, by a number or criteria, the muscle cells of the strand were differentiating normally and suitably organized for electrophysiological studies. PMID:4656702

Decreased hydrogen peroxide production and mitochondrial respiration in skeletal muscle but not cardiac muscle of the green-striped burrowing frog, a natural model of muscle disuse.

PubMed

Reilly, Beau D; Hickey, Anthony J R; Cramp, Rebecca L; Franklin, Craig E

2014-04-01

Suppression of disuse-induced muscle atrophy has been associated with altered mitochondrial reactive oxygen species (ROS) production in mammals. However, despite extended hindlimb immobility, aestivating animals exhibit little skeletal muscle atrophy compared with artificially immobilised mammalian models. Therefore, we studied mitochondrial respiration and ROS (H2O2) production in permeabilised muscle fibres of the green-striped burrowing frog, Cyclorana alboguttata. Mitochondrial respiration within saponin-permeabilised skeletal and cardiac muscle fibres was measured concurrently with ROS production using high-resolution respirometry coupled to custom-made fluorometers. After 4 months of aestivation, C. alboguttata had significantly depressed whole-body metabolism by ~70% relative to control (active) frogs, and mitochondrial respiration in saponin-permeabilised skeletal muscle fibres decreased by almost 50% both in the absence of ADP and during oxidative phosphorylation. Mitochondrial ROS production showed up to an 88% depression in aestivating skeletal muscle when malate, succinate and pyruvate were present at concentrations likely to reflect those in vivo. The percentage ROS released per O2 molecule consumed was also ~94% less at these concentrations, indicating an intrinsic difference in ROS production capacities during aestivation. We also examined mitochondrial respiration and ROS production in permeabilised cardiac muscle fibres and found that aestivating frogs maintained respiratory flux and ROS production at control levels. These results show that aestivating C. alboguttata has the capacity to independently regulate mitochondrial function in skeletal and cardiac muscles. Furthermore, this work indicates that ROS production can be suppressed in the disused skeletal muscle of aestivating frogs, which may in turn protect against potential oxidative damage and preserve skeletal muscle structure during aestivation and following arousal.

Cardiac arrest due to lymphocytic colitis: a case report

PubMed Central

2012-01-01

Introduction We present a case of cardiac arrest due to hypokalemia caused by lymphocytic colitis. Case presentation A 69-year-old Caucasian man presented four months prior to a cardiac arrest with watery diarrhea and was diagnosed with lymphocytic colitis. Our patient experienced a witnessed cardiac arrest at his general practitioner's surgery. Two physicians and the emergency medical services resuscitated our patient for one hour and four minutes before arriving at our university hospital. Our patient was defibrillated 16 times due to the recurrence of ventricular tachyarrhythmias. An arterial blood sample revealed a potassium level of 2.0 mmol/L (reference range: 3.5 to 4.6 mmol/L) and pH 6.86 (reference range: pH 7.37 to 7.45). As the potassium level was corrected, the propensity for ventricular tachyarrhythmias ceased. Our patient recovered from his cardiac arrest without any neurological deficit. Further tests and examinations revealed no other reason for the cardiac arrest. Conclusion Diarrhea can cause life-threatening situations due to the excretion of potassium, ultimately causing cardiac arrest due to hypokalemia. Physicians treating patients with severe diarrhea should consider monitoring their electrolyte levels. PMID:22405093

Wnt signaling balances specification of the cardiac and pharyngeal muscle fields

PubMed Central

Mandal, Amrita; Holowiecki, Andrew; Song, Yuntao Charlie; Waxman, Joshua S.

2017-01-01

Canonical Wnt/β-catenin (Wnt) signaling plays multiple conserved roles during fate specification of cardiac progenitors in developing vertebrate embryos. Although lineage analysis in ascidians and mice has indicated there is a close relationship between the cardiac second heart field (SHF) and pharyngeal muscle (PM) progenitors, the signals underlying directional fate decisions of the cells within the cardio-pharyngeal muscle field in vertebrates are not yet understood. Here, we examined the temporal requirements of Wnt signaling in cardiac and PM development. In contrast to a previous report in chicken embryos that suggested Wnt inhibits PM development during somitogenesis, we find that in zebrafish embryos Wnt signaling is sufficient to repress PM development during anterior-posterior patterning. Importantly, the temporal sensitivity of dorso-anterior PMs to increased Wnt signaling largely overlaps with when Wnt signaling promotes specification of the adjacent cardiac progenitors. Furthermore, we find that excess early Wnt signaling can cell autonomously promote expansion of the first heart field (FHF) progenitors at the expense of PM and SHF within the anterior lateral plate mesoderm (ALPM). Our study provides insight into an antagonistic developmental mechanism that balances the sizes of the adjacent cardiac and PM progenitor fields in early vertebrate embryos. PMID:28087459

Smooth muscle myosin light chain kinase efficiently phosphorylates serine 15 of cardiac myosin regulatory light chain

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

Josephson, Matthew P.; Sikkink, Laura A.; Penheiter, Alan R.

2011-12-16

Highlights: Black-Right-Pointing-Pointer Cardiac myosin regulatory light chain (MYL2) is phosphorylated at S15. Black-Right-Pointing-Pointer Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase. Black-Right-Pointing-Pointer It is a widely believed that MYL2 is a poor substrate for smMLCK. Black-Right-Pointing-Pointer In fact, smMLCK efficiently and rapidly phosphorylates S15 in MYL2. Black-Right-Pointing-Pointer Phosphorylation kinetics measured by novel fluorescence method without radioactivity. -- Abstract: Specific phosphorylation of the human ventricular cardiac myosin regulatory light chain (MYL2) modifies the protein at S15. This modification affects MYL2 secondary structure and modulates the Ca{sup 2+} sensitivity of contraction in cardiac tissue. Smooth muscle myosin light chainmore » kinase (smMLCK) is a ubiquitous kinase prevalent in uterus and present in other contracting tissues including cardiac muscle. The recombinant 130 kDa (short) smMLCK phosphorylated S15 in MYL2 in vitro. Specific modification of S15 was verified using the direct detection of the phospho group on S15 with mass spectrometry. SmMLCK also specifically phosphorylated myosin regulatory light chain S15 in porcine ventricular myosin and chicken gizzard smooth muscle myosin (S20 in smooth muscle) but failed to phosphorylate the myosin regulatory light chain in rabbit skeletal myosin. Phosphorylation kinetics, measured using a novel fluorescence method eliminating the use of radioactive isotopes, indicates similar Michaelis-Menten V{sub max} and K{sub M} for regulatory light chain S15 phosphorylation rates in MYL2, porcine ventricular myosin, and chicken gizzard myosin. These data demonstrate that smMLCK is a specific and efficient kinase for the in vitro phosphorylation of MYL2, cardiac, and smooth muscle myosin. Whether smMLCK plays a role in cardiac muscle regulation or response to a disease causing stimulus is unclear but it should be considered a potentially

Changes in the cardiac muscle electric activity as a result of Coronary Artery Bypass Graft operation

NASA Astrophysics Data System (ADS)

Grajek, Magdalena; Krzyminiewski, Ryszard; Kalawski, Ryszard; Kulczak, Mariusz

2008-01-01

Many bioelectric signals have a complex internal structure that can be a rich source of information on the tissue or cell processes. The structure of such signals can be analysed in detail by applying digital methods of signal processing. Therefore, of substantial use in diagnosis of the coronary arterial disease is the method of digital enhancement of increasing signal resolution ECG (NURSE-ECG), permitting detection of temporary changes in the electric potentials in the cardiac muscle in the process of depolarisation. Thanks to the application of NURSE-ECG it has become possible to detect relatively small changes in the electric activity of particular fragments of the cardiac muscle undetectable by the standard ECG method, caused by ischemia, the effect of a drug or infarct. The aim of this study was to identify and analyse changes in the electric activity of the cardiac muscle as a result of the Coronary Artery Bypass Graft (CABG) operation. In this study the method of NURSE-ECG has been applied in order to identify and analyse changes in the electric activity of the cardiac muscle as a result of the CABG operation. In the study performed in cooperation of the Institute of Physics Adam Mickiewicz University and the Strus Hospital, Cardiac Surgery Ward, 37 patients with advanced coronary arterial disease were asked to participate. The patients were examined prior to the operation, on the day after the operation and two months after the operation and a year after the operation. The ECG recordings were subjected to a numerical procedure of resolution enhancement by a NURSE-ECG program to reveal the tentative changes in the electric potential of the cardiac muscle on its depolarisation. Results of the study have shown that the NURSE ECG method can be applied to monitor changes in the electric activity of the cardiac muscle occurring as a result of CABG operation. One the second day after the operation in the majority of patients (70%) a rapid decrease of the total

Regulation of the Cardiac Muscle Ryanodine Receptor by O2 Tension and S-Nitrosoglutathione†

PubMed Central

Sun, Junhui; Yamaguchi, Naohiro; Xu, Le; Eu, Jerry P.; Stamler, Jonathan S.; Meissner, Gerhard

2009-01-01

The cardiac and skeletal muscle sarcoplasmic reticulum ryanodine receptor Ca2+ release channels contain thiols that are potential targets of endogenously produced reactive oxygen and nitrogen intermediates. Previously, we showed that the skeletal muscle ryanodine receptor (RyR1) has O2-sensitive thiols; only when these thiols are in the reduced state (pO2 ~ 10 mmHg) can physiological concentrations of NO (nanomolar) activate RyR1. Here, we report that cardiac muscle ryanodine receptor (RyR2) activity also depends on pO2, but unlike RyR1, RyR2 was not activated or S-nitrosylated directly by NO. Rather, activation and S-nitrosylation of RyR2 required S-nitrosoglutathione. The effects of peroxynitrite were indiscriminate on RyR1 and RyR2. Our results indicate that both RyR1 and RyR2 are pO2-responsive yet point to different mechanisms by which NO and S-nitrosoglutathione influence cardiac and skeletal muscle sarcoplasmic reticulum Ca2+ release. PMID:19053230

Autophagy is altered in skeletal and cardiac muscle of spontaneously hypertensive rats.

PubMed

Bloemberg, D; McDonald, E; Dulay, D; Quadrilatero, J

2014-02-01

Autophagy is a subcellular degradation mechanism important for muscle maintenance. Hypertension induces well-characterized pathological changes to the heart and is associated with impaired function and increased apoptotic signalling in skeletal muscle. We examined whether essential hypertension affects several autophagy markers in skeletal and cardiac muscle. Immunoblotting and qRT-PCR were used to measure autophagy-related proteins/mRNA in multiple skeletal muscles as well as left ventricle (LV) of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Skeletal muscles of hypertensive rats had decreased (P < 0.01) cross-sectional area of type I fibres (e.g. soleus WKY: 2952.9 ± 64.4 μm(2) vs. SHR: 2579.9 ± 85.8 μm(2)) and a fibre redistribution towards a 'fast' phenotype. Immunoblot analysis revealed that some SHR skeletal muscles displayed a decreased LC3II/I ratio (P < 0.05), but none showed differences in p62 protein. LC3 and LAMP2 mRNA levels were increased approx. 2-3-fold in all skeletal muscles (P < 0.05), while cathepsin activity, cathepsin L mRNA and Atg7 protein were increased 16-17% (P < 0.01), 2-3-fold (P < 0.05) and 29-49% (P < 0.01), respectively, in fast muscles of hypertensive animals. Finally, protein levels of BAG3, a marker of chaperone-assisted selective autophagy, were 18-25% lower (P < 0.05) in SHR skeletal muscles. In the LV of SHR, LC3I and p62 protein were elevated 34% (P < 0.05) and 47% (P < 0.01), respectively. Furthermore, p62 mRNA was 68% higher (P < 0.05), while LAMP2 mRNA was 45% lower (P < 0.05), in SHR cardiac muscle. There was no difference in Beclin1, Atg7, Bnip3 or BAG3 protein in the LV between strains. These results suggest that autophagy is altered in skeletal and cardiac muscle during hypertension. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Cardiac troponin T and fast skeletal muscle denervation in ageing.

PubMed

Xu, Zherong; Feng, Xin; Dong, Juan; Wang, Zhong-Min; Lee, Jingyun; Furdui, Cristina; Files, Daniel Clark; Beavers, Kristen M; Kritchevsky, Stephen; Milligan, Carolanne; Jin, Jian-Ping; Delbono, Osvaldo; Zhang, Tan

2017-10-01

Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle-specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown. Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real-time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ. Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region-but mainly in the fast-twitch, not the slow-twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ-again, preferentially in fast-twitch but not slow-twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii

Transplanted hematopoietic stem cells demonstrate impaired sarcoglycan expression after engraftment into cardiac and skeletal muscle.

PubMed

Lapidos, Karen A; Chen, Yiyin E; Earley, Judy U; Heydemann, Ahlke; Huber, Jill M; Chien, Marcia; Ma, Averil; McNally, Elizabeth M

2004-12-01

Pluripotent bone marrow-derived side population (BM-SP) stem cells have been shown to repopulate the hematopoietic system and to contribute to skeletal and cardiac muscle regeneration after transplantation. We tested BM-SP cells for their ability to regenerate heart and skeletal muscle using a model of cardiomyopathy and muscular dystrophy that lacks delta-sarcoglycan. The absence of delta-sarcoglycan produces microinfarcts in heart and skeletal muscle that should recruit regenerative stem cells. Additionally, sarcoglycan expression after transplantation should mark successful stem cell maturation into cardiac and skeletal muscle lineages. BM-SP cells from normal male mice were transplanted into female delta-sarcoglycan-null mice. We detected engraftment of donor-derived stem cells into skeletal muscle, with the majority of donor-derived cells incorporated within myofibers. In the heart, donor-derived nuclei were detected inside cardiomyocytes. Skeletal muscle myofibers containing donor-derived nuclei generally failed to express sarcoglycan, with only 2 sarcoglycan-positive fibers detected in the quadriceps muscle from all 14 mice analyzed. Moreover, all cardiomyocytes with donor-derived nuclei were sarcoglycan-negative. The absence of sarcoglycan expression in cardiomyocytes and skeletal myofibers after transplantation indicates impaired differentiation and/or maturation of bone marrow-derived stem cells. The inability of BM-SP cells to express this protein severely limits their utility for cardiac and skeletal muscle regeneration.

Cardiac troponin T and fast skeletal muscle denervation in ageing

PubMed Central

Xu, Zherong; Feng, Xin; Dong, Juan; Wang, Zhong‐Min; Lee, Jingyun; Furdui, Cristina; Files, Daniel Clark; Beavers, Kristen M.; Kritchevsky, Stephen; Milligan, Carolanne; Jin, Jian‐Ping; Delbono, Osvaldo

2017-01-01

Abstract Background Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast‐twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow‐twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre‐type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle‐specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown. Methods Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real‐time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ. Results Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region—but mainly in the fast‐twitch, not the slow‐twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ—again, preferentially in fast‐twitch but not slow‐twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i

Design and testing of regulatory cassettes for optimal activity in skeletal and cardiac muscles.

PubMed

Himeda, Charis L; Chen, Xiaolan; Hauschka, Stephen D

2011-01-01

Gene therapy for muscular dystrophies requires efficient gene delivery to the striated musculature and specific, high-level expression of the therapeutic gene in a physiologically diverse array of muscles. This can be achieved by the use of recombinant adeno-associated virus vectors in conjunction with muscle-specific regulatory cassettes. We have constructed several generations of regulatory cassettes based on the enhancer and promoter of the muscle creatine kinase gene, some of which include heterologous enhancers and individual elements from other muscle genes. Since the relative importance of many control elements varies among different anatomical muscles, we are aiming to tailor these cassettes for high-level expression in cardiac muscle, and in fast and slow skeletal muscles. With the achievement of efficient intravascular gene delivery to isolated limbs, selected muscle groups, and heart in large animal models, the design of cassettes optimized for activity in different muscle types is now a practical goal. In this protocol, we outline the key steps involved in the design of regulatory cassettes for optimal activity in skeletal and cardiac muscle, and testing in mature muscle fiber cultures. The basic principles described here can also be applied to engineering tissue-specific regulatory cassettes for other cell types.

Force development and intracellular Ca2+ in intact cardiac muscles from gravin mutant mice.

PubMed

Li, Zhitao; Singh, Sonal; Suryavanshi, Santosh V; Ding, Wengang; Shen, Xiaoxu; Wijaya, Cori S; Gao, Wei Dong; McConnell, Bradley K

2017-07-15

Gravin (AKAP12) is an A-kinase-anchoring-protein that scaffolds protein kinase A (PKA), β 2 -adrenergic receptor (β 2 -AR), protein phosphatase 2B and protein kinase C. Gravin facilitates β 2 -AR-dependent signal transduction through PKA to modulate cardiac excitation-contraction coupling and its removal positively affects cardiac contraction. Trabeculae from the right ventricles of gravin mutant (gravin-t/t) mice were employed for force determination. Simultaneously, corresponding intracellular Ca 2+ transient ([Ca 2+ ] i ) were measured. Twitch force (T f )-interval relationship, [Ca 2+ ] i -interval relationship, and the rate of decay of post-extrasysolic potentiation (R f ) were also obtained. Western blot analysis were performed to correlate sarcomeric protein expression with alterations in calcium cycling between the WT and gravin-t/t hearts. Gravin-t/t muscles had similar developed force compared to WT muscles despite having lower [Ca 2+ ] i at any given external Ca 2+ concentration ([Ca 2+ ] o ). The time to peak force and peak [Ca 2+ ] i were slower and the time to 75% relaxation was significantly prolonged in gravin-t/t muscles. Both T f -interval and [Ca 2+ ] i -interval relations were depressed in gravin-t/t muscles. R f , however, did not change. Furthermore, Western blot analysis revealed decreased ryanodine receptor (RyR2) phosphorylation in gravin-t/t hearts. Gravin-t/t cardiac muscle exhibits increased force development in responsiveness to Ca 2+ . The Ca 2+ cycling across the SR appears to be unaltered in gravin-t/t muscle. Our study suggests that gravin is an important component of cardiac contraction regulation via increasing myofilament sensitivity to calcium. Further elucidation of the mechanism can provide insights to role of gravin if any in the pathophysiology of impaired contractility. Copyright © 2017 Elsevier B.V. All rights reserved.

Functional Effects of Hyperthyroidism on Cardiac Papillary Muscle in Rats.

PubMed

Vieira, Fabricio Furtado; Olivoto, Robson Ruiz; Silva, Priscyla Oliveira da; Francisco, Julio Cesar; Fogaça, Rosalvo Tadeu Hochmuller

2016-12-01

Hyperthyroidism is currently recognized to affect the cardiovascular system, leading to a series of molecular and functional changes. However, little is known about the functional influence of hyperthyroidism in the regulation of cytoplasmic calcium and on the sodium/calcium exchanger (NCX) in the cardiac muscle. To evaluate the functional changes in papillary muscles isolated from animals with induced hyperthyroidism. We divided 36 Wistar rats into a group of controls and another of animals with hyperthyroidism induced by intraperitoneal T3 injection. We measured in the animals' papillary muscles the maximum contraction force, speed of contraction (+df/dt) and relaxation (-df/dt), contraction and relaxation time, contraction force at different concentrations of extracellular sodium, post-rest potentiation (PRP), and contraction force induced by caffeine. In hyperthyroid animals, we observed decreased PRP at all rest times (p < 0.05), increased +df/dt and -df/dt (p < 0.001), low positive inotropic response to decreased concentration of extracellular sodium (p < 0.001), reduction of the maximum force in caffeine-induced contraction (p < 0.003), and decreased total contraction time (p < 0.001). The maximal contraction force did not differ significantly between groups (p = 0.973). We hypothesize that the changes observed are likely due to a decrease in calcium content in the sarcoplasmic reticulum, caused by calcium leakage, decreased expression of NCX, and increased expression of a-MHC and SERCA2.

Changes in skeletal and cardiac muscle enzymes during the Scottish Coast to Coast Triathlon.

PubMed

Denvir, M A; Galloway, P J; Meighan, A S; Blyth, M; Alexander, C; Fleming, C; Frame, F

1999-04-01

While skeletal muscle injury is common after prolonged exercise, evidence in the literature supporting cardiac muscle injury is conflicting. Creatine kinase and cardiac troponin-I were measured, in 31 amateur athletes (25 male) before, and 12-24 hours after, a 300 km cycling/running/canoe triathlon event. A short questionnaire was used to assess level of fitness, training and previous experience. Creatine kinase levels were greater after the 45 km cross-country run compared with after a 155 km road cycle (60.5 +/- 62.8 iu/L/kg vs 19.3 +/- 9.6 iu/kg, P = 0.03). Individuals performing running and cycling events consecutively had creatine kinase similar to those observed after running alone (50.2 +/- 53.8 iu/L/kg vs 60.5 +/- 62.8 iu/L/kg, P = 0.55). Cardiac troponin-I was elevated above the normal range (0.1 ng/L) in six athletes (four in running and cycling events, one in the running and one in the cycling event). We conclude that running produces significantly more skeletal muscle injury than cycling and that strenuous endurance exercise involving running and cycling in amateur trained athletes is associated with release of cardiac specific enzymes. The functional and longer term consequences of this require further study.

Myofibril ATPase activity of cardiac and skeletal muscle of exhaustively exercised rats.

PubMed

Belcastro, A N; Turcotte, R; Rossiter, M; Secord, D; Maybank, P E

1984-01-01

The activation characteristics of Mg-ATP and Ca2+ on cardiac and skeletal muscle myofibril ATPase activity were studied in rats following a run to exhaustion. In addition, the effect of varying ionic strength was determined on skeletal muscle from exhausted animals. The exhausted group (E) ran at a speed of 25 m min-1 with an 8% incline. Myofibril ATPase activities for control (C) and E were determined with 1, 3 and 5 mM Mg-ATP and 1 and 10 microM Ca2+ at pH 7.0 and 30 degrees C. For control skeletal muscle, at 1 and 10 microM Ca2+, there was an increase in ATPase activity from 1 to 5 mM Mg-ATP (P less than 0.05). For E animals the myofibril ATPase activities at 10 microM Ca2+ and all Mg-ATP concentrations were similar to C (P greater than 0.05). At 1.0 microM Ca2+ and all Mg-ATP concentrations were similar to C (P greater than 0.05). At 1.0 microM Ca2+ the activities at 3 and 5 mM Mg-ATP were greater for the E animals (P less than 0.05). Increasing KCl concentrations resulted in greater inhibition for E animals. With cardiac muscle, the myofibril ATPase activities at 1.0 microM free Ca2+ were lower for E at all Mg-ATP levels (P less than 0.05). In contrast, at 10 microM Ca2+, the E group exhibited an elevated myofibril ATPase activity. The results indicate that Mg-ATP and Ca2+ activation of cardiac and skeletal muscle myofibril ATPase is altered with exhaustive exercise.

Single-unit muscle sympathetic nervous activity and its relation to cardiac noradrenaline spillover

PubMed Central

Lambert, Elisabeth A; Schlaich, Markus P; Dawood, Tye; Sari, Carolina; Chopra, Reena; Barton, David A; Kaye, David M; Elam, Mikael; Esler, Murray D; Lambert, Gavin W

2011-01-01

Abstract Recent work using single-unit sympathetic nerve recording techniques has demonstrated aberrations in the firing pattern of sympathetic nerves in a variety of patient groups. We sought to examine whether nerve firing pattern is associated with increased noradrenaline release. Using single-unit muscle sympathetic nerve recording techniques coupled with direct cardiac catheterisation and noradrenaline isotope dilution methodology we examined the relationship between single-unit firing patterns and cardiac and whole body noradrenaline spillover to plasma. Participants comprised patients with hypertension (n = 6), depression (n = 7) and panic disorder (n = 9) who were drawn from our ongoing studies. The patient groups examined did not differ in their single-unit muscle sympathetic nerve firing characteristics nor in the rate of spillover of noradrenaline to plasma from the heart. The median incidence of multiple spikes per beat was 9%. Patients were stratified according to the firing pattern: low level of incidence (less than 9% incidence of multiple spikes per beat) and high level of incidence (greater than 9% incidence of multiple spikes per beat). High incidence of multiple spikes within a cardiac cycle was associated with higher firing rates (P < 0.0001) and increased probability of firing (P < 0.0001). Whole body noradrenaline spillover to plasma and (multi-unit) muscle sympathetic nerve activity in subjects with low incidence of multiple spikes was not different to that of those with high incidence of multiple spikes. In those with high incidence of multiple spikes there occurred a parallel activation of the sympathetic outflow to the heart, with cardiac noradrenaline spillover to plasma being two times that of subjects with low nerve firing rates (11.0 ± 1.5 vs. 22.0 ± 4.5 ng min−1, P < 0.05). This study indicates that multiple within-burst firing and increased single-unit firing rates of the sympathetic outflow to the skeletal muscle vasculature is

Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle respiration in adult offspring.

PubMed

Beauchamp, Brittany; Thrush, A Brianne; Quizi, Jessica; Antoun, Ghadi; McIntosh, Nathan; Al-Dirbashi, Osama Y; Patti, Mary-Elizabeth; Harper, Mary-Ellen

2015-04-10

Intrauterine growth restriction (IUGR) is associated with an increased risk of developing obesity, insulin resistance and cardiovascular disease. However, its effect on energetics in heart remains unknown. In the present study, we examined respiration in cardiac muscle and liver from adult mice that were undernourished in utero. We report that in utero undernutrition is associated with impaired cardiac muscle energetics, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate and decreased proton leak respiration. No differences in oxidative characteristics were detected in liver. We also measured plasma acylcarnitine levels and found that short-chain acylcarnitines are increased with in utero undernutrition. Results reveal the negative impact of suboptimal maternal nutrition on adult offspring cardiac energy metabolism, which may have life-long implications for cardiovascular function and disease risk. © 2015 Authors.

Margaret Buckingham, discoveries in skeletal and cardiac muscle development, elected to the National Academy of Science.

PubMed

Rudnicki, Michael A

2012-06-07

Margaret Buckingham was presented as a newly elected member to the National Academy of Sciences on 28 April 2012. Over the course of her career, Dr Buckingham made many seminal contributions to the understanding of skeletal muscle and cardiac development. Her studies on cardiac progenitor populations has provided insight into understanding heart malformations, while her work on skeletal muscle progenitors has elucidated their embryonic origins and the transcriptional hierarchies controlling their developmental progression.

Respiratory muscle strength in relation to sarcopenia in elderly cardiac patients.

PubMed

Izawa, Kazuhiro P; Watanabe, Satoshi; Oka, Koichiro; Kasahara, Yusuke; Morio, Yuji; Hiraki, Koji; Hirano, Yasuyuki; Omori, Yutaka; Suzuki, Norio; Kida, Keisuke; Suzuki, Kengo; Akashi, Yoshihiro J

2016-12-01

Little information exists on the relation between respiratory muscle strength such as maximum inspiratory muscle pressure (MIP) and sarcopenia in elderly cardiac patients. The present study aimed to determine the differences in MIP, and cutoff values for MIP according to sarcopenia in elderly cardiac patients. We enrolled 63 consecutive elderly male patients aged ≥65 years with cardiac disease in this cross-sectional study. Sarcopenia was defined based on the European Working Group on Sarcopenia in Older People algorithm, and, accordingly, the patients were divided into two groups: the sarcopenia group (n = 24) and non-sarcopenia group (n = 39). The prevalence of sarcopenia in cardiac patients and MIP in the patients with and without sarcopenia were assessed to determine cutoff values of MIP. After adjustment for body mass index, the MIP in the sarcopenia group was significantly lower than that in the non-sarcopenia group (54.7 ± 36.8 cmH 2 O; 95 % CI 42.5-72.6 vs. 80.7 ± 34.7 cmH 2 O; 95 % CI 69.5-92.0; F = 4.89, p = 0.029). A receiver-operating characteristic curve analysis of patients with and without sarcopenia identified a cutoff value for MIP of 55.6 cmH 2 O, with a sensitivity of 0.76, 1-specificity of 0.37, and AUC of 0.70 (95 % CI 0.56-0.83; p = 0.01) in the study patients. Compared with elderly cardiac patients without sarcopenia, MIP in those with sarcopenia may be negatively affected. The MIP cutoff value reported here may be a useful minimum target value for identifying elderly male cardiac patients with sarcopenia.

[The expressions of HSP 70 mRNA and c-fos mRNA in the skeletal muscle and cardiac muscle of rabbits by electrocuted].

PubMed

Wang, Ye; Liu, Min; Cheng, Wei-bo; He, Gui-qiong; Li, Fan; Liao, Zhi-gang

2008-08-01

To study the changes of HSP 70 mRNA and c-fos mRNA expression and to find a method to differentiate antemortem from postmortem electrocution. Fifteen New Zealand rabbits were randomly divided into three groups, the antemortem electrocution group, the postmortem electrocution group, and the control group. Each group consists of five rabbits. The levels of HSP 70 mRNA and c-fos mRNA in skeletal muscle and cardiac muscle were examined with quantitative fluorescent RT-PCR. The levels of HSP 70 mRNA and c-fos mRNA in the antemortem electrocution group increased significantly (P<0.05), compared with that of the postmortem electrocution group. The changes of HSP 70 mRNA and c-fos mRNA expression in skeletal muscle and cardiac muscle can be used as an indicator to distinguish antemortem from postmortem electrocution.

Regular physical exercise improves cardiac autonomic and muscle vasodilatory responses to isometric exercise in healthy elderly.

PubMed

Sarmento, Adriana de Oliveira; Santos, Amilton da Cruz; Trombetta, Ivani Credidio; Dantas, Marciano Moacir; Oliveira Marques, Ana Cristina; do Nascimento, Leone Severino; Barbosa, Bruno Teixeira; Dos Santos, Marcelo Rodrigues; Andrade, Maria do Amparo; Jaguaribe-Lima, Anna Myrna; Brasileiro-Santos, Maria do Socorro

2017-01-01

The objective of this study was to evaluate cardiac autonomic control and muscle vasodilation response during isometric exercise in sedentary and physically active older adults. Twenty healthy participants, 10 sedentary and 10 physically active older adults, were evaluated and paired by gender, age, and body mass index. Sympathetic and parasympathetic cardiac activity (spectral and symbolic heart rate analysis) and muscle blood flow (venous occlusion plethysmography) were measured for 10 minutes at rest (baseline) and during 3 minutes of isometric handgrip exercise at 30% of the maximum voluntary contraction (sympathetic excitatory maneuver). Variables were analyzed at baseline and during 3 minutes of isometric exercise. Cardiac autonomic parameters were analyzed by Wilcoxon and Mann-Whitney tests. Muscle vasodilatory response was analyzed by repeated-measures analysis of variance followed by Tukey's post hoc test. Sedentary older adults had higher cardiac sympathetic activity compared to physically active older adult subjects at baseline (63.13±3.31 vs 50.45±3.55 nu, P =0.02). The variance (heart rate variability index) was increased in active older adults (1,438.64±448.90 vs 1,402.92±385.14 ms, P =0.02), and cardiac sympathetic activity (symbolic analysis) was increased in sedentary older adults (5,660.91±1,626.72 vs 4,381.35±1,852.87, P =0.03) during isometric handgrip exercise. Sedentary older adults showed higher cardiac sympathetic activity (spectral analysis) (71.29±4.40 vs 58.30±3.50 nu, P =0.03) and lower parasympathetic modulation (28.79±4.37 vs 41.77±3.47 nu, P =0.03) compared to physically active older adult subjects during isometric handgrip exercise. Regarding muscle vasodilation response, there was an increase in the skeletal muscle blood flow in the second (4.1±0.5 vs 3.7±0.4 mL/min per 100 mL, P =0.01) and third minute (4.4±0.4 vs 3.9±0.3 mL/min per 100 mL, P =0.03) of handgrip exercise in active older adults. The results indicate

Regular physical exercise improves cardiac autonomic and muscle vasodilatory responses to isometric exercise in healthy elderly

PubMed Central

Sarmento, Adriana de Oliveira; Santos, Amilton da Cruz; Trombetta, Ivani Credidio; Dantas, Marciano Moacir; Oliveira Marques, Ana Cristina; do Nascimento, Leone Severino; Barbosa, Bruno Teixeira; Dos Santos, Marcelo Rodrigues; Andrade, Maria do Amparo; Jaguaribe-Lima, Anna Myrna; Brasileiro-Santos, Maria do Socorro

2017-01-01

The objective of this study was to evaluate cardiac autonomic control and muscle vasodilation response during isometric exercise in sedentary and physically active older adults. Twenty healthy participants, 10 sedentary and 10 physically active older adults, were evaluated and paired by gender, age, and body mass index. Sympathetic and parasympathetic cardiac activity (spectral and symbolic heart rate analysis) and muscle blood flow (venous occlusion plethysmography) were measured for 10 minutes at rest (baseline) and during 3 minutes of isometric handgrip exercise at 30% of the maximum voluntary contraction (sympathetic excitatory maneuver). Variables were analyzed at baseline and during 3 minutes of isometric exercise. Cardiac autonomic parameters were analyzed by Wilcoxon and Mann–Whitney tests. Muscle vasodilatory response was analyzed by repeated-measures analysis of variance followed by Tukey’s post hoc test. Sedentary older adults had higher cardiac sympathetic activity compared to physically active older adult subjects at baseline (63.13±3.31 vs 50.45±3.55 nu, P=0.02). The variance (heart rate variability index) was increased in active older adults (1,438.64±448.90 vs 1,402.92±385.14 ms, P=0.02), and cardiac sympathetic activity (symbolic analysis) was increased in sedentary older adults (5,660.91±1,626.72 vs 4,381.35±1,852.87, P=0.03) during isometric handgrip exercise. Sedentary older adults showed higher cardiac sympathetic activity (spectral analysis) (71.29±4.40 vs 58.30±3.50 nu, P=0.03) and lower parasympathetic modulation (28.79±4.37 vs 41.77±3.47 nu, P=0.03) compared to physically active older adult subjects during isometric handgrip exercise. Regarding muscle vasodilation response, there was an increase in the skeletal muscle blood flow in the second (4.1±0.5 vs 3.7±0.4 mL/min per 100 mL, P=0.01) and third minute (4.4±0.4 vs 3.9±0.3 mL/min per 100 mL, P=0.03) of handgrip exercise in active older adults. The results indicate that

Cardiac cycle-synchronized electrical muscle stimulator for lower limb training with the potential to reduce the heart's pumping workload

PubMed Central

Matsuse, Hiroo; Akimoto, Ryuji; Kamiya, Shiro; Moritani, Toshio; Sasaki, Motoki; Ishizaki, Yuta; Ohtsuka, Masanori; Nakayoshi, Takaharu; Ueno, Takafumi; Shiba, Naoto; Fukumoto, Yoshihiro

2017-01-01

Background The lower limb muscle may play an important role in decreasing the heart’s pumping workload. Aging and inactivity cause atrophy and weakness of the muscle, leading to a loss of the heart-assisting role. An electrical lower limb muscle stimulator can prevent atrophy and weakness more effectively than conventional resistance training; however, it has been reported to increase the heart’s pumping workload in some situations. Therefore, more effective tools should be developed. Methods We newly developed a cardiac cycle-synchronized electrical lower limb muscle stimulator by combining a commercially available electrocardiogram monitor and belt electrode skeletal muscle electrical stimulator, making it possible to achieve strong and wide but not painful muscle contractions. Then, we tested the stimulator in 11 healthy volunteers to determine whether the special equipment enabled lower limb muscle training without harming the hemodynamics using plethysmography and a percutaneous cardiac output analyzer. Results In 9 of 11 subjects, the stimulator generated diastolic augmentation waves on the dicrotic notches and end-diastolic pressure reduction waves on the plethysmogram waveforms of the brachial artery, showing analogous waveforms in the intra-aortic balloon pumping heart-assisting therapy. The heart rate, stroke volume, and cardiac output significantly increased during the stimulation. There was no change in the systolic or diastolic blood pressure during the stimulation. Conclusion Cardiac cycle-synchronized electrical muscle stimulation for the lower limbs may enable muscle training without harmfully influencing the hemodynamics and with a potential to reduce the heart’s pumping workload, suggesting a promising tool for effectively treating both locomotor and cardiovascular disorders. PMID:29117189

Autonomic, functional, skeletal muscle, and cardiac abnormalities are associated with increased ergoreflex sensitivity in mitochondrial disease.

PubMed

Giannoni, Alberto; Aimo, Alberto; Mancuso, Michelangelo; Piepoli, Massimo Francesco; Orsucci, Daniele; Aquaro, Giovanni Donato; Barison, Andrea; De Marchi, Daniele; Taddei, Claudia; Cameli, Matteo; Raglianti, Valentina; Siciliano, Gabriele; Passino, Claudio; Emdin, Michele

2017-12-01

Mitochondrial disease (MD) is a genetic disorder affecting skeletal muscles, with possible myocardial disease. The ergoreflex, sensitive to skeletal muscle work, regulates ventilatory and autonomic responses to exercise. We hypothesized the presence of an increased ergoreflex sensitivity in MD patients, its association with abnormal ventilatory and autonomic responses, and possibly with subclinical cardiac involvement. Twenty-five MD patients (aged 46 ± 3 years, 32% male) with skeletal myopathy but without known cardiac disease, underwent a thorough evaluation including BNPs, galectin-3, soluble suppression of tumorigenesis 2 (sST2), high sensitivity troponin T/I, catecholamines, ECG, 24-h ECG recording, cardiopulmonary exercise testing, echocardiography, cardiac/muscle magnetic resonance (C/MMR), and ergoreflex assessment. Thirteen age- and sex-matched healthy controls were chosen. Among these myopathic patients, subclinical cardiac damage was detected in up to 80%, with 44% showing fibrosis at CMR. Ergoreflex sensitivity was markedly higher in patients than in controls (64% vs. 37%, P < 0.001), and correlated with muscle fat to water ratio and extracellular volume at MMR (both P < 0.05). Among patients, ergoreflex sensitivity was higher in those with cardiac involvement (P = 0.034). Patients showed a lower peak oxygen consumption (VO 2 /kg) than controls (P < 0.001), as well as ventilatory inefficiency (P = 0.024). Ergoreflex sensitivity correlated with reduced workload and peak VO 2 /kg (both P < 0.001), and several indicators of autonomic imbalance (P < 0.05). Plasma norepinephrine was the unique predictor of myocardial fibrosis at univariate analysis (P < 0.05). Skeletal myopathy in MD is characterized by enhanced ergoreflex sensitivity, which is associated with a higher incidence of cardiac involvement, exercise intolerance, and sympathetic activation. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

Relation between the Disability of the Arm, Shoulder and Hand Score and Muscle Strength in Post-Cardiac Surgery Patients.

PubMed

Izawa, Kazuhiro P; Kasahara, Yusuke; Hiraki, Koji; Hirano, Yasuyuki; Watanabe, Satoshi

2017-11-27

Background: The Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire is a valid and reliable patient-reported outcome measure. DASH can be assessed by self-reported upper extremity disability and symptoms. We aimed to examine the relationship between the physiological outcome of muscle strength and the DASH score after cardiac surgery. Methods: This cross-sectional study assessed 50 consecutive cardiac patients that were undergoing cardiac surgery. Physiological outcomes of handgrip strength and knee extensor muscle strength and the DASH score were measured at one month after cardiac surgery and were assessed. Results were analyzed using Spearman correlation coefficients. Results: The final analysis comprised 43 patients (men: 32, women: 11; age: 62.1 ± 9.1 years; body mass index: 22.1 ± 4.7 kg/m²; left ventricular ejection fraction: 53.5 ± 13.7%). Respective handgrip strength, knee extensor muscle strength, and DASH score were 27.4 ± 8.3 kgf, 1.6 ± 0.4 Nm/kg, and 13.3 ± 12.3, respectively. The DASH score correlated negatively with handgrip strength ( r = -0.38, p = 0.01) and with knee extensor muscle strength ( r = -0.32, p = 0.04). Conclusion: Physiological outcomes of both handgrip strength and knee extensor muscle strength correlated negatively with the DASH score. The DASH score appears to be a valuable tool with which to assess cardiac patients with poor physiological outcomes, particularly handgrip strength as a measure of upper extremity function, which is probably easier to follow over time than lower extremity function after patients complete cardiac rehabilitation.

Relation between the Disability of the Arm, Shoulder and Hand Score and Muscle Strength in Post-Cardiac Surgery Patients

PubMed Central

Kasahara, Yusuke; Hiraki, Koji; Hirano, Yasuyuki; Watanabe, Satoshi

2017-01-01

Background: The Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire is a valid and reliable patient-reported outcome measure. DASH can be assessed by self-reported upper extremity disability and symptoms. We aimed to examine the relationship between the physiological outcome of muscle strength and the DASH score after cardiac surgery. Methods: This cross-sectional study assessed 50 consecutive cardiac patients that were undergoing cardiac surgery. Physiological outcomes of handgrip strength and knee extensor muscle strength and the DASH score were measured at one month after cardiac surgery and were assessed. Results were analyzed using Spearman correlation coefficients. Results: The final analysis comprised 43 patients (men: 32, women: 11; age: 62.1 ± 9.1 years; body mass index: 22.1 ± 4.7 kg/m2; left ventricular ejection fraction: 53.5 ± 13.7%). Respective handgrip strength, knee extensor muscle strength, and DASH score were 27.4 ± 8.3 kgf, 1.6 ± 0.4 Nm/kg, and 13.3 ± 12.3, respectively. The DASH score correlated negatively with handgrip strength (r = −0.38, p = 0.01) and with knee extensor muscle strength (r = −0.32, p = 0.04). Conclusion: Physiological outcomes of both handgrip strength and knee extensor muscle strength correlated negatively with the DASH score. The DASH score appears to be a valuable tool with which to assess cardiac patients with poor physiological outcomes, particularly handgrip strength as a measure of upper extremity function, which is probably easier to follow over time than lower extremity function after patients complete cardiac rehabilitation. PMID:29186880

Evaluation of peripheral muscle strength of patients undergoing elective cardiac surgery: a longitudinal study.

PubMed

Santos, Kelli Maria Souza; Cerqueira Neto, Manoel Luiz de; Carvalho, Vitor Oliveira; Santana Filho, Valter Joviniano de; Silva Junior, Walderi Monteiro da; Araújo Filho, Amaro Afrânio; Cerqueira, Telma Cristina Fontes; Cacau, Lucas de Assis Pereira

2014-01-01

Peripheral muscle strength has been little explored in the literature in the context of cardiac rehabilitation. To evaluate the peripheral muscle strength of patients undergoing elective cardiac surgery. This was a longitudinal observational study. The peripheral muscle strength was measured using isometric dynamometry lower limb (knee extensors and flexors) at three different times: preoperatively (M1), the day of discharge (M2) and hospital discharge (M3). Participants received physiotherapy pre and postoperatively during the days of hospitalization during the morning and afternoon. Twenty-two patients were evaluated. The values of peripheral muscle strength of knee extensors preoperative found were about 50% lower than those predicted for the healthy population. When comparing muscle strength prior (M1), with the remaining evaluation, found himself in a fall of 29% for the movement of knee extension and 25% for knee flexion in M2 and a decrease of 10% movement for knee extension and 13% for knee flexion in M3 when comparing with M1. The values of peripheral muscle strength prior of the study patients were lower than predicted for the healthy population of the same age. After the surgical event this reduction is even more remarkable, being reestablished until the time of discharge, to values close to baseline.

Telocytes in skeletal, cardiac and smooth muscle interstitium: morphological and functional aspects.

PubMed

Marini, Mirca; Rosa, Irene; Ibba-Manneschi, Lidia; Manetti, Mirko

2018-04-25

Telocytes (TCs) represent a new distinct type of cells found in the stromal compartment of many organs, including the skeletal, cardiac and smooth muscles. TCs are morphologically defined as interstitial cells with a small cellular body from which arise very long (up to hundreds of micrometers) and thin moniliform processes (named telopodes) featuring the alternation of slender segments (called podomers) and small dilated portions (called podoms) accommodating some organelles. Although these stromal cells are mainly characterized by their ultrastructural traits, in the last few years TCs have been increasingly studied for their immunophenotypes, microRNA profiles, and gene expression and proteomic signatures. By their long-distance spreading telopodes, TCs build a three-dimensional network throughout the whole stromal space and communicate with each other and neighboring cells through homocellular and heterocellular junctions, respectively. Moreover, increasing evidence suggests that TCs may exert paracrine functions being able to transfer genetic information and signaling molecules to other cells via the release of different types of extracellular vesicles. A close relationship between TCs and stem/progenitor cell niches has also been described in several organs. However, the specific functions of TCs located in the muscle interstitium remain to be unraveled. Here, we review the morphological and possible functional aspects of TCs in skeletal, cardiac and smooth muscle tissues. The potential involvement of TCs in muscle tissue pathological changes and future possibilities for targeting TCs as a novel promising therapeutic strategy to foster muscle tissue regeneration and repair are also discussed.

Dynamic changes in genes related to glucose uptake and utilization during pig skeletal and cardiac muscle development.

PubMed

Guo, Yanqin; Jin, Long; Wang, Fengjiao; He, Mengnan; Liu, Rui; Li, Mingzhou; Shuai, Surong

2014-01-01

Skeletal and cardiac muscle have important roles in glucose uptake and utilization. However, changes in expression of protein coding genes and miRNAs that participate in glucose metabolism during development are not fully understood. In this study, we investigated the expression of genes related to glucose metabolism during muscle development. We found an age-dependent increase in gene expression in cardiac muscle, with enrichment in heart development- and energy-related metabolic processes. A subset of genes that were up-regulated until 30 or 180 days postnatally, and then down-regulated in psoas major muscle was significantly enriched in mitochondrial oxidative-related processes, while genes that up-regulated in longissimus doris muscle was significantly enriched in glycolysis-related processes. Meanwhile, expression of energy-related microRNAs decreased with increasing age. In addition, we investigated the correlation between microRNAs and mRNAs in three muscle types across different stages of development and found many potential microRNA-mRNA pairs involved in regulating glucose metabolism.

Endogenous Cardiac Troponin T Modulates Ca2+-Mediated Smooth Muscle Contraction

PubMed Central

Kajioka, Shunichi; Takahashi-Yanaga, Fumi; Shahab, Nouval; Onimaru, Mitsuho; Matsuda, Miho; Takahashi, Ryosuke; Asano, Haruhiko; Morita, Hiromitsu; Morimoto, Sachio; Yonemitsu, Yoshikazu; Hayashi, Maya; Seki, Narihito; Sasaguri, Toshiuyki; Hirata, Masato; Nakayama, Shinsuke; Naito, Seiji

2012-01-01

Mechanisms linked to actin filaments have long been thought to cooperate in smooth muscle contraction, although key molecules were unclear. We show evidence that cardiac troponin T (cTnT) substantially contributes to Ca2+-mediated contraction in a physiological range of cytosolic Ca2+ concentration ([Ca2+]i). cTnT was detected in various smooth muscles of the aorta, trachea, gut and urinary bladder, including in humans. Also, cTnT was distributed along with tropomyosin in smooth muscle cells, suggesting that these proteins are ready to cause smooth muscle contraction. In chemically permeabilised smooth muscle of cTnT+/− mice in which cTnT reduced to ~50%, the Ca2+-force relationship was shifted toward greater [Ca2+]i, indicating a sizeable contribution of cTnT to smooth muscle contraction at [Ca2+]i < 1 μM. Furthermore, addition of supplemental TnI and TnC reconstructed a troponin system to enhance contraction. The results indicated that a Tn/Tn-like system on actin-filaments cooperates together with the thick-filament pathway. PMID:23248744

Evaluation of microRNAs − 208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats

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

Calvano, Jacqueline, E-mail: Jacqueline.Calvano@bm

Conventional circulating biomarkers of cardiac and skeletal muscle (SKM) toxicity lack specificity and/or have a short half-life. MicroRNAs (miRNAs) are currently being assessed as biomarkers of tissue injury based on their long half-life in blood and selective expression in certain tissues. To assess the utility of miRNAs as biomarkers of cardiac and SKM injury, male Sprague–Dawley rats received a single dose of isoproterenol (ISO); metaproterenol (MET); allylamine (AAM); mitoxantrone (MIT); acetaminophen (APAP) or vehicle. Blood and tissues were collected from rats in each group at 4, 24 and 48 h. ISO, MET, and AAM induced cardiac and SKM lesions andmore » APAP induced liver specific lesions. There was no evidence of tissue injury with MIT by histopathology. Serum levels of candidate miRNAs were compared to conventional serum biomarkers of SKM/cardiac toxicity. Increases in heart specific miR-208 only occurred in rats with cardiac lesions alone and were increased for a longer duration than cardiac troponin and FABP3 (cardiac biomarkers). ISO, MET and AAM induced increases in MyL3 and skeletal muscle troponin (sTnl) (SKM biomarkers). MIT induced large increases in sTnl indicative of SKM toxicity, but sTnl levels were also increased in APAP-treated rats that lacked SKM toxicity. Serum levels of miR-133a/b (enriched in cardiac and SKM) increased following ISO, MET, AAM and MIT treatments but were absent in APAP-treated rats. Our results suggest that miR-133a/b are sensitive and specific markers of SKM and cardiac toxicity and that miR-208 used in combination with miR-133a/b can be used to differentiate cardiac from SKM toxicity. - Highlights: • MiR-208 is specifically expressed in rat hearts. • MiR-133a/b are enriched in rat cardiac/skeletal muscle. • MiR-133a/b are sensitive and specific markers of muscle/cardiac toxicity. • MiR-208 can be used to differentiate cardiac toxicity from skeletal muscle toxicity.« less

Evaluation of peripheral muscle strength of patients undergoing elective cardiac surgery: a longitudinal study

PubMed Central

Santos, Kelli Maria Souza; de Cerqueira Neto, Manoel Luiz; Carvalho, Vitor Oliveira; de Santana Filho, Valter Joviniano; da Silva Junior, Walderi Monteiro; Araújo Filho, Amaro Afrânio; Cerqueira, Telma Cristina Fontes; Cacau, Lucas de Assis Pereira

2014-01-01

Introduction Peripheral muscle strength has been little explored in the literature in the context of cardiac rehabilitation. Objective To evaluate the peripheral muscle strength of patients undergoing elective cardiac surgery. Methods This was a longitudinal observational study. The peripheral muscle strength was measured using isometric dynamometry lower limb (knee extensors and flexors) at three different times: preoperatively (M1), the day of discharge (M2) and hospital discharge (M3). Participants received physiotherapy pre and postoperatively during the days of hospitalization during the morning and afternoon. Results Twenty-two patients were evaluated. The values of peripheral muscle strength of knee extensors preoperative found were about 50% lower than those predicted for the healthy population. When comparing muscle strength prior (M1), with the remaining evaluation, found himself in a fall of 29% for the movement of knee extension and 25% for knee flexion in M2 and a decrease of 10% movement for knee extension and 13% for knee flexion in M3 when comparing with M1. Conclusion The values of peripheral muscle strength prior of the study patients were lower than predicted for the healthy population of the same age. After the surgical event this reduction is even more remarkable, being reestablished until the time of discharge, to values close to baseline. PMID:25372909

NK4 Antagonizes Tbx1/10 to Promote Cardiac versus Pharyngeal Muscle Fate in the Ascidian Second Heart Field

PubMed Central

Wang, Wei; Razy-Krajka, Florian; Siu, Eric; Ketcham, Alexandra; Christiaen, Lionel

2013-01-01

The heart and head muscles share common developmental origins and genetic underpinnings in vertebrates, including humans. Parts of the heart and cranio-facial musculature derive from common mesodermal progenitors that express NKX2-5, ISL1, and TBX1. This ontogenetic kinship is dramatically reflected in the DiGeorge/Cardio-Velo-Facial syndrome (DGS/CVFS), where mutations of TBX1 cause malformations in the pharyngeal apparatus and cardiac outflow tract. Cardiac progenitors of the first heart field (FHF) do not require TBX1 and segregate precociously from common progenitors of the second heart field (SHF) and pharyngeal muscles. However, the cellular and molecular mechanisms that govern heart versus pharyngeal muscle specification within this lineage remain elusive. Here, we harness the simplicity of the ascidian larva to show that, following asymmetric cell division of common progenitors, NK4/NKX2-5 promotes GATAa/GATA4/5/6 expression and cardiac specification in the second heart precursors by antagonizing Tbx1/10-mediated inhibition of GATAa and activation of Collier/Olf/EBF (COE), the determinant of atrial siphon muscle (ASM) specification. Our results uncover essential regulatory connections between the conserved cardio-pharyngeal factor Tbx1/10 and muscle determinant COE, as well as a mutual antagonism between NK4 and Tbx1/10 activities upstream of GATAa and COE. The latter cross-antagonism underlies a fundamental heart versus pharyngeal muscle fate choice that occurs in a conserved lineage of cardio-pharyngeal progenitors. We propose that this basic ontogenetic motif underlies cardiac and pharyngeal muscle development and evolution in chordates. PMID:24311985

Habitual exercise program protects murine intestinal, skeletal, and cardiac muscles against aging.

PubMed

Rosa, Eloi F; Silva, Antonio C; Ihara, Silvia S M; Mora, Oswaldo A; Aboulafia, Jeannine; Nouailhetas, Viviane L A

2005-10-01

Aging and aerobic exercise are two conditions known to interfere with health and quality of life, most likely by inducing oxidative stress to the organism. We studied the effects of aging on the morphological and functional properties of skeletal, cardiac, and intestinal muscles and their corresponding oxidative status in C57BL/6 mice and investigated whether a lifelong moderate exercise program would exert a protective effect against some deleterious effects of aging. As expected, aged animals presented a significant reduction of physical performance, accompanied by a decrease of gastrocnemius cross-sectional area and cardiac hypertrophy. However, most interesting was that aging dramatically interfered with the intestinal structure, causing a significant thickening of the ileum muscular layer. Senescent intestinal myocytes displayed many mitochondria with disorganized cristae and the presence of cytosolic lamellar corpuscles. Lipid peroxidation of ileum and gastrocnemius muscle, but not of the heart, increased in aged mice, thus suggesting enhanced oxidative stress. With exception of the intestinal muscle responsiveness, animals submitted to a daily session of 60 min, 5 days/wk, at 13 up to 21 m/min of moderate running in treadmill during animal life span exhibited a reversion of all the observed aging effects on intestinal, skeletal, and heart muscles. The introduction of this lifelong exercise protocol prevented the enhancement of lipid peroxidation and sarcopenia and also preserved cellular and ultracellular structures of the ileum. This is the first time that the protective effect of a lifelong regular aerobic physical activity against the deleterious effects of aging on intestinal muscle was demonstrated.

Cardiac-locked bursts of muscle sympathetic nerve activity are absent in familial dysautonomia

PubMed Central

Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Axelrod, Felicia B; Kaufmann, Horacio

2013-01-01

Familial dysautonomia (Riley–Day syndrome) is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced pain and temperature sensibilities and absent baroreflexes, causing orthostatic hypotension as well as labile blood pressure that increases markedly during emotional excitement. Given the apparent absence of functional baroreceptor afferents, we tested the hypothesis that the normal cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in patients with familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 12 patients with familial dysautonomia. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during a manoeuvre that unloads the baroreceptors. Conversely, skin sympathetic nerve activity (SSNA), recorded in four patients, appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement. PMID:23165765

From syncitium to regulated pump: a cardiac muscle cellular update

PubMed Central

2011-01-01

The primary purpose of this article is to present a basic overview of some key teaching concepts that should be considered for inclusion in an six- to eight-lecture introductory block on the regulation of cardiac performance for graduate students. Within the context of cardiac excitation-contraction coupling, this review incorporates information on Ca2+ microdomains and local control theory, with particular emphasis on the role of Ca2+ sparks as a key regulatory component of ventricular myocyte contraction dynamics. Recent information pertaining to local Ca2+ cycling in sinoatrial nodal cells (SANCs) as a mechanism underlying cardiac automaticity is also presented as part of the recently described coupled-clock pacemaker system. The details of this regulation are emerging; however, the notion that the sequestration and release of Ca2+ from internal stores in SANCs (similar to that observed in ventricular myocytes) regulates the rhythmic excitation of the heart (i.e., membrane ion channels) is an important advancement in this area. The regulatory role of cardiac adrenergic receptors on cardiac rate and function is also included, and fundamental concepts related to intracellular signaling are discussed. An important point of emphasis is that whole organ cardiac dynamics can be traced back to cellular events regulating intracellular Ca2+ homeostasis and, as such, provides an important conceptual framework from which students can begin to think about whole organ physiology in health and disease. Greater synchrony of Ca2+-regulatory mechanisms between ventricular and pacemaker cells should enhance student comprehension of complex regulatory phenomenon in cardiac muscle. PMID:21385997

Skeletal muscle damage and impaired regeneration due to LPL-mediated lipotoxicity

PubMed Central

Tamilarasan, K P; Temmel, H; Das, S K; Al Zoughbi, W; Schauer, S; Vesely, P W; Hoefler, G

2012-01-01

According to the concept of lipotoxicity, ectopic accumulation of lipids in non-adipose tissue induces pathological changes. The most prominent effects are seen in fatty liver disease, lipid cardiomyopathy, non-insulin-dependent diabetes mellitus, insulin resistance and skeletal muscle myopathy. We used the MCK(m)-hLPL mouse distinguished by skeletal and cardiac muscle-specific human lipoprotein lipase (hLPL) overexpression to investigate effects of lipid overload in skeletal muscle. We were intrigued to find that ectopic lipid accumulation induced proteasomal activity, apoptosis and skeletal muscle damage. In line with these findings we observed reduced Musculus gastrocnemius and Musculus quadriceps mass in transgenic animals, accompanied by severely impaired physical endurance. We suggest that muscle loss was aggravated by impaired muscle regeneration as evidenced by reduced cross-sectional area of regenerating myofibers after cardiotoxin-induced injury in MCK(m)-hLPL mice. Similarly, an almost complete loss of myogenic potential was observed in C2C12 murine myoblasts upon overexpression of LPL. Our findings directly link lipid overload to muscle damage, impaired regeneration and loss of performance. These findings support the concept of lipotoxicity and are a further step to explain pathological effects seen in muscle of obese patients, patients with the metabolic syndrome and patients with cancer-associated cachexia. PMID:22825472

Observational Study of Human Electrical Muscle Incapacitation and Cardiac Effects

DTIC Science & Technology

2016-05-01

the American College of Cardiology Foundation. Circulation. 2010 Mar 2; 121(8):1047-1060. 12. U.S. Department of Health and Human Services, Food and...AFRL-RH-FS-TR-2016-0010 Observational Study of Human Electrical Muscle Incapacitation and Cardiac Effects John A. Gibbons Brian B. Lupfer Alan...Ashworth Human Effectiveness Directorate Bioeffects Division Andrew J. Mojica KBRwyle Inc. Mark E. Peele USARMY MEDCOM Brooke Army Medical Center

Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans.

PubMed

Wallin, B G; Esler, M; Dorward, P; Eisenhofer, G; Ferrier, C; Westerman, R; Jennings, G

1992-01-01

1. Muscle sympathetic nerve activity (MSA) was recorded in the peroneal nerve at the knee by microneurography in ten healthy subjects and determinations were made simultaneously of intra-arterial blood pressure, and whole-body and cardiac noradrenaline spillover to plasma. Measurements were made at rest, during isometric handgrip at 30% of maximum power and during stress induced by forced mental arithmetic. 2. At rest there were significant positive correlations between spontaneous MSA (expressed as number of sympathetic bursts min-1) and both spillover of noradrenaline from the heart and concentration of noradrenaline in coronary sinus venous plasma. 3. Both isometric handgrip and mental arithmetic led to sustained increases of blood pressure, heart rate and MSA. Plasma concentrations of noradrenaline and spillover of noradrenaline (total body and cardiac) increased. In general the effects were more pronounced during handgrip than during stress. 4. When comparing effects during handgrip and stress the ratio between the fractional increases of MSA and cardiac noradrenaline spillover were significantly greater during handgrip. 5. The data suggest (a) that there are proportional interindividual differences in the strength of resting sympathetic activity to heart and skeletal muscle which are determined by a common mechanism and (b) that handgrip and mental stress are associated with differences in balance between sympathetic outflows to heart and skeletal muscle.

[Evaluation on stability of internal controls in human cardiac muscle by real-time RT-PCR during early postmortem interval].

PubMed

Zhang, Ping; Ma, Kai-Jun; Zhang, Heng; Wang, Hui-Jun; Shen, Yi-Wen; Chen, Long

2012-04-01

To explore the stability of internal controls in human cardiac muscle by real-time RT-PCR during early postmortem interval (PMI) in order to find the most stable marker. Ten individuals with similar environmental conditions (the average store temperature: 25 degrees C) and different PMI ranging from 4.3 to 22.3 h were selected. Total RNA was extracted from each sample and six commonly internal controls were used including beta-actin, GAPDH, B2M, U6, 18S rRNA and HSA-miR-1, and the expression was detected in cardiac muscle by real-time RT-PCR. The expression stability of internal controls was evaluated using genormPLUS software during early PMI. The internal control with the most stability was selected. The relationship between the most stable marker and its expression level affected by some other parameters such as age, gender and cause of death was also analyzed. The U6 showed the most stable expression during early PMI in cardiac muscle, and its expression level was not affected by those parameters including age, gender and cause of death (P > 0.05). U6 may be a valuable internal control for the study of relationship between PMI determination and degradation of nucleic acid in human cardiac muscle by real-time RT-PCR.

Zebrafish Cardiac Muscle Thick Filaments: Isolation Technique and Three-Dimensional Structure

PubMed Central

González-Solá, Maryví; AL-Khayat, Hind A.; Behra, Martine; Kensler, Robert W.

2014-01-01

To understand how mutations in thick filament proteins such as cardiac myosin binding protein-C or titin, cause familial hypertrophic cardiomyopathies, it is important to determine the structure of the cardiac thick filament. Techniques for the genetic manipulation of the zebrafish are well established and it has become a major model for the study of the cardiovascular system. Our goal is to develop zebrafish as an alternative system to the mammalian heart model for the study of the structure of the cardiac thick filaments and the proteins that form it. We have successfully isolated thick filaments from zebrafish cardiac muscle, using a procedure similar to those for mammalian heart, and analyzed their structure by negative-staining and electron microscopy. The isolated filaments appear well ordered with the characteristic 42.9 nm quasi-helical repeat of the myosin heads expected from x-ray diffraction. We have performed single particle image analysis on the collected electron microscopy images for the C-zone region of these filaments and obtained a three-dimensional reconstruction at 3.5 nm resolution. This reconstruction reveals structure similar to the mammalian thick filament, and demonstrates that zebrafish may provide a useful model for the study of the changes in the cardiac thick filament associated with disease processes. PMID:24739166

Massive palmitoylation-dependent endocytosis during reoxygenation of anoxic cardiac muscle

PubMed Central

Lin, Mei-Jung; Fine, Michael; Lu, Jui-Yun; Hofmann, Sandra L; Frazier, Gary; Hilgemann, Donald W

2013-01-01

In fibroblasts, large Ca transients activate massive endocytosis (MEND) that involves membrane protein palmitoylation subsequent to mitochondrial permeability transition pore (PTP) openings. Here, we characterize this pathway in cardiac muscle. Myocytes with increased expression of the acyl transferase, DHHC5, have decreased Na/K pump activity. In DHHC5-deficient myocytes, Na/K pump activity and surface area/volume ratios are increased, the palmitoylated regulatory protein, phospholemman (PLM), and the cardiac Na/Ca exchanger (NCX1) show greater surface membrane localization, and MEND is inhibited in four protocols. Both electrical and optical methods demonstrate that PTP-dependent MEND occurs during reoxygenation of anoxic hearts. Post-anoxia MEND is ablated in DHHC5-deficient hearts, inhibited by cyclosporine A (CsA) and adenosine, promoted by staurosporine (STS), reduced in hearts lacking PLM, and correlates with impaired post-anoxia contractile function. Thus, the MEND pathway appears to be deleterious in severe oxidative stress but may constitutively contribute to cardiac sarcolemma turnover in dependence on metabolic stress. DOI: http://dx.doi.org/10.7554/eLife.01295.001 PMID:24282237

Animal models of cardiac cachexia.

PubMed

Molinari, Francesca; Malara, Natalia; Mollace, Vincenzo; Rosano, Giuseppe; Ferraro, Elisabetta

2016-09-15

Cachexia is the loss of body weight associated with several chronic diseases including chronic heart failure (CHF). The cachectic condition is mainly due to loss of skeletal muscle mass and adipose tissue depletion. The majority of experimental in vivo studies on cachexia rely on animal models of cancer cachexia while a reliable and appropriate model for cardiac cachexia has not yet been established. A critical issue in generating a cardiac cachexia model is that genetic modifications or pharmacological treatments impairing the heart functionality and used to obtain the heart failure model might likely impair the skeletal muscle, this also being a striated muscle and sharing with the myocardium several molecular and physiological mechanisms. On the other hand, often, the induction of heart damage in the several existing models of heart failure does not necessarily lead to skeletal muscle loss and cachexia. Here we describe the main features of cardiac cachexia and illustrate some animal models proposed for cardiac cachexia studies; they include the genetic calsequestrin and Dahl salt-sensitive models, the monocrotaline model and the surgical models obtained by left anterior descending (LAD) ligation, transverse aortic constriction (TAC) and ascending aortic banding. The availability of a specific animal model for cardiac cachexia is a crucial issue since, besides the common aspects of cachexia in the different syndromes, each disease has some peculiarities in its etiology and pathophysiology leading to cachexia. Such peculiarities need to be unraveled in order to find new targets for effective therapies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cardiac conduction system

MedlinePlus Videos and Cool Tools

... cardiac muscle cells in the walls of the heart that send signals to the heart muscle causing it to contract. The main components ... the cardiac conduction system's electrical activity in the heart.

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.

Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging.

PubMed

Zhou, Jin; Chong, Shu Yun; Lim, Andrea; Singh, Brijesh K; Sinha, Rohit A; Salmon, Adam B; Yen, Paul M

2017-02-26

Aging causes a general decline in cellular metabolic activity, and function in different tissues and whole body homeostasis. However, the understanding about the metabolomic and autophagy changes in skeletal muscle and heart during aging is still limited. We thus examined markers for macroautophagy, chaperone-mediated autophagy (CMA), mitochondrial quality control, as well as cellular metabolites in skeletal and cardiac muscle from young (5 months old) and aged (27 months old) mice. We found decreased autophagic degradation of p62 and increased ubiquitinated proteins in both tissues from aged mice, suggesting a decline in macroautophagy during aging. In skeletal muscle from aged mice, there also was a decline in LC3B-I conjugation to phosphatidylethanolamine (PE) possibly due to decreased protein levels of ATG3 and ATG12-ATG5. The CMA markers, LAMP-2A and Hsc70, and mitochondrial turnover markers, Drp1, PINK1 and PGC1α also were decreased. Metabolomics analysis showed impaired β-oxidation in heart of aged mice, whereas increased branched-chain amino acids (BCAAs) and ceramide levels were found in skeletal muscle of aged mice that in turn, may contribute to insulin resistance in muscle. Taken together, our studies showed similar declines in macroautophagy but distinct effects on CMA, mitochondrial turnover, and metabolic dysfunction in muscle vs. heart during aging.

Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging

PubMed Central

Zhou, Jin; Yun Chong, Shu; Lim, Andrea; Singh, Brijesh K.; Sinha, Rohit A.; Salmon, Adam B.; Yen, Paul M.

2017-01-01

Aging causes a general decline in cellular metabolic activity, and function in different tissues and whole body homeostasis. However, the understanding about the metabolomic and autophagy changes in skeletal muscle and heart during aging is still limited. We thus examined markers for macroautophagy, chaperone-mediated autophagy (CMA), mitochondrial quality control, as well as cellular metabolites in skeletal and cardiac muscle from young (5 months old) and aged (27 months old) mice. We found decreased autophagic degradation of p62 and increased ubiquitinated proteins in both tissues from aged mice, suggesting a decline in macroautophagy during aging. In skeletal muscle from aged mice, there also was a decline in LC3B-I conjugation to phosphatidylethanolamine (PE) possibly due to decreased protein levels of ATG3 and ATG12-ATG5. The CMA markers, LAMP-2A and Hsc70, and mitochondrial turnover markers, Drp1, PINK1 and PGC1α also were decreased. Metabolomics analysis showed impaired β-oxidation in heart of aged mice, whereas increased branched-chain amino acids (BCAAs) and ceramide levels were found in skeletal muscle of aged mice that in turn, may contribute to insulin resistance in muscle. Taken together, our studies showed similar declines in macroautophagy but distinct effects on CMA, mitochondrial turnover, and metabolic dysfunction in muscle vs. heart during aging. PMID:28238968

Measuring the mechanical efficiency of a working cardiac muscle sample at body temperature using a flow-through calorimeter.

PubMed

Taberner, Andrew J; Johnston, Callum M; Pham, Toan; June-Chiew Han; Ruddy, Bryan P; Loiselle, Denis S; Nielsen, Poul M F

2015-08-01

We have developed a new `work-loop calorimeter' that is capable of measuring, simultaneously, the work-done and heat production of isolated cardiac muscle samples at body temperature. Through the innovative use of thermoelectric modules as temperature sensors, the development of a low-noise fluid-flow system, and implementation of precise temperature control, the heat resolution of this device is 10 nW, an improvement by a factor of ten over previous designs. These advances have allowed us to conduct the first flow-through measurements of work output and heat dissipation from cardiac tissue at body temperature. The mechanical efficiency is found to vary with peak stress, and reaches a peak value of approximately 15 %, a figure similar to that observed in cardiac muscle at lower temperatures.

miR669a and miR669q prevent skeletal muscle differentiation in postnatal cardiac progenitors

PubMed Central

Crippa, Stefania; Cassano, Marco; Messina, Graziella; Galli, Daniela; Galvez, Beatriz G.; Curk, Tomaz; Altomare, Claudia; Ronzoni, Flavio; Toelen, Jaan; Gijsbers, Rik; Debyser, Zeger; Janssens, Stefan; Zupan, Blaz; Zaza, Antonio; Cossu, Giulio

2011-01-01

Postnatal heart stem and progenitor cells are a potential therapeutic tool for cardiomyopathies, but little is known about the mechanisms that control cardiac differentiation. Recent work has highlighted an important role for microribonucleic acids (miRNAs) as regulators of cardiac and skeletal myogenesis. In this paper, we isolated cardiac progenitors from neonatal β-sarcoglycan (Sgcb)–null mouse hearts affected by dilated cardiomyopathy. Unexpectedly, Sgcb-null cardiac progenitors spontaneously differentiated into skeletal muscle fibers both in vitro and when transplanted into regenerating muscles or infarcted hearts. Differentiation potential correlated with the absence of expression of a novel miRNA, miR669q, and with down-regulation of miR669a. Other miRNAs are known to promote myogenesis, but only miR669a and miR669q act upstream of myogenic regulatory factors to prevent myogenesis by directly targeting the MyoD 3′ untranslated region. This finding reveals an added level of complexity in the mechanism of the fate choice of mesoderm progenitors and suggests that using endogenous cardiac stem cells therapeutically will require specially tailored procedures for certain genetic diseases. PMID:21708977

Chronic hindlimb suspension unloading markedly decreases turnover rates of skeletal and cardiac muscle proteins and adipose tissue triglycerides.

PubMed

Bederman, Ilya R; Lai, Nicola; Shuster, Jeffrey; Henderson, Leigh; Ewart, Steven; Cabrera, Marco E

2015-07-01

We previously showed that a single bolus of "doubly-labeled" water ((2)H2 (18)O) can be used to simultaneously determine energy expenditure and turnover rates (synthesis and degradation) of tissue-specific lipids and proteins by modeling labeling patterns of protein-bound alanine and triglyceride-bound glycerol (Bederman IR, Dufner DA, Alexander JC, Previs SF. Am J Physiol Endocrinol Metab 290: E1048-E1056, 2006). Using this novel method, we quantified changes in the whole body and tissue-specific energy balance in a rat model of simulated "microgravity" induced by hindlimb suspension unloading (HSU). After chronic HSU (3 wk), rats exhibited marked atrophy of skeletal and cardiac muscles and significant decrease in adipose tissue mass. For example, soleus muscle mass progressively decreased 11, 43, and 52%. We found similar energy expenditure between control (90 ± 3 kcal · kg(-1)· day(-1)) and hindlimb suspended (81 ± 6 kcal/kg day) animals. By comparing food intake (∼ 112 kcal · kg(-1) · day(-1)) and expenditure, we found that animals maintained positive calorie balance proportional to their body weight. From multicompartmental fitting of (2)H-labeling patterns, we found significantly (P < 0.005) decreased rates of synthesis (percent decrease from control: cardiac, 25.5%; soleus, 70.3%; extensor digitorum longus, 44.9%; gastrocnemius, 52.5%; and adipose tissue, 39.5%) and rates of degradation (muscles: cardiac, 9.7%; soleus, 52.0%; extensor digitorum longus, 27.8%; gastrocnemius, 37.4%; and adipose tissue, 50.2%). Overall, HSU affected growth of young rats by decreasing the turnover rates of proteins in skeletal and cardiac muscles and adipose tissue triglycerides. Specifically, we found that synthesis rates of skeletal and cardiac muscle proteins were affected to a much greater degree compared with the decrease in degradation rates, resulting in large negative balance and significant tissue loss. In contrast, we found a small decrease in adipose tissue

Resting and post-exercise serum biomarkers of cardiac and skeletal muscle damage in adolescent runners.

PubMed

Nie, J; Tong, T K; George, K; Fu, F H; Lin, H; Shi, Q

2011-10-01

This study examined the response of serum biomarkers of cardiac and skeletal muscle damage at rest and after a routine workout of 21 km run in 12 male adolescent (16.2±0.6 years) long-distance runners. Biomarkers of cardiac [troponins (cTnT, cTnI), creatine kinase MB mass (CK-Mbmass)] and skeletal muscle [creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hydroxybutyrate dehydrogenase (HBD)] damage were assayed at rest, 2, 4 and 24 h post-exercise. At rest, cTnT and cTnI were not detectable; however, CK, CK-MBmass, AST, ALT and HBD were above corresponding clinical cut-off values. Post-exercise significant elevations above rest were observed for all biomarkers, except ALT, 2 and 4 h following the run, and remained elevated in cTnI, CK, CK-MBmass, LDH and AST 24 h post-workout. A significant increase in data points above clinical cut-off values from rest to post-exercise was reported for cTnT, cTnI and CK at 2 and 4 h, and in cTnI and CK 24 h post-exercise. In conclusion, a 21 km run in adolescent runners increased post-exercise biomarkers of cardiac and skeletal muscle damage. © 2010 John Wiley & Sons A/S.

Proteomics and immunohistochemistry identify the expression of α-cardiac myosin heavy chain in the jaw-closing muscles of sooty mangabeys (order Primates).

PubMed

Wall, Christine E; Holmes, Megan; Soderblom, Erik J; Taylor, Andrea B

2018-07-01

The jaw-closing muscles of humans and nonprimate mammals express alpha-cardiac fibers but MyHC α-cardiac has not been identified in the jaw adductors of nonhuman primates. We determined whether MyHC α-cardiac is expressed in the superficial masseter and temporalis muscles of the sooty mangabey (Cercocebus atys), an African Old World monkey that specializes on hard seeds. LC-MS/MS based proteomics was used to identify the presence of MyHC Iα. Immunohistochemistry was used to analyze the composition and distribution of fiber types in the superficial masseter and temporalis muscles of eight C. atys. Serial sections were stained against MyHC α-cardiac (MYH6), as well as MyHC-1 (NOQ7.5.4D), MyHC-2 (MY-32), and MyHC-M (2F4). Proteomics analysis identified the presence of Myosin-6 (MyHC α-cardiac) in both heart atrium and superficial masseter. MyHC α-cardiac was expressed in abundance in the superficial masseter and temporalis muscles of all eight individuals and hybrid fibers were common. The identification of MyHC α-cardiac in the jaw adductors of sooty mangabeys is a novel finding for nonhuman primates. The abundance of MyHC α-cardiac indicates a fatigue-resistant fiber population characterized by intermediate speed of contraction between pure MyHC-1 and MyHC-2 isoforms. We suggest that α-cardiac fibers may be advantageous to sooty mangabeys, whose feeding behavior includes frequent crushing of relatively large, hard seeds during the power stroke of ingestion. Additional studies comparing jaw-adductor fiber phenotype of hard-object feeding primates and other mammals are needed to explore this relationship further. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Histopathological and immunohistochemical features of cardiac myxomas].

PubMed

Hernández-Bringas, Omar; Ortiz-Hidalgo, Carlos

2013-01-01

Mixomas are the most common primary cardiac tumors with an estimate incidence of 0,5-1 per 10(6) individuals per year. These tumors have generated interest due to their unique location (left side of the atrial septum near the fossa ovalis), variable clinical presentation and undefined histogenesis. Most cardiac myxomas occur sporadically while approximately 10% of diagnosed cases develop as part of Carney complex. This neoplasm is of uncertain histogenesis, however, endothelial, neurogenic, fibroblastic, and cardiac and smooth muscle cells differentiation has been proposed, and rarely glandular differentiation has been observed. Recently, due to the expression of certain cardiomyocyte-specific factors, an origin of mesenchymal cardiomyocytes progenitor cells has been suggested. Histologically cardiac myxomas are mainly composed of stellated, fusiform and polygonal cells, immersed in an amorphous myxoid matrix. Immunohistochemically some endothelial markers, such as CD31, CD34, FVIIIAg, are present. Positive staining has also been reported for S-100 protein, calretinin, vimentin, desmin, smooth muscle myosin, CD56, α1 antitrypsin and α 1antichymotrypsin. Surgical resection is currently the only treatment of choice. We present in this article a histopathological and immunohistochemical review of cardiac myxomas. Copyright © 2012 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

Sarcopenia, cachexia, and muscle performance in heart failure: Review update 2016.

PubMed

Saitoh, Masakazu; Ishida, Junichi; Doehner, Wolfram; von Haehling, Stephan; Anker, Markus S; Coats, Andrew J S; Anker, Stefan D; Springer, Jochen

2017-07-01

Cachexia in the context of heart failure (HF) has been termed cardiac cachexia, and represents a progressive involuntary weight loss. Cachexia is mainly the result of an imbalance in the homeostasis of muscle protein synthesis and degradation due to a lower activity of protein synthesis pathways and an over-activation of protein degradation. In addition, muscle wasting leads to of impaired functional capacity, even after adjusting for clinical relevant variables in patients with HF. However, there is no sufficient therapeutic strategy in muscle wasting in HF patients and very few studies in animal models. Exercise training represents a promising intervention that can prevent or even reverse the process of muscle wasting, and worsening the muscle function and performance in HF with muscle wasting and cachexia. The pathological mechanisms and effective therapeutic approach of cardiac cachexia remain uncertain, because of the difficulty to establish animal cardiac cachexia models, thus novel animal models are warranted. Furthermore, the use of improved animal models will lead to a better understanding of the pathways that modulate muscle wasting and therapeutics of muscle wasting of cardiac cachexia. Copyright © 2017 Elsevier B.V. All rights reserved.

Zebrafish cardiac muscle thick filaments: isolation technique and three-dimensional structure.

PubMed

González-Solá, Maryví; Al-Khayat, Hind A; Behra, Martine; Kensler, Robert W

2014-04-15

To understand how mutations in thick filament proteins such as cardiac myosin binding protein-C or titin, cause familial hypertrophic cardiomyopathies, it is important to determine the structure of the cardiac thick filament. Techniques for the genetic manipulation of the zebrafish are well established and it has become a major model for the study of the cardiovascular system. Our goal is to develop zebrafish as an alternative system to the mammalian heart model for the study of the structure of the cardiac thick filaments and the proteins that form it. We have successfully isolated thick filaments from zebrafish cardiac muscle, using a procedure similar to those for mammalian heart, and analyzed their structure by negative-staining and electron microscopy. The isolated filaments appear well ordered with the characteristic 42.9 nm quasi-helical repeat of the myosin heads expected from x-ray diffraction. We have performed single particle image analysis on the collected electron microscopy images for the C-zone region of these filaments and obtained a three-dimensional reconstruction at 3.5 nm resolution. This reconstruction reveals structure similar to the mammalian thick filament, and demonstrates that zebrafish may provide a useful model for the study of the changes in the cardiac thick filament associated with disease processes. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Effect of voluntary physical activity initiated at age 7 months on skeletal hindlimb and cardiac muscle function in mdx mice of both genders.

PubMed

Ferry, Arnaud; Benchaouir, Rachid; Joanne, Pierre; Peat, Rachel A; Mougenot, Nathalie; Agbulut, Onnik; Butler-Browne, Gillian

2015-11-01

The effects of voluntary activity initiated in adult mdx (C57BL/10ScSc-DMD(mdx) /J) mice on skeletal and cardiac muscle function have not been studied extensively. We studied the effects of 3 months of voluntary wheel running initiated at age 7 months on hindlimb muscle weakness, increased susceptibility to muscle contraction-induced injury, and left ventricular function in mdx mice. We found that voluntary wheel running did not worsen the deficit in force-generating capacity and the force drop after lengthening contractions in either mdx mouse gender. It increased the absolute maximal force of skeletal muscle in female mdx mice. Moreover, it did not affect left ventricular function, structural heart dimensions, cardiac gene expression of inflammation, fibrosis, or remodeling markers. These results indicate that voluntary activity initiated at age 7 months had no detrimental effects on skeletal or cardiac muscles in either mdx mouse gender. © 2015 Wiley Periodicals, Inc.

The pathogenesis and treatment of cardiac atrophy in cancer cachexia.

PubMed

Murphy, Kate T

2016-02-15

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. In addition to a loss of skeletal muscle mass and function, many patients with cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer cachexia is described as cardiac cachexia. The cardiac alterations may be due to underlying heart disease, the cancer itself, or problems initiated by the cancer treatment and, unfortunately, remains largely underappreciated by clinicians and basic scientists. Despite recent major advances in the treatment of cancer, little progress has been made in the treatment of cardiac cachexia in cancer, and much of this is due to lack of information regarding the mechanisms. This review focuses on the cardiac atrophy associated with cancer cachexia, describing some of the known mechanisms and discussing the current and future therapeutic strategies to treat this condition. Above all else, improved awareness of the condition and an increased focus on identification of mechanisms and therapeutic targets will facilitate the eventual development of an effective treatment for cardiac atrophy in cancer cachexia. Copyright © 2016 the American Physiological Society.

Effect of Ca/sup 2 +/ overload on phosphoinositide (PI) metabolism in cardiac muscle

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

Otani, H.; Otani, H.; Engelman, R.M.

1986-05-01

The investigated the relationship between Ca/sup 2 +/ load and PI metabolism in isolated rat papillary muscle labeled with (/sup 3/H)inositol. Increase in (Ca/sup 2 +/)/sub o/ from 0-3.6 mM reduced the incorporation of (/sup 3/H) inositol into PI moderately and increased the resting tension slightly. The incorporation of the label into PI was unchanged by 10 ..mu..m A-23187 at 1.8 mM (Ca/sup 2 +/)/sub o/ that increased the contractility by 70% without a significant change in the resting tension. However, either 10.8 mM (Ca/sup 2 +/)/sub o/ or 0.3 mM ouabain at 1.8 mM (Ca/sup 2 +/)/sub o/ markedlymore » decreased the PI labeling with corresponding increase in the resting tension while inclusion of excess EGTA greatly enhanced the radioactivity in PI. Determination of the PI breakdown and the inositol phosphates production by pulse-chase experiments revealed that the reduced PI turnover in the Ca/sup 2 +/-overload muscle was due to both inhibition of the synthesis and stimulation of the breakdown of this lipid that accounted for 30% decrease in the labeled PI from the muscle during 45 min without significant loss of the net PI pool size, suggesting the presence of a relatively smaller compartment of PI pool undergoing a rapid breakdown during Ca/sup 2 +/ overload. The authors propose that alteration of Ca/sup 2 +/ homeostasis may modulate the production of putative second messengers, inositol trisphosphate and diacylglycerol, which feed back to regulate (Ca/sup 2 +/)/sub i/ in cardiac muscle.« less

Simultaneous measurement of cerebral and muscle tissue parameters during cardiac arrest and cardiopulmonary resuscitation

NASA Astrophysics Data System (ADS)

Nosrati, Reyhaneh; Ramadeen, Andrew; Hu, Xudong; Woldemichael, Ermias; Kim, Siwook; Dorian, Paul; Toronov, Vladislav

2015-03-01

In this series of animal experiments on resuscitation after cardiac arrest we had a unique opportunity to measure hyperspectral near-infrared spectroscopy (hNIRS) parameters directly on the brain dura, or on the brain through the intact pig skull, and simultaneously the muscle hNIRS parameters. Simultaneously the arterial blood pressure and carotid and femoral blood flow were recorded in real time using invasive sensors. We used a novel hyperspectral signalprocessing algorithm to extract time-dependent concentrations of water, hemoglobin, and redox state of cytochrome c oxidase during cardiac arrest and resuscitation. In addition in order to assess the validity of the non-invasive brain measurements the obtained results from the open brain was compared to the results acquired through the skull. The comparison of hNIRS data acquired on brain surface and through the adult pig skull shows that in both cases the hemoglobin and the redox state cytochrome c oxidase changed in similar ways in similar situations and in agreement with blood pressure and flow changes. The comparison of simultaneously measured brain and muscle changes showed expected differences. Overall the results show feasibility of transcranial hNIRS measurements cerebral parameters including the redox state of cytochrome oxidase in human cardiac arrest patients.

Effect of L-Carnitine Supplementation on Apelin and Apelin Receptor (Apj) Expression in Cardiac Muscle of Obese Diabetic Rats.

PubMed

Ranjbar Kohan, Neda; Nazifi, Saeed; Tabandeh, Mohammad Reza; Ansari Lari, Maryam

2018-10-01

L-carnitine (LC) has been shown to protect cardiac metabolism in diabetes patients with cardiovascular diseases (CVDs). Apelin, a newly discovered adipocytokines, is an important regulator of cardiac muscle function; however, the role of the level of expression of Apelin axis in improvement of cardiac function by LC in diabetic patients, is not clear. In the present study, obese insulin-resistant rats were used to determine the effect of LC, when given orally with a high-calorie diet, on Apelin and Apelin receptor (Apj) expression in cardiac muscle. In this experimental study, rats were fed with high-fat/high-carbohydrate diet for five weeks and subsequently were injected with streptozotocin 30 mg/kg for induction of obesity and insulin resistance. After confirming the induction of diabetes (serum glucose above 7.5 mmol/L), the animals received LC 300 mg/kg in drinking water for 28 days. On days 0, 14 and 28 after treatment, cardiac Apelin and Apj gene expression was evaluated by real time polymerase chain reaction (PCR) analysis. Serum levels of insulin, Apelin, glucose, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and the homeostasis model assessment of insulin resistance (HOMA-IR) were also measured using commercial kits. Cardiac Apelin and Apj expression and serum Apelin were increased in obese rats, while LC supplementation decreased the serum levels of Apelin and down-regulated Apelin and Apj expression in cardiac muscle. These changes were associated with reduced insulin resistance markers and serum inflammatory factors and improved lipid profile. We concluded that LC supplementation could attenuate the over-expression of Apelin axis in heart of diabetic rats, a novel mechanism by which LC improves cardiovascular complications in diabetic patients. Copyright© by Royan Institute. All rights reserved.

Muscle Contraction.

PubMed

Sweeney, H Lee; Hammers, David W

2018-02-01

SUMMARYMuscle cells are designed to generate force and movement. There are three types of mammalian muscles-skeletal, cardiac, and smooth. Skeletal muscles are attached to bones and move them relative to each other. Cardiac muscle comprises the heart, which pumps blood through the vasculature. Skeletal and cardiac muscles are known as striated muscles, because the filaments of actin and myosin that power their contraction are organized into repeating arrays, called sarcomeres, that have a striated microscopic appearance. Smooth muscle does not contain sarcomeres but uses the contraction of filaments of actin and myosin to constrict blood vessels and move the contents of hollow organs in the body. Here, we review the principal molecular organization of the three types of muscle and their contractile regulation through signaling mechanisms and discuss their major structural and functional similarities that hint at the possible evolutionary relationships between the cell types. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Orientation of Myosin Binding Protein C in the Cardiac Muscle Sarcomere Determined by Domain-Specific Immuno-EM

PubMed Central

Lee, Kyounghwan; Harris, Samantha P.; Sadayappan, Sakthivel; Craig, Roger

2014-01-01

Myosin binding protein-C is a thick filament protein of vertebrate striated muscle. The cardiac isoform (cMyBP-C) is essential for normal cardiac function, and mutations in cMyBP-C cause cardiac muscle disease. The rod-shaped molecule is composed primarily of 11 immunoglobulin- or fibronectin-like domains, and is located at 9 sites, 43 nm apart, in each half of the A-band. To understand how cMyBP-C functions, it is important to know its structural organization in the sarcomere, as this will affect its ability to interact with other sarcomeric proteins. Several models have been proposed, in which cMyBP-C wraps around, extends radially from, or runs axially along the thick filament. Our goal was to define cMyBP-C orientation by determining the relative axial positions of different cMyBP-C domains. Immuno-electron microscopy was performed using mouse cardiac myofibrils labeled with antibodies specific to the N- and C-terminal domains and to the middle of cMyBP-C. Antibodies to all regions of the molecule, except the C-terminus, labeled at the same nine axial positions in each half A-band, consistent with a circumferential and/or radial rather than an axial orientation of the bulk of the molecule. The C-terminal antibody stripes were slightly displaced axially, demonstrating an axial orientation of the C-terminal 3 domains, with the C-terminus closer to the M-line. These results, combined with previous studies, suggest that the C-terminal domains of cMyBP-C run along the thick filament surface, while the N-terminus extends towards neighboring thin filaments. This organization provides a structural framework for understanding cMyBP-C’s modulation of cardiac muscle contraction. PMID:25451032

Functional Tissue Engineering: A Prevascularized Cardiac Muscle Construct for Validating Human Mesenchymal Stem Cells Engraftment Potential In Vitro

PubMed Central

Fuseler, John W.; Potts, Jay D.; Davis, Jeffrey M.; Price, Robert L.

2018-01-01

The influence of somatic stem cells in the stimulation of mammalian cardiac muscle regeneration is still in its early stages, and so far, it has been difficult to determine the efficacy of the procedures that have been employed. The outstanding question remains whether stem cells derived from the bone marrow or some other location within or outside of the heart can populate a region of myocardial damage and transform into tissue-specific differentiated progenies, and also exhibit functional synchronization. Consequently, this necessitates the development of an appropriate in vitro three-dimensional (3D) model of cardiomyogenesis and prompts the development of a 3D cardiac muscle construct for tissue engineering purposes, especially using the somatic stem cell, human mesenchymal stem cells (hMSCs). To this end, we have created an in vitro 3D functional prevascularized cardiac muscle construct using embryonic cardiac myocytes (eCMs) and hMSCs. First, to generate the prevascularized scaffold, human cardiac microvascular endothelial cells (hCMVECs) and hMSCs were cocultured onto a 3D collagen cell carrier (CCC) for 7 days under vasculogenic culture conditions; hCMVECs/hMSCs underwent maturation, differentiation, and morphogenesis characteristic of microvessels, and formed dense vascular networks. Next, the eCMs and hMSCs were cocultured onto this generated prevascularized CCCs for further 7 or 14 days in myogenic culture conditions. Finally, the vascular and cardiac phenotypic inductions were characterized at the morphological, immunological, biochemical, molecular, and functional levels. Expression and functional analyses of the differentiated progenies revealed neo-cardiomyogenesis and neo-vasculogenesis. In this milieu, for instance, not only were hMSCs able to couple electromechanically with developing eCMs but were also able to contribute to the developing vasculature as mural cells, respectively. Hence, our unique 3D coculture system provides us a reproducible

NAD+ : A big player in cardiac and skeletal muscle remodeling and aging.

PubMed

Chaturvedi, Pankaj; Tyagi, Suresh C

2018-03-01

In the past decade, NAD+ has gained importance for its beneficial effects as antioxidant and anti-aging molecule. A paper in science by Zhang et al. () has described that NAD+ when replenished, ameliorates muscle dystrophy in mice by improving mitochondrial function. NAD+ was also demonstrated by the authors to improve the life span of mice. Cox et al. () demonstrated the cardiac effects of NAD+ which mitigated chronic heart failure via mitochondrial redox state mechanism. Cox et al. () also demonstrated that NAD+ is provided in the drinking water, it improves cardiac relaxation in volume overload model of heart failure. Although NAD+ has a profound anti-aging and anti-oxidant effects, its effect on humans and use as a dietary supplement needs more exploration. © 2017 Wiley Periodicals, Inc.

A Novel Human Tissue-Engineered 3-D Functional Vascularized Cardiac Muscle Construct

PubMed Central

Valarmathi, Mani T.; Fuseler, John W.; Davis, Jeffrey M.; Price, Robert L.

2017-01-01

Organ tissue engineering, including cardiovascular tissues, has been an area of intense investigation. The major challenge to these approaches has been the inability to vascularize and perfuse the in vitro engineered tissue constructs. Attempts to provide oxygen and nutrients to the cells contained in the biomaterial constructs have had varying degrees of success. The aim of this current study is to develop a three-dimensional (3-D) model of vascularized cardiac tissue to examine the concurrent temporal and spatial regulation of cardiomyogenesis in the context of postnatal de novo vasculogenesis during stem cell cardiac regeneration. In order to achieve the above aim, we have developed an in vitro 3-D functional vascularized cardiac muscle construct using human induced pluripotent stem cell-derived embryonic cardiac myocytes (hiPSC-ECMs) and human mesenchymal stem cells (hMSCs). First, to generate the prevascularized scaffold, human cardiac microvascular endothelial cells (hCMVECs) and hMSCs were co-cultured onto a 3-D collagen cell carrier (CCC) for 7 days under vasculogenic culture conditions. In this milieu, hCMVECs/hMSCs underwent maturation, differentiation, and morphogenesis characteristic of microvessels, and formed extensive plexuses of vascular networks. Next, the hiPSC-ECMs and hMSCs were co-cultured onto this generated prevascularized CCCs for further 7 or 14 days in myogenic culture conditions. Finally, the vascular and cardiac phenotypic inductions were analyzed at the morphological, immunological, biochemical, molecular, and functional levels. Expression and functional analyses of the differentiated cells revealed neo-angiogenesis and neo-cardiomyogenesis. Thus, our unique 3-D co-culture system provided us the apt in vitro functional vascularized 3-D cardiac patch that can be utilized for cellular cardiomyoplasty. PMID:28194397

Impact of Chronic Alcohol Ingestion on Cardiac Muscle Protein Expression

PubMed Central

Fogle, Rachel L.; Lynch, Christopher J.; Palopoli, Mary; Deiter, Gina; Stanley, Bruce A.; Vary, Thomas C.

2014-01-01

cardiac muscle protein expression represents a fundamental alteration induced by chronic alcohol consumption, consistent with changes in myocardial wall thickness measured under the same conditions. PMID:20477769

Myostatin promotes distinct responses on protein metabolism of skeletal and cardiac muscle fibers of rodents.

PubMed

Manfredi, L H; Paula-Gomes, S; Zanon, N M; Kettelhut, I C

2017-10-19

Myostatin is a novel negative regulator of skeletal muscle mass. Myostatin expression is also found in heart in a much less extent, but it can be upregulated in pathological conditions, such as heart failure. Myostatin may be involved in inhibiting protein synthesis and/or increasing protein degradation in skeletal and cardiac muscles. Herein, we used cell cultures and isolated muscles from rats to determine protein degradation and synthesis. Muscles incubated with myostatin exhibited an increase in proteolysis with an increase of Atrogin-1, MuRF1 and LC3 genes. Extensor digitorum longus muscles and C2C12 myotubes exhibited a reduction in protein turnover. Cardiomyocytes showed an increase in proteolysis by activating autophagy and the ubiquitin proteasome system, and a decrease in protein synthesis by decreasing P70S6K. The effect of myostatin on protein metabolism is related to fiber type composition, which may be associated to the extent of atrophy mediated effect of myostatin on muscle.

Myostatin promotes distinct responses on protein metabolism of skeletal and cardiac muscle fibers of rodents

PubMed Central

Manfredi, L.H.; Paula-Gomes, S.; Zanon, N.M.; Kettelhut, I.C.

2017-01-01

Myostatin is a novel negative regulator of skeletal muscle mass. Myostatin expression is also found in heart in a much less extent, but it can be upregulated in pathological conditions, such as heart failure. Myostatin may be involved in inhibiting protein synthesis and/or increasing protein degradation in skeletal and cardiac muscles. Herein, we used cell cultures and isolated muscles from rats to determine protein degradation and synthesis. Muscles incubated with myostatin exhibited an increase in proteolysis with an increase of Atrogin-1, MuRF1 and LC3 genes. Extensor digitorum longus muscles and C2C12 myotubes exhibited a reduction in protein turnover. Cardiomyocytes showed an increase in proteolysis by activating autophagy and the ubiquitin proteasome system, and a decrease in protein synthesis by decreasing P70S6K. The effect of myostatin on protein metabolism is related to fiber type composition, which may be associated to the extent of atrophy mediated effect of myostatin on muscle. PMID:29069231

A novel steroid-like compound F90927 exerting positive-inotropic effects in cardiac muscle.

PubMed

Pignier, Christophe; Keller, Markus; Vié, Bruno; Vacher, Bernard; Santelli, Maurice; Niggli, Ernst; Egger, Marcel; Le Grand, Bruno

2006-04-01

Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. F90363 is a racemic mixture composed of the stereoisomers (-)-F90926 and (+)-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10(3) times higher than F90927 and most likely resulting from an unspecific interaction. The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca2+ current I(Ca(L)) as a main target of F90927, while excluding other components of cardiac Ca2+ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. alpha- and beta-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. However, vessel contraction and stiffening of the cardiac muscle at high doses (>30 microM, 0.36 mg kg(-1), respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

Iodine-131 induces apoptosis in human cardiac muscle cells through the p53/Bax/caspase-3 and PIDD/caspase-2/ t‑BID/cytochrome c/caspase-3 signaling pathway.

PubMed

Wang, Yansheng; Liu, Changqing; Wang, Jianchun; Zhang, Yang; Chen, Linlin

2017-09-01

The aim of this study was to elucidate the effects of iodine-131 on the induction of apoptosis in human cardiac muscle cells and the underlying molecular mechanisms. We found that iodine-131 reduced cell proliferation, induced apoptosis, induced p53, PIDD, t-BID (mitochondria) protein expression, suppressed cytochrome c (mitochondria) protein expression, and increased Bax protein expression, and promoted caspase-2, -3 and -9 expression levels in human cardiac muscle cells. Meanwhile, si-p53 inhibited the effects of iodine-131 on the reduction in cell proliferation and induction of apoptosis in human cardiac muscle cells through regulation of Bax/cytochrome c/caspase-3 and PIDD/caspase‑2/t-BID/cytochrome c/caspase-3 signaling pathway. After si-Bax reduced the effects of iodine-131, it reduced cell proliferation and induced apoptosis in human cardiac muscle cells through the cytochrome c/caspase-3 signaling pathway. However, si-caspase-2 also reduced the effects of iodine-131 on the reduction of cell proliferation and induction of apoptosis in human cardiac muscle cells through the t-BID/cytochrome c/caspase-3 signaling pathway. These findings demonstrated that iodine-131 induces apoptosis in human cardiac muscle cells through the p53/Bax/caspase-3 and PIDD/caspase-2/t-BID/cytochrome c/caspase-3 signaling pathway.

Exercise training in Tgαq*44 mice during the progression of chronic heart failure: cardiac vs. peripheral (soleus muscle) impairments to oxidative metabolism.

PubMed

Grassi, Bruno; Majerczak, Joanna; Bardi, Eleonora; Buso, Alessia; Comelli, Marina; Chlopicki, Stefan; Guzik, Magdalena; Mavelli, Irene; Nieckarz, Zenon; Salvadego, Desy; Tyrankiewicz, Urszula; Skórka, Tomasz; Bottinelli, Roberto; Zoladz, Jerzy A; Pellegrino, Maria Antonietta

2017-08-01

Cardiac function, skeletal (soleus) muscle oxidative metabolism, and the effects of exercise training were evaluated in a transgenic murine model (Tgα q *44) of chronic heart failure during the critical period between the occurrence of an impairment of cardiac function and the stage at which overt cardiac failure ensues (i.e., from 10 to 12 mo of age). Forty-eight Tgα q *44 mice and 43 wild-type FVB controls were randomly assigned to control groups and to groups undergoing 2 mo of intense exercise training (spontaneous running on an instrumented wheel). In mice evaluated at the beginning and at the end of training we determined: exercise performance (mean distance covered daily on the wheel); cardiac function in vivo (by magnetic resonance imaging); soleus mitochondrial respiration ex vivo (by high-resolution respirometry); muscle phenotype [myosin heavy chain (MHC) isoform content; citrate synthase (CS) activity]; and variables related to the energy status of muscle fibers [ratio of phosphorylated 5'-AMP-activated protein kinase (AMPK) to unphosphorylated AMPK] and mitochondrial biogenesis and function [peroxisome proliferative-activated receptor-γ coactivator-α (PGC-1α)]. In the untrained Tgα q *44 mice functional impairments of exercise performance, cardiac function, and soleus muscle mitochondrial respiration were observed. The impairment of mitochondrial respiration was related to the function of complex I of the respiratory chain, and it was not associated with differences in CS activity, MHC isoforms, p-AMPK/AMPK, and PGC-1α levels. Exercise training improved exercise performance and cardiac function, but it did not affect mitochondrial respiration, even in the presence of an increased percentage of type 1 MHC isoforms. Factors "upstream" of mitochondria were likely mainly responsible for the improved exercise performance. NEW & NOTEWORTHY Functional impairments in exercise performance, cardiac function, and soleus muscle mitochondrial respiration

Hypertrophic cardiomyopathy mutation in cardiac troponin T (R95H) attenuates length-dependent activation in guinea pig cardiac muscle fibers.

PubMed

Mickelson, Alexis V; Chandra, Murali

2017-12-01

The central region of cardiac troponin T (TnT) is important for modulating the dynamics of muscle length-mediated cross-bridge recruitment. Therefore, hypertrophic cardiomyopathy mutations in the central region may affect cross-bridge recruitment dynamics to alter myofilament Ca 2+ sensitivity and length-dependent activation of cardiac myofilaments. Given the importance of the central region of TnT for cardiac contractile dynamics, we studied if hypertrophic cardiomyopathy-linked mutation (TnT R94H )-induced effects on contractile function would be differently modulated by sarcomere length (SL). Recombinant wild-type TnT (TnT WT ) and the guinea pig analog of the human R94H mutation (TnT R95H ) were reconstituted into detergent-skinned cardiac muscle fibers from guinea pigs. Steady-state and dynamic contractile measurements were made at short and long SLs (1.9 and 2.3 µm, respectively). Our results demonstrated that TnT R95H increased pCa 50 (-log of free Ca 2+ concentration) to a greater extent at short SL; TnT R95H increased pCa 50 by 0.11 pCa units at short SL and 0.07 pCa units at long SL. The increase in pCa 50 associated with an increase in SL from 1.9 to 2.3 µm (ΔpCa 50 ) was attenuated nearly twofold in TnT R95H fibers; ΔpCa 50 was 0.09 pCa units for TnT WT fibers but only 0.05 pCa units for TnT R95H fibers. The SL dependency of rate constants of cross-bridge distortion dynamics and tension redevelopment was also blunted by TnT R95H Collectively, our observations on the SL dependency of pCa 50 and rate constants of cross-bridge distortion dynamics and tension redevelopment suggest that mechanisms underlying the length-dependent activation cardiac myofilaments are attenuated by TnT R95H NEW & NOTEWORTHY Mutant cardiac troponin T (TnT R95H ) differently affects myofilament Ca 2+ sensitivity at short and long sarcomere length, indicating that mechanisms underlying length-dependent activation are altered by TnT R95H TnT R95H enhances myofilament Ca 2

Cardiac muscle wasting in individuals with cancer cachexia.

PubMed

Barkhudaryan, Anush; Scherbakov, Nadja; Springer, Jochen; Doehner, Wolfram

2017-11-01

Cachexia is a severe complication of cancer that adversely affects the course of the disease and is associated with high rates of mortality. Patients with cancer manifest symptoms, such as fatigue, shortness of breath, and impaired exercise tolerance, which are clinical signs of chronic heart failure. The aim of this study was to evaluate cardiac muscle wasting in cancer individuals. We retrospectively analysed 177 individuals who died of cancer, including 58 lung, 60 pancreatic, and 59 gastrointestinal (GI) cancers, and 42 cancer-free controls who died of other, non-cardiovascular reasons. Cancer cachexia (CC) was defined based on clinical and/or pathological diagnosis, body mass index (BMI) <20.0 kg/m 2 and/or oedema-free body weight loss of 5.0% during the previous year or less. The pathology reports were analysed for BMI, heart weight (HW), and left and right ventricular wall thicknesses (LVWT and RVWT, respectively). The analysis of clinical data included recording of biochemical parameters and medication data of study patients. CC was detected in 54 (30.5%) subjects. Individuals with CC had a significantly lower HW than non-cachectic subjects (363.1 ± 86.2 vs. 447.0 ± 128.9 g, P < 0.001) and control group (412.9 ± 75.8 g, P < 0.05). BMI correlated with HW in cases with GI cancer (r = 0.44, P < 0.001), lung cancer (r = 0.53, P < 0.0001), and pancreatic cancer (r = 0.39, P < 0.01). Body weight loss in individuals with lung, pancreatic, and GI cancers is accompanied by a decrease in HW. In patients with CC who receive cancer treatment, screening for cardiac muscle wasting may have clinical importance. © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

A Cycling Movement Based System for Real-Time Muscle Fatigue and Cardiac Stress Monitoring and Analysis

PubMed Central

Chen, Szi-Wen; Liaw, Jiunn-Woei; Chang, Ya-Ju; Chan, Hsiao-Lung; Chiu, Li-Yu

2015-01-01

In this study, we defined a new parameter, referred to as the cardiac stress index (CSI), using a nonlinear detrended fluctuation analysis (DFA) of heart rate (HR). Our study aimed to incorporate the CSI into a cycling based fatigue monitoring system developed in our previous work so the muscle fatigue and cardiac stress can be both continuously and quantitatively assessed for subjects undergoing the cycling exercise. By collecting electrocardiogram (ECG) signals, the DFA scaling exponent α was evaluated on the RR time series extracted from a windowed ECG segment. We then obtained the running estimate of α by shifting a one-minute window by a step of 20 seconds so the CSI, defined as the percentage of all the less-than-one α values, can be synchronously updated every 20 seconds. Since the rating of perceived exertion (RPE) scale is considered as a convenient index which is commonly used to monitor subjective perceived exercise intensity, we then related the Borg RPE scale value to the CSI in order to investigate and quantitatively characterize the relationship between exercise-induced fatigue and cardiac stress. Twenty-two young healthy participants were recruited in our study. Each participant was asked to maintain a fixed pedaling speed at a constant load during the cycling exercise. Experimental results showed that a decrease in DFA scaling exponent α or an increase in CSI was observed during the exercise. In addition, the Borg RPE scale and CSI were positively correlated, suggesting that the factors due to cardiac stress might also contribute to fatigue state during physical exercise. Since the CSI can effectively quantify the cardiac stress status during physical exercise, our system may be used in sports medicine, or used by cardiologists who carried out stress tests for monitoring heart condition in patients with heart diseases. PMID:26115515

Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival

PubMed Central

Ramos, Fresnida J.; Chen, Steven C.; Garelick, Michael G.; Dai, Dao-Fu; Liao, Chen-Yu; Schreiber, Katherine H.; MacKay, Vivian L.; An, Elroy H.; Strong, Randy; Ladiges, Warren C.; Rabinovitch, Peter S.; Kaeberlein, Matt; Kennedy, Brian K.

2013-01-01

Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna–/– mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna–/– mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors. PMID:22837538

skNAC, a Smyd1-interacting transcription factor, is involved in cardiac development and skeletal muscle growth and regeneration.

PubMed

Park, Chong Yon; Pierce, Stephanie A; von Drehle, Morgan; Ivey, Kathryn N; Morgan, Jayson A; Blau, Helen M; Srivastava, Deepak

2010-11-30

Cardiac and skeletal muscle development and maintenance require complex interactions between DNA-binding proteins and chromatin remodeling factors. We previously reported that Smyd1, a muscle-restricted histone methyltransferase, is essential for cardiogenesis and functions with a network of cardiac regulatory proteins. Here we show that the muscle-specific transcription factor skNAC is the major binding partner for Smyd1 in the developing heart. Targeted deletion of skNAC in mice resulted in partial embryonic lethality by embryonic day 12.5, with ventricular hypoplasia and decreased cardiomyocyte proliferation that were similar but less severe than in Smyd1 mutants. Expression of Irx4, a ventricle-specific transcription factor down-regulated in hearts lacking Smyd1, also depended on the presence of skNAC. Viable skNAC(-/-) adult mice had reduced postnatal skeletal muscle growth and impaired regenerative capacity after cardiotoxin-induced injury. Satellite cells isolated from skNAC(-/-) mice had impaired survival compared with wild-type littermate satellite cells. Our results indicate that skNAC plays a critical role in ventricular cardiomyocyte expansion and regulates postnatal skeletal muscle growth and regeneration in mice.

Severe isolated tricuspid insufficiency due to tricuspid papillary muscle rupture after a fall from a horse: treatment with port access minimally invasive cardiac surgery.

PubMed

Öz, Kürsad; Mayeran, Yousef; Van Praet, Frank; Codens, Jose; Vanerman, Hugo

2014-04-01

We report on the successful treatment of tricuspid valve insufficiency due to blunt chest injury using port-access minimally invasive cardiac surgery. The optimal surgical treatment of traumatic valvular insufficiency is discussed, including a brief review of the relevant literature.

[Cardiac arrest due to accidental hypothermia and prolonged cardiopulmonary resuscitation].

PubMed

Kot, P; Botella, J

2010-11-01

In cardiac arrest produced by accidental hypothermia, cardiopulmonary resuscitation must be prolonged until normal body temperature is achieved. There are different rewarming methods. In theory, the more invasive ones are elective in patients with cardiac arrest because of their higher rewarming speed. However, it has not been proven that these methods are better than the non-invasive ones. We present a case report of a patient with cardiac arrest due to accidental hypothermia who was treated without interruption for three hours with heart massage. This is the longest successful cardiopulmonary resuscitation known up-to-date in Spain. In order to rewarm the body, a combination of non-invasive methods was used: active external rewarming with convective warm air, gastric and bladder lavage with warm saline solution and intravenous warm saline infusion. This case shows that it is possible to treat hypothermic cardiac arrest successfully through these rewarming methods, which are both easy to apply and feasible in any hospital. Copyright © 2009 Elsevier España, S.L. y SEMICYUC. All rights reserved.

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations

PubMed Central

Lalani, Seema R.; Liu, Pengfei; Rosenfeld, Jill A.; Watkin, Levi B.; Chiang, Theodore; Leduc, Magalie S.; Zhu, Wenmiao; Ding, Yan; Pan, Shujuan; Vetrini, Francesco; Miyake, Christina Y.; Shinawi, Marwan; Gambin, Tomasz; Eldomery, Mohammad K.; Akdemir, Zeynep Hande Coban; Emrick, Lisa; Wilnai, Yael; Schelley, Susan; Koenig, Mary Kay; Memon, Nada; Farach, Laura S.; Coe, Bradley P.; Azamian, Mahshid; Hernandez, Patricia; Zapata, Gladys; Jhangiani, Shalini N.; Muzny, Donna M.; Lotze, Timothy; Clark, Gary; Wilfong, Angus; Northrup, Hope; Adesina, Adekunle; Bacino, Carlos A.; Scaglia, Fernando; Bonnen, Penelope E.; Crosson, Jane; Duis, Jessica; Maegawa, Gustavo H.B.; Coman, David; Inwood, Anita; McGill, Jim; Boerwinkle, Eric; Graham, Brett; Beaudet, Art; Eng, Christine M.; Hanchard, Neil A.; Xia, Fan; Orange, Jordan S.; Gibbs, Richard A.; Lupski, James R.; Yang, Yaping

2016-01-01

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3–9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3–9. Additionally, a homozygous exons 4–6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3–9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations. PMID:26805781

Sarcomere mechanics in uniform and non-uniform cardiac muscle: a link between pump function and arrhythmias.

PubMed

ter Keurs, Henk E D J; Shinozaki, Tsuyoshi; Zhang, Ying Ming; Zhang, Mei Luo; Wakayama, Yuji; Sugai, Yoshinao; Kagaya, Yutaka; Miura, Masahito; Boyden, Penelope A; Stuyvers, Bruno D M; Landesberg, Amir

2008-01-01

Starling's Law and the well-known end-systolic pressure-volume relationship (ESPVR) of the left ventricle reflect the effect of sarcomere length (SL) on stress (sigma) development and shortening by myocytes in the uniform ventricle. We show here that tetanic contractions of rat cardiac trabeculae exhibit a sigma-SL relationship at saturating [Ca2+] that depends on sarcomere geometry in a manner similar to skeletal sarcomeres and the existence of opposing forces in cardiac muscle shortened below slack length. The sigma-SL-[Ca2+]free relationships (sigma-SL-CaR) at submaximal [Ca2+] in intact and skinned trabeculae were similar, albeit that the sensitivity for Ca2+ of intact muscle was higher. We analyzed the mechanisms underlying the sigma-SL-CaR using a kinetic model where we assumed that the rates of Ca2+ binding by Troponin-C (Tn-C) and/or cross-bridge (XB) cycling are determined by SL, [Ca2+] or stress. We analyzed the correlation between the model results and steady state stress measurements at varied SL and [Ca2+] from skinned rat cardiac trabeculae to test the hypotheses that: (i) the dominant feedback mechanism is SL, stress or [Ca2+]-dependent; and (ii) the feedback mechanism regulates: Tn-C-Ca2+ affinity, XB kinetics or, unitary XB-force. The analysis strongly suggests that feedback of the number of strong XBs to cardiac Tn-C-Ca2+ affinity is the dominant mechanism that regulates XB recruitment. Application of this concept in a mathematical model of twitch-stress accurately reproduced the sigma-SL-CaR and the time course of twitch-stress as well as the time course of intracellular [Ca2+]i. Modeling of the response of the cardiac twitch to rapid stress changes using the above feedback model uniquely predicted the occurrence of [Ca2+]i transients as a result of accelerated Ca2+ dissociation from Tn-C. The above concept has important repercussions for the non-uniformly contracting heart in which arrhythmogenic Ca2+ waves arise from weakened areas in cardiac

Long-term administration of the TNF blocking drug Remicade (cV1q) to mdx mice reduces skeletal and cardiac muscle fibrosis, but negatively impacts cardiac function

PubMed Central

Ermolova, N.E.; Martinez, L.; Vetrone, S.A.; Jordan, M. C.; Roos, K. .P.; Sweeney, H.L.; Spencer, M.J.

2014-01-01

Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in the gene encoding dystrophin (DYS). Tumor necrosis factor (TNF) has been implicated in the pathogenesis of DMD since short-term treatment of mdx mice with TNF blocking drugs proved beneficial; however, it is not clear whether long-term treatment will also improve long-term outcomes of fibrosis and cardiac health. In this investigation, short and long-term dosing studies were carried out using the TNF blocking drug Remicade and a variety of outcome measures were assessed. Here we show no demonstrable benefit to muscle strength or morphology with 10mg/kg or 20 mg/kg Remicade; however, 3mg/kg produced positive strength benefits. Remicade treatment correlated with reductions in myostatin mRNA in the heart, and concomitant reductions in cardiac and skeletal fibrosis. Surprisingly, although Remicade treated mdx hearts were less fibrotic, reductions in LV mass and ejection fraction were also observed, and these changes coincided with reductions in AKT phosphorylation on threonine 308. Thus, TNF blockade benefits mdx skeletal muscle strength and fibrosis, but negatively impacts AKT activation, leading to deleterious changes to dystrophic heart function. These studies uncover a previously unknown relationship between TNF blockade and alteration of muscle growth signaling pathways. PMID:24844454

Suppression of skeletal muscle signal using a crusher coil: A human cardiac (31) p-MR spectroscopy study at 7 tesla.

PubMed

Schaller, Benoit; Clarke, William T; Neubauer, Stefan; Robson, Matthew D; Rodgers, Christopher T

2016-03-01

The translation of sophisticated phosphorus MR spectroscopy ((31)P-MRS) protocols to 7 Tesla (T) is particularly challenged by the issue of radiofrequency (RF) heating. Legal limits on RF heating make it hard to reliably suppress signals from skeletal muscle that can contaminate human cardiac (31)P spectra at 7T. We introduce the first surface-spoiling crusher coil for human cardiac (31)P-MRS at 7T. A planar crusher coil design was optimized with simulations and its performance was validated in phantoms. Crusher gradient pulses (100 μs) were then applied during human cardiac (31)P-MRS at 7T. In a phantom, residual signals were 50 ± 10% with BISTRO (B1 -insensitive train to obliterate signal), and 34 ± 8% with the crusher coil. In vivo, residual signals in skeletal muscle were 49 ± 4% using BISTRO, and 24 ± 5% using the crusher coil. Meanwhile, in the interventricular septum, spectral quality and metabolite quantification did not differ significantly between BISTRO (phosphocreatine/adenosine triphosphate [PCr/ATP] = 2.1 ± 0.4) and the crusher coil (PCr/ATP = 1.8 ± 0.4). However, the specific absorption rate (SAR) decreased from 96 ± 1% of the limit (BISTRO) to 16 ± 1% (crusher coil). A crusher coil is an SAR-efficient alternative for selectively suppressing skeletal muscle during cardiac (31)P-MRS at 7T. A crusher coil allows the use of sequence modules that would have been SAR-prohibitive, without compromising skeletal muscle suppression. © 2015 The Authors. Magnetic Resonance in Medicine Published by Wiley Periodicals, Inc. on behalf of International Society of Medicine in Resonance.

Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

PubMed Central

Cammarato, Anthony; Dambacher, Corey M.; Knowles, Aileen F.; Kronert, William A.; Bodmer, Rolf

2008-01-01

Striated muscle myosin is a multidomain ATP-dependent molecular motor. Alterations to various domains affect the chemomechanical properties of the motor, and they are associated with skeletal and cardiac myopathies. The myosin transducer domain is located near the nucleotide-binding site. Here, we helped define the role of the transducer by using an integrative approach to study how Drosophila melanogaster transducer mutations D45 and Mhc5 affect myosin function and skeletal and cardiac muscle structure and performance. We found D45 (A261T) myosin has depressed ATPase activity and in vitro actin motility, whereas Mhc5 (G200D) myosin has these properties enhanced. Depressed D45 myosin activity protects against age-associated dysfunction in metabolically demanding skeletal muscles. In contrast, enhanced Mhc5 myosin function allows normal skeletal myofibril assembly, but it induces degradation of the myofibrillar apparatus, probably as a result of contractile disinhibition. Analysis of beating hearts demonstrates depressed motor function evokes a dilatory response, similar to that seen with vertebrate dilated cardiomyopathy myosin mutations, and it disrupts contractile rhythmicity. Enhanced myosin performance generates a phenotype apparently analogous to that of human restrictive cardiomyopathy, possibly indicating myosin-based origins for the disease. The D45 and Mhc5 mutations illustrate the transducer's role in influencing the chemomechanical properties of myosin and produce unique pathologies in distinct muscles. Our data suggest Drosophila is a valuable system for identifying and modeling mutations analogous to those associated with specific human muscle disorders. PMID:18045988

Skeletal muscle

USDA-ARS?s Scientific Manuscript database

There are approximately 650-850 muscles in the human body these include skeletal (striated), smooth and cardiac muscle. The approximation is based on what some anatomists consider separate muscle or muscle systems. Muscles are classified based on their anatomy (striated vs. smooth) and if they are v...

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1

PubMed Central

Bouitbir, Jamal; Charles, Anne-Laure; Echaniz-Laguna, Andoni; Kindo, Michel; Daussin, Frédéric; Auwerx, Johan; Piquard, François; Geny, Bernard; Zoll, Joffrey

2012-01-01

Aims Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). Methods and results In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Conclusion Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles. PMID:21775390

Cardiac mechanics: Physiological, clinical, and mathematical considerations

NASA Technical Reports Server (NTRS)

Mirsky, I. (Editor); Ghista, D. N.; Sandler, H.

1974-01-01

Recent studies concerning the basic physiological and biochemical principles underlying cardiac muscle contraction, methods for the assessment of cardiac function in the clinical situation, and mathematical approaches to cardiac mechanics are presented. Some of the topics covered include: cardiac ultrastructure and function in the normal and failing heart, myocardial energetics, clinical applications of angiocardiography, use of echocardiography for evaluating cardiac performance, systolic time intervals in the noninvasive assessment of left ventricular performance in man, evaluation of passive elastic stiffness for the left ventricle and isolated heart muscle, a conceptual model of myocardial infarction and cardiogenic shock, application of Huxley's sliding-filament theory to the mechanics of normal and hypertrophied cardiac muscle, and a rheological modeling of the intact left ventricle. Individual items are announced in this issue.

Suppression of skeletal muscle signal using a crusher coil: A human cardiac 31p‐MR spectroscopy study at 7 tesla

PubMed Central

Clarke, William T.; Neubauer, Stefan; Robson, Matthew D.; Rodgers, Christopher T.

2015-01-01

Purpose The translation of sophisticated phosphorus MR spectroscopy (31P‐MRS) protocols to 7 Tesla (T) is particularly challenged by the issue of radiofrequency (RF) heating. Legal limits on RF heating make it hard to reliably suppress signals from skeletal muscle that can contaminate human cardiac 31P spectra at 7T. We introduce the first surface‐spoiling crusher coil for human cardiac 31P‐MRS at 7T. Methods A planar crusher coil design was optimized with simulations and its performance was validated in phantoms. Crusher gradient pulses (100 μs) were then applied during human cardiac 31P‐MRS at 7T. Results In a phantom, residual signals were 50 ± 10% with BISTRO (B1‐insensitive train to obliterate signal), and 34 ± 8% with the crusher coil. In vivo, residual signals in skeletal muscle were 49 ± 4% using BISTRO, and 24 ± 5% using the crusher coil. Meanwhile, in the interventricular septum, spectral quality and metabolite quantification did not differ significantly between BISTRO (phosphocreatine/adenosine triphosphate [PCr/ATP] = 2.1 ± 0.4) and the crusher coil (PCr/ATP = 1.8 ± 0.4). However, the specific absorption rate (SAR) decreased from 96 ± 1% of the limit (BISTRO) to 16 ± 1% (crusher coil). Conclusion A crusher coil is an SAR‐efficient alternative for selectively suppressing skeletal muscle during cardiac 31P‐MRS at 7T. A crusher coil allows the use of sequence modules that would have been SAR‐prohibitive, without compromising skeletal muscle suppression. Magn Reson Med 75:962–972, 2016. © 2015 The Authors. Magnetic Resonance in Medicine Published by Wiley Periodicals, Inc. on behalf of International Society of Medicine in Resonance. PMID:25924813

Improving cardiac conduction with a skeletal muscle sodium channel by gene and cell therapy

PubMed Central

Lu, Jia; Wang, Hong-Zhan; Jia, Zhiheng; Zuckerman, Joan; Lu, Zhongju; Guo, Yuanjian; Boink, Gerard J.J.; Brink, Peter R.; Robinson, Richard B.; Entcheva, Emilia; Cohen, Ira S.

2012-01-01

The voltage-gated Na+ channel is a critical determinant of the action potential upstroke. Increasing Na+ conductance may speed action potential propagation. Here we propose use of the skeletal muscle Na+ channel SkM1 as a more favorable gene than the cardiac isoform SCN5A to enhance conduction velocity in depolarized cardiac tissue. We used cells which electrically coupled with cardiac myocytes as a delivery platform to introduce the Na+ channels. HEK293 cells were stably transfected with SkM1 or SCN5A. SkM1 had a more depolarized (18mV shift) inactivation curve than SCN5A. We also found that SkM1 recovered faster from inactivation than SCN5A. When coupled with SkM1 expressing cells, cultured myocytes showed an increase in the dV/dtmax of the action potential. Expression of SCN5A had no such effect. In an in vitro cardiac syncytium, coculture of neonatal cardiac myocytes with SkM1 expressing but not SCN5A expressing cells significantly increased the conduction velocity under both normal and depolarized conditions. In an in vitro re-entry model induced by high frequency stimulation, expression of SkM1 also enhanced angular velocity of the induced re-entry. These results suggest that cells carrying a Na+ channel with a more depolarized inactivation curve can improve cardiac excitability and conduction in depolarized tissues. PMID:22526298

Spatial nonuniformity of contraction causes arrhythmogenic Ca2+ waves in rat cardiac muscle.

PubMed

Ter Keurs, Henk E D J; Wakayama, Yuji; Miura, Masahito; Stuyvers, Bruno D; Boyden, Penelope A; Landesberg, Amir

2005-06-01

Landesberg and Sideman's four state model of the cardiac cross-bridge (XB) hypothesizes a feedback of force development to Ca(2+) binding by troponin C (TnC). We have further modeled this behavior and observed that the force (F)-Ca(2+) relationship as well as the F-sarcomere length (SL) relationship and the time course of F and Ca(2+) transients in cardiac muscle can be reproduced faithfully by a single effect of F on deformation of the TnC-Ca complex and, thereby, on the dissociation rate of Ca(2+). Furthermore, this feedback predicts that rapid decline of F in the activated sarcomere causes release of Ca(2+) from TnC-Ca(2+), which is sufficient to initiate arrhythmogenic Ca(2+) release from the sarcoplasmic reticulum (SR). This work investigated the initiation of Ca(2+) waves underlying triggered propagated contractions (TPCs) in rat cardiac trabeculae under conditions that simulate functional nonuniformity caused by mechanical or ischemic local damage of the myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small constant flow jet of solution that reduces excitation-contraction coupling in myocytes within that segment. Force was measured, and SL as well as [Ca(2+)](i) were measured regionally. When the jet contained caffeine, 2,3-butanedione monoxime or low-[Ca(2+)], muscle-twitch F decreased and the sarcomeres in the exposed segment were stretched by shortening the normal regions outside the jet. During relaxation, the sarcomeres in the exposed segment shortened rapidly. Short trains of stimulation at 2.5 Hz reproducibly caused Ca(2+) waves to rise from the borders exposed to the jet. Ca(2+) waves started during F relaxation of the last stimulated twitch and propagated into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were triggered when the amplitude of the Ca(2+) wave increased by raising [Ca(2+)](o). The arrhythmias disappeared when the muscle

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy*

PubMed Central

Woodall, Benjamin P.; Woodall, Meryl C.; Luongo, Timothy S.; Grisanti, Laurel A.; Tilley, Douglas G.; Elrod, John W.; Koch, Walter J.

2016-01-01

GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds progression to heart failure. Despite the importance of this kinase in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease. In this study we generated a novel skeletal muscle-specific GRK2 knock-out (KO) mouse (MLC-Cre:GRK2fl/fl) to gain a better understanding of the role of GRK2 in skeletal muscle physiology. In isolated muscle mechanics testing, GRK2 ablation caused a significant decrease in the specific force of contraction of the fast-twitch extensor digitorum longus muscle yet had no effect on the slow-twitch soleus muscle. Despite these effects in isolated muscle, exercise capacity was not altered in MLC-Cre:GRK2fl/fl mice compared with wild-type controls. Skeletal muscle hypertrophy stimulated by clenbuterol, a β2-adrenergic receptor (β2AR) agonist, was significantly enhanced in MLC-Cre:GRK2fl/fl mice; mechanistically, this seems to be due to increased clenbuterol-stimulated pro-hypertrophic Akt signaling in the GRK2 KO skeletal muscle. In summary, our study provides the first insights into the role of GRK2 in skeletal muscle physiology and points to a role for GRK2 as a modulator of contractile properties in skeletal muscle as well as β2AR-induced hypertrophy. PMID:27566547

Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy.

PubMed

Woodall, Benjamin P; Woodall, Meryl C; Luongo, Timothy S; Grisanti, Laurel A; Tilley, Douglas G; Elrod, John W; Koch, Walter J

2016-10-14

GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds progression to heart failure. Despite the importance of this kinase in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease. In this study we generated a novel skeletal muscle-specific GRK2 knock-out (KO) mouse (MLC-Cre:GRK2 fl/fl ) to gain a better understanding of the role of GRK2 in skeletal muscle physiology. In isolated muscle mechanics testing, GRK2 ablation caused a significant decrease in the specific force of contraction of the fast-twitch extensor digitorum longus muscle yet had no effect on the slow-twitch soleus muscle. Despite these effects in isolated muscle, exercise capacity was not altered in MLC-Cre:GRK2 fl/fl mice compared with wild-type controls. Skeletal muscle hypertrophy stimulated by clenbuterol, a β 2 -adrenergic receptor (β 2 AR) agonist, was significantly enhanced in MLC-Cre:GRK2 fl/fl mice; mechanistically, this seems to be due to increased clenbuterol-stimulated pro-hypertrophic Akt signaling in the GRK2 KO skeletal muscle. In summary, our study provides the first insights into the role of GRK2 in skeletal muscle physiology and points to a role for GRK2 as a modulator of contractile properties in skeletal muscle as well as β 2 AR-induced hypertrophy. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Traumatic Tricuspid Regurgitation Following Cardiac Massage

PubMed Central

Na, Sungwon; Nam, Sang Beom; Lee, Yong Kyung; Oh, Young Jun

2007-01-01

We report a 66-yr-old male patient who developed tricuspid regurgitation secondary to internal cardiac massage. After uneventful off-pump coronary artery bypass surgery, the subject experienced cardiac arrest in the intensive care unit. External cardiac massage was initiated and internal cardiac massage was performed eventually. A transesophageal echocardiography revealed avulsion of the anterior papillary muscle and chordae to the anterior leaflet after successful cardiopulmonary resuscitation. Emergency repair of the papillary muscle was performed under cardiopulmonary bypass. PMID:17728519

Measurement of high-resolution mechanical contraction of cardiac muscle by induced eddy current.

PubMed

Lee, Young-Jae; Lee, Kang-Hwi; Kang, Seung-Jin; Kim, Kyeung-Nam; Khang, Seonah; Koo, Hye Ran; Gi, Sunok; Lee, Joo Hyeon; Lee, Jeong-Whan

2014-01-01

There are many types of devices which help to manage a personal health conditions such as heartbeat chest belt, pedometer and smart watch. And the most common device has the relationship with heart rate or ECG data. However, users have to attach some electrode or fasten the belt on the bare skin to measure bio-signal information. Therefore, most of people want more convenient and short-ready-time and no-need to attach electrode. In this paper, we proposed the high-resolution measuring system of mechanical activity of cardiac muscle and thereby measure heartbeat. The principle of the proposed measuring method is that the alternating current generate alternating magnetic field around coil. This primary magnetic field induces eddy current which makes magnetic field against primary coil in the nearby objects. To measure high-resolution changes of the induced secondary magnetic fields, we used digital Phase-locked loop(PLL) circuit which provides more high-resolution traces of frequency changes than the previous studies based on digital frequency counter method. As a result of our preliminary experiment, peak-peak intervals of the proposed method showed high correlation with R-R intervals of clinical ECG signals(r=0.9249). Also, from signal traces of the proposed method, we might make a conjecture that the contraction of atrium or ventricle is reflected by changing conductivity of cardiac muscle which is beating ceaselessly.

Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells

PubMed Central

Jackson, Kathyjo A.; Majka, Susan M.; Wang, Hongyu; Pocius, Jennifer; Hartley, Craig J.; Majesky, Mark W.; Entman, Mark L.; Michael, Lloyd H.; Hirschi, Karen K.; Goodell, Margaret A.

2001-01-01

Myocyte loss in the ischemically injured mammalian heart often leads to irreversible deficits in cardiac function. To identify a source of stem cells capable of restoring damaged cardiac tissue, we transplanted highly enriched hematopoietic stem cells, the so-called side population (SP) cells, into lethally irradiated mice subsequently rendered ischemic by coronary artery occlusion for 60 minutes followed by reperfusion. The engrafted SP cells (CD34–/low, c-Kit+, Sca-1+) or their progeny migrated into ischemic cardiac muscle and blood vessels, differentiated to cardiomyocytes and endothelial cells, and contributed to the formation of functional tissue. SP cells were purified from Rosa26 transgenic mice, which express lacZ widely. Donor-derived cardiomyocytes were found primarily in the peri-infarct region at a prevalence of around 0.02% and were identified by expression of lacZ and α-actinin, and lack of expression of CD45. Donor-derived endothelial cells were identified by expression of lacZ and Flt-1, an endothelial marker shown to be absent on SP cells. Endothelial engraftment was found at a prevalence of around 3.3%, primarily in small vessels adjacent to the infarct. Our results demonstrate the cardiomyogenic potential of hematopoietic stem cells and suggest a therapeutic strategy that eventually could benefit patients with myocardial infarction. PMID:11390421

Maximum shortening velocity of lymphatic muscle approaches that of striated muscle.

PubMed

Zhang, Rongzhen; Taucer, Anne I; Gashev, Anatoliy A; Muthuchamy, Mariappan; Zawieja, David C; Davis, Michael J

2013-11-15

Lymphatic muscle (LM) is widely considered to be a type of vascular smooth muscle, even though LM cells uniquely express contractile proteins from both smooth muscle and cardiac muscle. We tested the hypothesis that LM exhibits an unloaded maximum shortening velocity (Vmax) intermediate between that of smooth muscle and cardiac muscle. Single lymphatic vessels were dissected from the rat mesentery, mounted in a servo-controlled wire myograph, and subjected to isotonic quick release protocols during spontaneous or agonist-evoked contractions. After maximal activation, isotonic quick releases were performed at both the peak and plateau phases of contraction. Vmax was 0.48 ± 0.04 lengths (L)/s at the peak: 2.3 times higher than that of mesenteric arteries and 11.4 times higher than mesenteric veins. In cannulated, pressurized lymphatic vessels, shortening velocity was determined from the maximal rate of constriction [rate of change in internal diameter (-dD/dt)] during spontaneous contractions at optimal preload and minimal afterload; peak -dD/dt exceeded that obtained during any of the isotonic quick release protocols (2.14 ± 0.30 L/s). Peak -dD/dt declined with pressure elevation or activation using substance P. Thus, isotonic methods yielded Vmax values for LM in the mid to high end (0.48 L/s) of those the recorded for phasic smooth muscle (0.05-0.5 L/s), whereas isobaric measurements yielded values (>2.0 L/s) that overlapped the midrange of values for cardiac muscle (0.6-3.3 L/s). Our results challenge the dogma that LM is classical vascular smooth muscle, and its unusually high Vmax is consistent with the expression of cardiac muscle contractile proteins in the lymphatic vessel wall.

Single cardiac ventricular myosins are autonomous motors

PubMed Central

Wang, Yihua; Yuan, Chen-Ching; Kazmierczak, Katarzyna; Szczesna-Cordary, Danuta

2018-01-01

Myosin transduces ATP free energy into mechanical work in muscle. Cardiac muscle has dynamically wide-ranging power demands on the motor as the muscle changes modes in a heartbeat from relaxation, via auxotonic shortening, to isometric contraction. The cardiac power output modulation mechanism is explored in vitro by assessing single cardiac myosin step-size selection versus load. Transgenic mice express human ventricular essential light chain (ELC) in wild- type (WT), or hypertrophic cardiomyopathy-linked mutant forms, A57G or E143K, in a background of mouse α-cardiac myosin heavy chain. Ensemble motility and single myosin mechanical characteristics are consistent with an A57G that impairs ELC N-terminus actin binding and an E143K that impairs lever-arm stability, while both species down-shift average step-size with increasing load. Cardiac myosin in vivo down-shifts velocity/force ratio with increasing load by changed unitary step-size selections. Here, the loaded in vitro single myosin assay indicates quantitative complementarity with the in vivo mechanism. Both have two embedded regulatory transitions, one inhibiting ADP release and a second novel mechanism inhibiting actin detachment via strain on the actin-bound ELC N-terminus. Competing regulators filter unitary step-size selection to control force-velocity modulation without myosin integration into muscle. Cardiac myosin is muscle in a molecule. PMID:29669825

Accessory papillary muscles and papillary muscle hypertrophy are associated with sudden cardiac arrest of unknown cause.

PubMed

Uhm, Jae-Sun; Youn, Jong-Chan; Lee, Hye-Jeong; Park, Junbeom; Park, Jin-Kyu; Shim, Chi Young; Hong, Geu-Ru; Joung, Boyoung; Pak, Hui-Nam; Lee, Moon-Hyoung

2015-10-15

The present study was performed for elucidating the associations between the morphology of the papillary muscles (PMs) and sudden cardiac arrest (SCA). We retrospectively reviewed history, laboratory data, electrocardiography, echocardiography, coronary angiography, and cardiac CT/MRI for 190 patients with SCA. The prevalence of accessory PMs and PM hypertrophy in patients with SCA of unknown cause was compared with that in patients with SCA of known causes and 98 age- and sex-matched patients without SCA. An accessory PM was defined as a PM with origins separated from the anterolateral and posteromedial PMs, or a PM that branched into two or three bellies at the base of the anterolateral or posteromedial PM. PM hypertrophy was defined as at least one of the two PMs having a diameter of ≥1.1cm. In 49 patients (age 49.9±15.9years; 38 men) the cause of SCA was unknown, whereas 141 (age 54.2±16.6years; 121 men) had a known cause. The prevalence of accessory PMs was significantly higher in the unknown-cause group than in the known-cause group (24.5% and 7.8%, respectively; p=0.002) or the no-SCA group (7.1%, p=0.003). The same was true for PM hypertrophy (unknown-cause 12.2%, known-cause 2.1%, p=0.010; no SCA group 1.0%, p=0.006). By logistic regression, accessory PM and PM hypertrophy were independently associated with sudden cardiac arrest of unknown cause. An accessory PM and PM hypertrophy are associated with SCA of unknown cause. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block.

PubMed

Varghese, Anthony; Spindler, Anthony J; Paterson, David; Noble, Denis

2015-11-15

While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na(+) channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2-6.67 Hz) and exposed to various concentrations (5 × 10(-6) to 500 × 10(-6) mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10(-4) mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10(-6) mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na(+) channel blockers. Copyright © 2015 the American Physiological Society.

Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block

PubMed Central

Spindler, Anthony J.; Paterson, David; Noble, Denis

2015-01-01

While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na+ channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2–6.67 Hz) and exposed to various concentrations (5 × 10−6 to 500 × 10−6 mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10−4 mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10−6 mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na+ channel blockers. PMID:26342072

Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

PubMed

Parvatiyar, Michelle S; Marshall, Jamie L; Nguyen, Reginald T; Jordan, Maria C; Richardson, Vanitra A; Roos, Kenneth P; Crosbie-Watson, Rachelle H

2015-12-23

Duchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin-binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy. SSPN-null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β-adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN-null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α-, δ-, and γ-subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx(TG)) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix. SSPN regulates sarcolemmal expression of laminin-binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

N-Glycolylneuraminic acid deficiency worsens cardiac and skeletal muscle pathophysiology in α-sarcoglycan-deficient mice

PubMed Central

Martin, Paul T; Camboni, Marybeth; Xu, Rui; Golden, Bethannie; Chandrasekharan, Kumaran; Wang, Chiou-Miin; Varki, Ajit; Janssen, Paul M L

2013-01-01

Roughly 3 million years ago, an inactivating deletion occurred in CMAH, the human gene encoding CMP-Neu5Ac (cytidine-5′-monophospho-N-acetylneuraminic acid) hydroxylase (Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A. 1998. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci USA. 95:11751–11756). This inactivating deletion is now homozygous in all humans, causing the loss of N-glycolylneuraminic acid (Neu5Gc) biosynthesis in all human cells and tissues. The CMAH enzyme is active in other mammals, including mice, where Neu5Gc is an abundant form of sialic acid on cellular membranes, including those in cardiac and skeletal muscle. We recently demonstrated that the deletion of mouse Cmah worsened the severity of pathophysiology measures related to muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy (Chandrasekharan K, Yoon JH, Xu Y, deVries S, Camboni M, Janssen PM, Varki A, Martin PT. 2010. A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med. 2:42–54). Here, we demonstrate similar changes in cardiac and skeletal muscle pathology and physiology resulting from Cmah deletion in α-sarcoglycan-deficient (Sgca−/−) mice, a model for limb girdle muscular dystrophy 2D. These experiments demonstrate that loss of mouse Cmah can worsen disease severity in more than one form of muscular dystrophy and suggest that Cmah may be a general genetic modifier of muscle disease. PMID:23514716

Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell-Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine.

PubMed

Gao, Ling; Gregorich, Zachery R; Zhu, Wuqiang; Mattapally, Saidulu; Oduk, Yasin; Lou, Xi; Kannappan, Ramaswamy; Borovjagin, Anton V; Walcott, Gregory P; Pollard, Andrew E; Fast, Vladimir G; Hu, Xinyang; Lloyd, Steven G; Ge, Ying; Zhang, Jianyi

2018-04-17

Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm) by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human induced-pluripotent stem cells in a fibrin scaffold and then culturing the construct on a dynamic (rocking) platform. In vitro assessments of hCMPs suggest maturation in response to dynamic culture stimulation. In vivo assessments were conducted in a porcine model of myocardial infarction (MI). Animal groups included: MI hearts treated with 2 hCMPs (MI+hCMP, n=13), MI hearts treated with 2 cell-free open fibrin patches (n=14), or MI hearts with neither experimental patch (n=15); a fourth group of animals underwent sham surgery (Sham, n=8). Cardiac function and infarct size were evaluated by MRI, arrhythmia incidence by implanted loop recorders, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Additional studies examined the myocardial protein expression profile changes and potential mechanisms of action that related to exosomes from the cell patch. The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force generation, suggesting a maturation process during the dynamic culture. The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the periscar boarder zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that

Spatial nonuniformity of excitation-contraction coupling causes arrhythmogenic Ca2+ waves in rat cardiac muscle.

PubMed

Wakayama, Yuji; Miura, Masahito; Stuyvers, Bruno D; Boyden, Penelope A; ter Keurs, Henk E D J

2005-06-24

Ca2+ waves underlying triggered propagated contractions (TPCs) are initiated in damaged regions in cardiac muscle and cause arrhythmias. We studied Ca2+ waves underlying TPCs in rat cardiac trabeculae under experimental conditions that simulate the functional nonuniformity caused by local mechanical or ischemic local damage of myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small jet of solution with a composition that reduces excitation-contraction coupling (ECC) in myocytes within that segment. The jet solution contained either caffeine (5 mmol/L), 2,3-butanedione monoxime (BDM; 20 mmol/L), or low Ca2+ concentration ([Ca2+]; 0.2 mmol/L). Force was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques in 15 trabeculae. Simultaneously, [Ca2+]i was measured locally using epifluorescence of Fura-2. The jet of solution was applied perpendicularly to a small muscle region (200 to 300 microm) at constant flow. When the jet contained caffeine, BDM, or low [Ca2+], during the stimulated twitch, muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening normal regions outside the jet. Typical protocols for TPC induction (7.5 s-2.5 Hz stimulus trains at 23 degrees C; [Ca2+]o=2.0 mmol/L) reproducibly generated Ca2+ waves that arose from the border between shortening and stretched regions. Such Ca2+ waves started during force-relaxation of the last stimulated twitch of the train and propagated (0.2 to 2.8 mm/sec) into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were induced when the amplitude of the Ca2+-wave was increased by raising [Ca2+]o. Arrhythmias disappeared rapidly when uniformity of ECC throughout the muscle was restored by turning the jet off. These results show, for the first time, that nonuniform ECC can cause Ca2+ waves underlying TPCs and suggest that Ca2+ dissociated

Force Generation via β-Cardiac Myosin, Titin, and α-Actinin Drives Cardiac Sarcomere Assembly from Cell-Matrix Adhesions.

PubMed

Chopra, Anant; Kutys, Matthew L; Zhang, Kehan; Polacheck, William J; Sheng, Calvin C; Luu, Rebeccah J; Eyckmans, Jeroen; Hinson, J Travis; Seidman, Jonathan G; Seidman, Christine E; Chen, Christopher S

2018-01-08

Truncating mutations in the sarcomere protein titin cause dilated cardiomyopathy due to sarcomere insufficiency. However, it remains mechanistically unclear how these mutations decrease sarcomere content in cardiomyocytes. Utilizing human induced pluripotent stem cell-derived cardiomyocytes, CRISPR/Cas9, and live microscopy, we characterize the fundamental mechanisms of human cardiac sarcomere formation. We observe that sarcomerogenesis initiates at protocostameres, sites of cell-extracellular matrix adhesion, where nucleation and centripetal assembly of α-actinin-2-containing fibers provide a template for the fusion of Z-disk precursors, Z bodies, and subsequent striation. We identify that β-cardiac myosin-titin-protocostamere form an essential mechanical connection that transmits forces required to direct α-actinin-2 centripetal fiber assembly and sarcomere formation. Titin propagates diastolic traction stresses from β-cardiac myosin, but not α-cardiac myosin or non-muscle myosin II, to protocostameres during sarcomerogenesis. Ablating protocostameres or decoupling titin from protocostameres abolishes sarcomere assembly. Together these results identify the mechanical and molecular components critical for human cardiac sarcomerogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

[Analysis of surgical treatment with pectoralis major muscle flap for deep sternal infection after cardiac surgery: a case series of 189 patients].

PubMed

Liu, Dong; Wang, Wenzhang; Cai, Aibing; Han, Zhiyi; Li, Xiyuan; Ma, Jiagui

2015-03-01

To analyze and summarize the clinical features and experience in surgical treatment of deep sternal infection (DSWI). This was a retrospective study. From January 2008 to December 2013, 189 patients with secondary DSWI after cardiac surgery underwent the pectoralis major muscle flap transposition in our department. There were 116 male and 73 female patients. The mean age was (54 ± 21) years, the body mass index was (26. 1 ± 1. 3) kg/m2. The incidence of postoperation DSWI were after isolated coronary artery bypass grafting (CABG) in 93 patients, after other heart surgery plus CABG in 13 patients, after valve surgery in 47 patients, after thoracic aortic surgery in 16 patients, after congenital heart disease in 18 patients, and after cardiac injury in 2 patients. Clean patients' wound and extract secretions, clear the infection thoroughly by surgery and select antibiotics based on susceptibility results, and then repair the wound with appropriate muscle flap, place drain tube with negative pressure. Of all the 189 patients, 184 used isolate pectoralis, 1 used isolate rectus, and 4 used pectoralis plus rectus. The operative wounds of 179 patients were primary healing (94. 7%). Hospital discharge was postponed by 1 week for 7 patients, due to subcutaneous wound infection. Subcutaneous wound infection occurred again in 8 patients 1 week after hospital discharge, and their wounds healed after wound dressing. Nine patients (4. 7%) did not recover, due to residue of the sequestrum and costal chondritis, whom were later cured by undergoing a second treatment of debridement and pectoralis major muscle flap transposition. Eight patients died, in which 2 died of respiratory failure, 2 died of bacterial endocarditis with septicemia, 2 died of renal failure, 1 died of intraoperative bleeding leading to brain death and the 1 died of heart failure. The mortality rate was 4. 2% . The average length of postoperative hospital stay was (14 ± 5) days. The longest postoperative

Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction

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

Muthu, Priya; Wang, Li; Yuan, Chen-Ching

2012-04-02

The myosin essential light chain (ELC) is a structural component of the actomyosin cross-bridge, but its function is poorly understood, especially the role of the cardiac specific N-terminal extension in modulating actomyosin interaction. Here, we generated transgenic (Tg) mice expressing the A57G (alanine to glycine) mutation in the cardiac ELC known to cause familial hypertrophic cardiomyopathy (FHC). The function of the ELC N-terminal extension was investigated with the Tg-{Delta}43 mouse model, whose myocardium expresses a truncated ELC. Low-angle X-ray diffraction studies on papillary muscle fibers in rigor revealed a decreased interfilament spacing ({approx} 1.5 nm) and no alterations in cross-bridgemore » mass distribution in Tg-A57G mice compared to Tg-WT, expressing the full-length nonmutated ELC. The truncation mutation showed a 1.3-fold increase in I{sub 1,1}/I{sub 1,0}, indicating a shift of cross-bridge mass from the thick filament backbone toward the thin filaments. Mechanical studies demonstrated increased stiffness in Tg-A57G muscle fibers compared to Tg-WT or Tg-{Delta}43. The equilibrium constant for the cross-bridge force generation step was smallest in Tg-{Delta}43. These results support an important role for the N-terminal ELC extension in prepositioning the cross-bridge for optimal force production. Subtle changes in the ELC sequence were sufficient to alter cross-bridge properties and lead to pathological phenotypes.« less

Putting out the fire: what terminates calcium-induced calcium release in cardiac muscle?

PubMed

Stern, Michael D; Cheng, Heping

2004-06-01

The majority of contractile calcium in cardiac muscle is released from stores in the sarcoplasmic reticulum (SR), by a process of calcium-induced calcium release (CICR) through ryanodine receptors. Because CICR is intrinsically self-reinforcing, the stability of and graded regulation of cardiac EC coupling appear paradoxical. It is now well established that this gradation results from the stochastic recruitment of varying numbers of elementary local release events, which may themselves be regenerative, and which can be directly observed as calcium sparks. Ryanodine receptors (RyRs) are clustered in dense lattices, and most calcium sparks are now believed to involve activation of multiple RyRs. This implies that local CICR is regenerative, requiring a mechanism to terminate it. It was initially assumed that this mechanism was inactivation of the RyR, but during the decade since the discovery of sparks, no sufficiently strong inactivation mechanism has been demonstrated in vitro and all empirically determined gating schemes for the RyR give unstable EC coupling in Monte Carlo simulations. We consider here possible release termination mechanisms. Stochastic attrition is the spontaneous decay of active clusters due to random channel closure; calculations show that it is much too slow unless assisted by another process. Calcium-dependent RyR inactivation involving third-party proteins remains a viable but speculative mechanism; current candidates include calmodulin and sorcin. Local depletion of SR release terminal calcium could terminate release, however calculations and measurements leave it uncertain whether a sufficient diffusion resistance exists within the SR to sustain such depletion. Depletion could be assisted by dependence of RyR activity on SR lumenal [Ca(2+)]. There is substantial evidence for such lumenal activation, but it is not clear if it is a strong enough effect to account for the robust termination of sparks. The existence of direct interactions

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy.

PubMed

Petchey, Louisa K; Risebro, Catherine A; Vieira, Joaquim M; Roberts, Tom; Bryson, John B; Greensmith, Linda; Lythgoe, Mark F; Riley, Paul R

2014-07-01

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

PubMed Central

Petchey, Louisa K.; Risebro, Catherine A.; Vieira, Joaquim M.; Roberts, Tom; Bryson, John B.; Greensmith, Linda; Lythgoe, Mark F.; Riley, Paul R.

2014-01-01

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease. PMID:24938781

Strategic Positioning and Biased Activity of the Mitochondrial Calcium Uniporter in Cardiac Muscle*

PubMed Central

De La Fuente, Sergio; Fernandez-Sanz, Celia; Vail, Caitlin; Agra, Elorm J.; Holmstrom, Kira; Sun, Junhui; Mishra, Jyotsna; Williams, Dewight; Finkel, Toren; Murphy, Elizabeth; Joseph, Suresh K.; Sheu, Shey-Shing; Csordás, György

2016-01-01

Control of myocardial energetics by Ca2+ signal propagation to the mitochondrial matrix includes local Ca2+ delivery from sarcoplasmic reticulum (SR) ryanodine receptors (RyR2) to the inner mitochondrial membrane (IMM) Ca2+ uniporter (mtCU). mtCU activity in cardiac mitochondria is relatively low, whereas the IMM surface is large, due to extensive cristae folding. Hence, stochastically distributed mtCU may not suffice to support local Ca2+ transfer. We hypothesized that mtCU concentrated at mitochondria-SR associations would promote the effective Ca2+ transfer. mtCU distribution was determined by tracking MCU and EMRE, the proteins essential for channel formation. Both proteins were enriched in the IMM-outer mitochondrial membrane (OMM) contact point submitochondrial fraction and, as super-resolution microscopy revealed, located more to the mitochondrial periphery (inner boundary membrane) than inside the cristae, indicating high accessibility to cytosol-derived Ca2+ inputs. Furthermore, MCU immunofluorescence distribution was biased toward the mitochondria-SR interface (RyR2), and this bias was promoted by Ca2+ signaling activity in intact cardiomyocytes. The SR fraction of heart homogenate contains mitochondria with extensive SR associations, and these mitochondria are highly enriched in EMRE. Size exclusion chromatography suggested for EMRE- and MCU-containing complexes a wide size range and also revealed MCU-containing complexes devoid of EMRE (thus disabled) in the mitochondrial but not the SR fraction. Functional measurements suggested more effective mtCU-mediated Ca2+ uptake activity by the mitochondria of the SR than of the mitochondrial fraction. Thus, mtCU “hot spots” can be formed at the cardiac muscle mitochondria-SR associations via localization and assembly bias, serving local Ca2+ signaling and the excitation-energetics coupling. PMID:27637331

Ichthyophonus-induced cardiac damage: a mechanism for reduced swimming stamina in salmonids.

PubMed

Kocan, R; Lapatra, S; Gregg, J; Winton, J; Hershberger, P

2006-09-01

Swimming stamina, measured as time-to-fatigue, was reduced by approximately two-thirds in rainbow trout experimentally infected with Ichthyophonus. Intensity of Ichthyophonus infection was most severe in cardiac muscle but multiple organs were infected to a lesser extent. The mean heart weight of infected fish was 40% greater than that of uninfected fish, the result of parasite biomass, infiltration of immune cells and fibrotic (granuloma) tissue surrounding the parasite. Diminished swimming stamina is hypothesized to be due to cardiac failure resulting from the combination of parasite-damaged heart muscle and low myocardial oxygen supply during sustained aerobic exercise. Loss of stamina in Ichthyophonus-infected salmonids could explain the poor performance previously reported for wild Chinook and sockeye salmon stocks during their spawning migration.

Neuromuscular blockade in cardiac surgery: an update for clinicians.

PubMed

Hemmerling, Thomas M; Russo, Gianluca; Bracco, David

2008-01-01

There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary) sufficiently profound neuromuscular blockade during surgery and immediate re-establishment of normal neuromuscular transmission at the end of surgery. Postoperative residual muscle paralysis is one of the major hurdles for immediate or early extubation after cardiac surgery. Nondepolarising neuromuscular blocking drugs for cardiac surgery should therefore be easy to titrate, of rapid onset and short duration of action with a pathway of elimination independent from hepatic or renal dysfunction, and should equally not affect haemodynamic stability. The difference between repetitive bolus application and continuous infusion is outlined in this review, with the pharmacodynamic and pharmacokinetic characteristics of vecuronium, pancuronium, rocuronium, and cisatracurium. Kinemyography and acceleromyography are the most important currently used neuromuscular monitoring methods. Whereas monitoring at the adductor pollicis muscle is appropriate at the end of surgery, monitoring of the corrugator supercilii muscle better reflects neuromuscular blockade at more central, profound muscles, such as the diaphragm, larynx, or thoraco-abdominal muscles. In conclusion, cisatracurium or rocuronium is recommended for neuromuscular blockade in modern cardiac surgery.

Vascular smooth muscle cell polyploidy and cardiomyocyte hypertrophy due to chronic NOS inhibition in vivo.

PubMed

Devlin, A M; Brosnan, M J; Graham, D; Morton, J J; McPhaden, A R; McIntyre, M; Hamilton, C A; Reid, J L; Dominiczak, A F

1998-01-01

To assess the vascular and cardiac response to NO (nitric oxide) synthase (NOS) blockade in vivo, Wistar-Kyoto rats (WKY) were treated for 3 wk with NG-nitro-L-arginine methyl ester (L-NAME; 10 mg.kg-1.day-1). L-NAME treatment induced hypertension that was associated with increased plasma renin activity. Flow cytometry cell cycle DNA analysis showed that aortic vascular smooth muscle cells (VSMC) from L-NAME-treated WKY had a significantly higher polyploid population compared with WKY controls. Using organ bath experiments, we have shown that aortic rings from L-NAME-treated WKY have an increased contractile response to phenylephrine and impaired relaxation to carbachol compared with control rings. NOS blockade in vivo caused a significant increase in cardiac and left ventricular hypertrophy. Northern mRNA analysis of the myocardium showed that L-NAME treatment caused reexpression of the fetal skeletal alpha-actin isoform without alterations in collagen type I expression, a pattern indicating true hypertrophy of the cardiomyocytes. These studies provide further insight to confirm that NO deficiency in vivo results in the development of vascular and cardiac hypertrophy.

Do interindividual differences in cardiac output during submaximal exercise explain differences in exercising muscle oxygenation and ratings of perceived exertion?

PubMed

Bentley, Robert F; Jones, Joshua H; Hirai, Daniel M; Zelt, Joel T; Giles, Matthew D; Raleigh, James P; Quadrilatero, Joe; Gurd, Brendon J; Neder, J Alberto; Tschakovsky, Michael E

2018-01-01

Considerable interindividual differences in the Q˙-V˙O2 relationship during exercise have been documented but implications for submaximal exercise tolerance have not been considered. We tested the hypothesis that these interindividual differences were associated with differences in exercising muscle deoxygenation and ratings of perceived exertion (RPE) across a range of submaximal exercise intensities. A total of 31 (21 ± 3 years) healthy recreationally active males performed an incremental exercise test to exhaustion 24 h following a resting muscle biopsy. Cardiac output (Q˙ L/min; inert gas rebreathe), oxygen uptake (V˙O2 L/min; breath-by-breath pulmonary gas exchange), quadriceps saturation (near infrared spectroscopy) and exercise tolerance (6-20; Borg Scale RPE) were measured. The Q˙-V˙O2 relationship from 40 to 160 W was used to partition individuals post hoc into higher (n = 10; 6.3 ± 0.4) versus lower (n = 10; 3.7 ± 0.4, P < 0.001) responders. The Q˙-V˙O2 difference between responder types was not explained by arterial oxygen content differences (P = 0.5) or peripheral skeletal muscle characteristics (P from 0.1 to 0.8) but was strongly associated with stroke volume (P < 0.05). Despite considerable Q˙-V˙O2 difference between groups, no difference in quadriceps deoxygenation was observed during exercise (all P > 0.4). Lower cardiac responders had greater leg (P = 0.027) and whole body (P = 0.03) RPE only at 185 W, but this represented a higher %peak V˙O2 in lower cardiac responders (87 ± 15% vs. 66 ± 12%, P = 0.005). Substantially lower Q˙-V˙O2 in the lower responder group did not result in altered RPE or exercising muscle deoxygenation. This suggests substantial recruitment of blood flow redistribution in the lower responder group as part of protecting matching of exercising muscle oxygen delivery to demand. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The

Cardiac myofilaments: mechanics and regulation

NASA Technical Reports Server (NTRS)

de Tombe, Pieter P.; Bers, D. M. (Principal Investigator)

2003-01-01

The mechanical properties of the cardiac myofilament are an important determinant of pump function of the heart. This report is focused on the regulation of myofilament function in cardiac muscle. Calcium ions form the trigger that induces activation of the thin filament which, in turn, allows for cross-bridge formation, ATP hydrolysis, and force development. The structure and protein-protein interactions of the cardiac sarcomere that are responsible for these processes will be reviewed. The molecular mechanism that underlies myofilament activation is incompletely understood. Recent experimental approaches have been employed to unravel the mechanism and regulation of myofilament mechanics and energetics by activator calcium and sarcomere length, as well as contractile protein phosphorylation mediated by protein kinase A. Central to these studies is the question whether such factors impact on muscle function simply by altering thin filament activation state, or whether modulation of cross-bridge cycling also plays a part in the responses of muscle to these stimuli.

[Sudden cardiac death due to sarcoidosis. Case report].

PubMed

Sejben, István; Som, Zoltán; Cserni, Gábor

2017-07-01

Sarcoidosis is a systemic granulomatous disease of unknown aetiology, which is characterized by bilateral hilar lymphadenopathy and pulmonary disease. Clinically detected cardiac involvement occurs in 5% of sarcoid patients, although cardiac manifestations are discovered in 25% of the cases at autopsy. Sarcoid heart disease frequently causes atrioventricular block. The authors present the case of a 44-year-old man with bradycardia. On admission, second degree Mobitz II, then third degree atrioventricular block was diagnosed. Coronarography showed normal coronary arteries. 2.5 years following artificial Biotronik Entovis DR type pacemaker implantation, sudden cardiac death occurred. Autopsy revealed sarcoidosis with cardiac, pulmonary, splenic, renal and lymph node involvement. In case of young or middle-aged patients with atrioventricular block, it is best to search for other causes if the most common coronary origin can be excluded. Orv Hetil. 2017; 158(27): 1067-1070.

Effect of inspiratory muscle training before cardiac surgery in routine care.

PubMed

Valkenet, Karin; de Heer, Frederiek; Backx, Frank J G; Trappenburg, Jaap C A; Hulzebos, Erik H J; Kwant, Simone; van Herwerden, Lex A; van de Port, Ingrid G L

2013-05-01

Inspiratory muscle training (IMT) before cardiac surgery has proved to be a promising intervention to reduce postoperative pneumonia in a randomized controlled trial setting. Effects of IMT in routine care have not been reported. The purpose of this study was to investigate the effect of IMT before cardiac surgery on postoperative pneumonia in routine care at a Dutch university medical center using propensity scoring. This was an observational cohort study. All candidates for cardiac surgery were preoperatively stratified by a physical therapist for low risk or high risk for postoperative pulmonary complications. Patients at high risk either engaged in an unsupervised IMT program (20 minutes a day) at home for at least 2 weeks before surgery (group 1) or received usual care (no IMT) (group 2). Results in terms of outcome measures were adjusted with propensity scores to reduce bias caused by nonrandom treatment assignment. The results showed that of the 94 patients at high risk in group 1, 1 patient (1.1%) developed a postoperative pneumonia. In group 2, 8 out of the 252 patients at high risk (3.2%) developed this pulmonary complication (adjusted odds ratio=0.34, 95% confidence interval=0.04-3.38). No significant differences were found regarding median (25th-75th percentile) ventilation time (7 [5-9] hours versus 7 [5-10] hours), length of stay in the intensive care unit (23 [21-24] hours versus 23 [21-25] hours), or total postoperative length of stay (7 [6-11] days versus 7 [5-9] days). The most important limitations of this study were confounding, incomplete data collection, and a low incidence of the primary outcome. Propensity scoring is believed to be a valuable tool of great potential interest to researchers in the field of observational studies. Whether IMT in routine care resulted in less postoperative pneumonia cannot be concluded.

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.

KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, mediates both smooth muscle cell activation and cardiac hypertrophy.

PubMed

Nagai, Ryozo; Shindo, Takayuki; Manabe, Ichiro; Suzuki, Toru; Kurabayashi, Masahiko

2003-01-01

Cardiac and vascular biology need to be approached interactively because they share many common biological features as seen in activation of the local renin-angiotensin system, angiogenesis, and extracellular matrix production. We previously reported KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, to activate various gene promoters that are activated in phenotypically modulated smooth muscle cells, such as a nonmuscle type myosin heavy chain gene SMemb, plasminogen activator inhibitor-1 (PAI-1), iNOS, PDGF-A, Egr-1 and VEGF receptors at least in vitro. KLF5/BTEB2 mRNA levels are downregulated with vascular development but upregulated in neointima that is produced in response to vascular injury. Mitogenic stimulation activates KLF5/BTEB2 gene expression through MEK1 and Egr-1. Chromatin immunoprecipitation assay showed KLF5/BTEB2 to be induced and to bind the promoter of the PDGF-A gene in response to angiotensin II stimulation. In order to define the role of KLF5/BTEB2 in cardiovascular remodeling, we targeted the KLF5/BTEB2 gene in mice. Homozygous mice resulted in early embryonic lethality whereas heterozygous mice were apparently normal. However, in response to external stress, arteries of heterozygotes exhibited diminished levels of smooth muscle and adventitial cell activation. Furthermore, cardiac fibrosis and hypertrophy induced by continuous angiotensin II infusion. We also found that RARa binds KLF5/BTEB2, and that Am80, a potent synthetic RAR agonist, inhibits angiotensin II-induced cardiac hypertrophy. These results indicate that KLF5/BTEB2 is an essential transcription factor that causes not only smooth muscle phenotypic modulation but also cardiac hypertrophy and fibrosis.

Hypertrophic gene expression induced by chronic stretch of excised mouse heart muscle.

PubMed

Raskin, Anna M; Hoshijima, Masahiko; Swanson, Eric; McCulloch, Andrew D; Omens, Jeffrey H

2009-09-01

Altered mechanical stress and strain in cardiac myocytes induce modifications in gene expression that affects cardiac remodeling and myocyte contractile function. To study the mechanisms of mechanotransduction in cardiomyocytes, probing alterations in mechanics and gene expression has been an effective strategy. However, previous studies are self-limited due to the general use of isolated neonatal rodent myocytes or intact animals. The main goal of this study was to develop a novel tissue culture chamber system for mouse myocardium that facilitates loading of cardiac tissue, while measuring tissue stress and deformation within a physiological environment. Intact mouse right ventricular papillary muscles were cultured in controlled conditions with superfusate at 95% O2/ 5% CO2, and 34 degrees C, such that cell to extracellular matrix adhesions as well as cell to cell adhesions were undisturbed and both passive and active mechanical properties were maintained without significant changes. The system was able to measure the induction of hypertrophic markers (BNP, ANP) in tissue after 2 hrs and 5 hrs of stretch. ANP induction was highly correlated with the diastolic load of the muscle but not with developed systolic load. Load induced ANP expression was blunted in muscles from muscle-LIM protein knockout mice, in which defective mechanotransduction pathways have been predicted.

Striated Muscle Function, Regeneration, and Repair

PubMed Central

Shadrin, I.Y.; Khodabukus, A.; Bursac, N.

2016-01-01

As the only striated muscle tissues in the body, skeletal and cardiac muscle share numerous structural and functional characteristics, while exhibiting vastly different size and regenerative potential. Healthy skeletal muscle harbors a robust regenerative response that becomes inadequate after large muscle loss or in degenerative pathologies and aging. In contrast, the mammalian heart loses its regenerative capacity shortly after birth, leaving it susceptible to permanent damage by acute injury or chronic disease. In this review, we compare and contrast the physiology and regenerative potential of native skeletal and cardiac muscles, mechanisms underlying striated muscle dysfunction, and bioengineering strategies to treat muscle disorders. We focus on different sources for cellular therapy, biomaterials to augment the endogenous regenerative response, and progress in engineering and application of mature striated muscle tissues in vitro and in vivo. Finally, we discuss the challenges and perspectives in translating muscle bioengineering strategies to clinical practice. PMID:27271751

Ichthyophonus-induced cardiac damage: a mechanism for reduced swimming stamina in salmonids

USGS Publications Warehouse

Kocan, R.; LaPatra, S.; Gregg, J.; Winton, J.; Hershberger, P.

2006-01-01

Swimming stamina, measured as time-to-fatigue, was reduced by approximately two-thirds in rainbow trout experimentally infected with Ichthyophonus. Intensity of Ichthyophonus infection was most severe in cardiac muscle but multiple organs were infected to a lesser extent. The mean heart weight of infected fish was 40% greater than that of uninfected fish, the result of parasite biomass, infiltration of immune cells and fibrotic (granuloma) tissue surrounding the parasite. Diminished swimming stamina is hypothesized to be due to cardiac failure resulting from the combination of parasite-damaged heart muscle and low myocardial oxygen supply during sustained aerobic exercise. Loss of stamina in Ichthyophonus-infected salmonids could explain the poor performance previously reported for wild Chinook and sockeye salmon stocks during their spawning migration. ?? 2006 Blackwell Publishing Ltd.

Skeletal muscle biopsy studies of cardiac patients.

PubMed

Fekete, G; Boros, Z; Cserhalmi, L; Apor, P

1987-01-01

Eleven patients diagnosed and treated for congestive cardiomyopathy (COCM) of unknown aetiology, and another 10 patients, with congestive alcoholic heart muscle disease (ACOCM) were studied. Muscle biopsy samples were obtained from the vastus lateralis (VL) and the gastrocnemius (G) muscles. In part of the sample muscle the fibre pattern was classified by means of ATPase activity staining, a technique based on the pH lability of the fibres concerned. Fibre typing and area measurements were carried out by light microscope. The other part of the sample was used as muscle homogenate of which the Ca2+-activated ATPase activity as well as citrate synthetase (CS) and aldolase activities were measured. No significant difference was found in these enzyme activities between the two groups of patients. The proportion of the slow twitch (ST) fibres in the VL, mainly in the patients with ACOCM, was lower as compared to data for healthy subjects. A similar tendency was revealed for G. In both muscles tested, the area of ST fibres was smaller in the ACOCM group. The fast twitch (FT) fibre area proved to be slightly different in the two groups of subjects tested. Occurrence of degenerative signs in the histological tests was higher in the ACOCM than in the COCM group. It was concluded that differences in the skeletal muscles of patients with ACOCM and COCM may primarily account for the alcoholism. The disease of the heart muscle has little effect on the function of skeletal muscle. Even so, a low amount or lack of physical activity may have an unfavourable influence on the skeletal muscles of patients with heart muscle disease.

Determination of cardiac size following space missions of different durations: the second manned Skylab mission.

PubMed

Nicogossian, A; Hoffler, G W; Johnson, R L; Gowen, R J

1976-04-01

A simple method to estimate cardiac size from single frontal plane chest roentgenograms has been described. Pre- and postflight chest X-rays from Apollo 17, and Skylab 2 and 3 have been analyzed for changes in the cardiac silhouette size. The data obtained from the computed cardiothoracic areal ratios compared well with the clinical cardiothoracic diametral ratios (r = .86). Though an overall postflight decrease in cardiac size is evident, the mean difference was not statistically significant (n = 8). The individual decreases in the cardiac silhouette size postflight are thought to be due to decrements in intracardiac chamber volumes rather than in myocardial muscle mass.

Determination of cardiac size following space missions of different durations - The second manned Skylab mission

NASA Technical Reports Server (NTRS)

Nicogossian, A.; Hoffler, G. W.; Johnson, R. L.; Gowen, R. J.

1976-01-01

A simple method to estimate cardiac size from single frontal plane chest roentgenograms has been described. Pre- and postflight chest X-rays from Apollo 17, and Skylab 2 and 3 have been analyzed for changes in the cardiac silhouette size. The data obtained from the computed cardiothoracic areal ratios compared well with the clinical cardiothoracic diametral ratios (r = .86). Though an overall postflight decrease in cardiac size is evident, the mean difference was not statistically significant (n = 8). The individual decreases in the cardiac silhouette size postflight are thought to be due to decrements in intracardiac chamber volumes rather than in myocardial muscle mass.

Cardiac implantable electronic device infection due to Mycobacterium species: a case report and review of the literature.

PubMed

Al-Ghamdi, Bandar; Widaa, Hassan El; Shahid, Maie Al; Aladmawi, Mohammed; Alotaibi, Jawaher; Sanei, Aly Al; Halim, Magid

2016-08-24

Infection of cardiac implantable electronic devices is a serious cardiovascular disease and it is associated with a high mortality. Mycobacterium species may rarely cause cardiac implantable electronic devices infection. We are reporting a case of miliary tuberculosis in an Arab patient with dilated cardiomyopathy and a cardiac resynchronization therapy-defibrillator device that was complicated with infection of his cardiac resynchronization therapy-defibrillator device. To our knowledge, this is the third case in the literature with such a presentation and all patients died during the course of treatment. This underscores the importance of early diagnosis and management. We also performed a literature review of reported cases of cardiac implantable electronic devices infection related to Mycobacterium species. Cardiac implantable electronic devices infection due to Mycobacterium species is an uncommon but a well-known entity. Early diagnosis and prompt management may result in a better outcome.

THE LOCALIZATION OF CHOLINESTERASE ACTIVITY IN RAT CARDIAC MUSCLE BY ELECTRON MICROSCOPY

PubMed Central

Karnovsky, Morris J.

1964-01-01

A method has been developed for localizing sites of cholinesterase activity in rat cardiac muscle by electron microscopy. The method utilizes thiocholine esters as substrates, and is believed to be dependent on the reduction of ferricyanide to ferrocyanide by thiocholine released by enzymatic activity. The ferrocyanide thus formed is captured by copper to form fine, electron-opaque deposits of copper ferrocyanide, which sharply delineate sites of enzymatic activity at the ultrastructural level. Cholinesterase activity in formalin-fixed heart muscle was localized: (a) in longitudinal elements of the sarcoplasmic reticulum, but not in the T, or transverse, elements; and (b) in the A band, with virtually no activity noted in the M band, or in the H zone. The I band was also negative. No activity was detected in the sarcolemma, or in invaginations of the sarcolemma at the level of the Z band. The perinuclear element of the sarcoplasmic (endoplasmic) reticulum was frequently strongly positive. Activity at all sites was completely abolished by omitting the substrates, or by inhibition with eserine 10-4 M and diisopropylfluorophosphate 10-5 M. Eserine 10-5 M completely inhibited reaction in the sarcoplasmic reticulum, and virtually abolished that in the A band. These observations, together with the use of the relatively specific substrates and suitable controls to eliminate non-enzymatic staining, indicate that cholinesterase activity was being demonstrated. The activity in rat heart against different substrates was that of non-specific cholinesterases, in accordance with biochemical data. The activity in the A band was considered to be probably due to myosincholinesterase. It is proposed that the localization of cholinesterases in myocardium at the ultrastructural level should be taken into account in considering the possible functions of these myocardial enzymes, and it is hoped that knowledge of their localization will open up new avenues of approach in considering

Massive pericardial effusion without cardiac tamponade due to subclinical hypothyroidism (Hashimoto's disease).

PubMed

Papakonstantinou, Panteleimon E; Gourniezakis, Nikolaos; Skiadas, Christos; Patrianakos, Alexandros; Gikas, Achilleas

2018-05-01

Hypothyroidism is a significant cause of pericardial effusion. However, large pericardial effusions due to hypothyroidism are extremely rare. Hormone replacement therapy is the cornerstone of treatment for hypothyroidism and regular follow-up of patients after initiation of the therapy is indicated. Herein, the case of a 70-year-old woman with a massive pericardial effusion due to Hashimoto's disease is presented. A 70-year-old female from a rural village on the island of Crete, Greece, was admitted to our hospital due to a urinary tract infection. She was under hormone replacement therapy with levothyroxine 100 µg once a day for Hashimoto's disease. Two years previously, the patient had had an episode of pericarditis due to hypothyroidism and had undergone a computed tomography-guided pericardiocentesis. The patient did not have regular follow-up and did not take the hormone replacement therapy properly. On admission, the patient's chest X-ray incidentally showed a possible pericardial effusion. The patient was referred for echocardiography, which revealed a massive pericardial effusion. Beck's triad was absent. Thyroid hormones were consistent with subclinical hypothyroidism: thyroid-stimulating hormone (TSH) 30.25 mIU/mL (normal limits: 0.25-3.43); free thyroxin 4 0.81 ng/dL (normal limits: 0.7-1.94). The patient had a score of 5 on the scale outlined by the European Society of Cardiology (ESC) position statement on triage strategy for cardiac tamponade and, despite the absence of cardiac tamponade, a pericardiocentesis was performed after 48 hours. The patient was treated with 125 µg levothyroxine orally once daily. This was a rare case of an elderly female patient from a rural village with chronic massive pericardial effusion due to subclinical hypothyroidism without cardiac tamponade. Hypothyroidism should be included in the differential diagnosis of pericardial effusion, especially in a case of unexplained pericardial fluid. Initiation of hormone

Cardiac treatment in neuro-muscular diseases.

PubMed

Nigro, G; Politano, L; Passamano, L; Palladino, A; De Luca, F; Nigro, Ge; Comi, L I

2006-12-01

The authors have been treating heart involvement in muscle dystrophy since 1978. However, this study aimed to define recent therapeutic protocols, evaluating the results of cardiac treatment, performed between 1st February 2004 and 31st July, 2006. In this period, 100 Becker, 136 Duchenne, 44 Limb-girdle and 116 Steinert patients were treated. In that same period, a large group of MD patients refusing cardiac therapy have also been followed. All patients had previously been classified in the appropriate stage of cardiomyopathy and examined at least twice every year and even every week if presenting heart failure. The results show the usefulness of the recent protocols of treatment of cardiac involvement in muscle dystrophy patients.

Cardiac muscle regeneration: lessons from development

PubMed Central

Mercola, Mark; Ruiz-Lozano, Pilar; Schneider, Michael D.

2011-01-01

The adult human heart is an ideal target for regenerative intervention since it does not functionally restore itself after injury yet has a modest regenerative capacity that could be enhanced by innovative therapies. Adult cardiac cells with regenerative potential share gene expression signatures with early fetal progenitors that give rise to multiple cardiac cell types, suggesting that the evolutionarily conserved regulatory networks that drive embryonic heart development might also control aspects of regeneration. Here we discuss commonalities of development and regeneration, and the application of the rich developmental biology heritage to achieve therapeutic regeneration of the human heart. PMID:21325131

Localization of premature ventricular contractions from the papillary muscles using the standard 12-lead electrocardiogram: a feasibility study using a novel cardiac isochrone positioning system.

PubMed

van Dam, Peter M; Boyle, Noel G; Laks, Michael M; Tung, Roderick

2016-12-01

The precise localization of the site of origin of a premature ventricular contraction (PVC) prior to ablation can facilitate the planning and execution of the electrophysiological procedure. In clinical practice, the targeted ablation site is estimated from the standard 12-lead ECG. The accuracy of this qualitative estimation has limitations, particularly in the localization of PVCs originating from the papillary muscles. Clinical available electrocardiographic imaging (ECGi) techniques that incorporate patient-specific anatomy may improve the localization of these PVCs, but require body surface maps with greater specificity for the epicardium. The purpose of this report is to demonstrate that a novel cardiac isochrone positioning system (CIPS) program can accurately detect the specific location of the PVC on the papillary muscle using only a 12-lead ECG. Cardiac isochrone positioning system uses three components: (i) endocardial and epicardial cardiac anatomy and torso geometry derived from MRI, (ii) the patient-specific electrode positions derived from an MRI model registered 3D image, and (iii) the 12-lead ECG. CIPS localizes the PVC origin by matching the anatomical isochrone vector with the ECG vector. The predicted PVC origin was compared with the site of successful ablation or stimulation. Three patients who underwent electrophysiological mapping and ablation of PVCs originating from the papillary muscles were studied. CIPS localized the PVC origin for all three patients to the correct papillary muscle and specifically to the base, mid, or apical region. A simplified form of ECGi utilizing only 12 standard electrocardiographic leads may facilitate accurate localization of the origin of papillary muscle PVCs. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

Effect of Statins on Skeletal Muscle: Exercise, Myopathy, and Muscle Outcomes

PubMed Central

Parker, Beth A.; Thompson, Paul D.

2012-01-01

Statins are effective for reducing low-density lipoprotein cholesterol and cardiac events, but can produce muscle side effects. We have hypothesized that statin-related muscle complaints are exacerbated by exercise and influenced by factors including mitochondrial dysfunction, membrane disruption and/or calcium handling. The interaction between statins, exercise and muscle symptoms may be more effectively diagnosed and treated as rigorous scientific studies accumulate. PMID:23000957

Desmin Cytoskeleton Linked to Muscle Mitochondrial Distribution and Respiratory Function

PubMed Central

Milner, Derek J.; Mavroidis, Manolis; Weisleder, Noah; Capetanaki, Yassemi

2000-01-01

Ultrastructural studies have previously suggested potential association of intermediate filaments (IFs) with mitochondria. Thus, we have investigated mitochondrial distribution and function in muscle lacking the IF protein desmin. Immunostaining of skeletal muscle tissue sections, as well as histochemical staining for the mitochondrial marker enzymes cytochrome C oxidase and succinate dehydrogenase, demonstrate abnormal accumulation of subsarcolemmal clumps of mitochondria in predominantly slow twitch skeletal muscle of desmin-null mice. Ultrastructural observation of desmin-null cardiac muscle demonstrates in addition to clumping, extensive mitochondrial proliferation in a significant fraction of the myocytes, particularly after work overload. These alterations are frequently associated with swelling and degeneration of the mitochondrial matrix. Mitochondrial abnormalities can be detected very early, before other structural defects become obvious. To investigate related changes in mitochondrial function, we have analyzed ADP-stimulated respiration of isolated muscle mitochondria, and ADP-stimulated mitochondrial respiration in situ using saponin skinned muscle fibers. The in vitro maximal rates of respiration in isolated cardiac mitochondria from desmin-null and wild-type mice were similar. However, mitochondrial respiration in situ is significantly altered in desmin-null muscle. Both the maximal rate of ADP-stimulated oxygen consumption and the dissociation constant (K m) for ADP are significantly reduced in desmin-null cardiac and soleus muscle compared with controls. Respiratory parameters for desmin-null fast twitch gastrocnemius muscle were unaffected. Additionally, respiratory measurements in the presence of creatine indicate that coupling of creatine kinase and the adenine translocator is lost in desmin-null soleus muscle. This coupling is unaffected in cardiac muscle from desmin-null animals. All of these studies indicate that desmin IFs play a significant

Nanomaterials for Cardiac Myocyte Tissue Engineering.

PubMed

Amezcua, Rodolfo; Shirolkar, Ajay; Fraze, Carolyn; Stout, David A

2016-07-19

Since their synthesizing introduction to the research community, nanomaterials have infiltrated almost every corner of science and engineering. Over the last decade, one such field has begun to look at using nanomaterials for beneficial applications in tissue engineering, specifically, cardiac tissue engineering. During a myocardial infarction, part of the cardiac muscle, or myocardium, is deprived of blood. Therefore, the lack of oxygen destroys cardiomyocytes, leaving dead tissue and possibly resulting in the development of arrhythmia, ventricular remodeling, and eventual heart failure. Scarred cardiac muscle results in heart failure for millions of heart attack survivors worldwide. Modern cardiac tissue engineering research has developed nanomaterial applications to combat heart failure, preserve normal heart tissue, and grow healthy myocardium around the infarcted area. This review will discuss the recent progress of nanomaterials for cardiovascular tissue engineering applications through three main nanomaterial approaches: scaffold designs, patches, and injectable materials.

An anomalous subdiffusion model for calcium spark in cardiac myocytes

NASA Astrophysics Data System (ADS)

Tan, Wenchang; Fu, Chaoqi; Fu, Ceji; Xie, Wenjun; Cheng, Heping

2007-10-01

The elementary events of excitation-contraction coupling in heart muscle are Ca2+ sparks, which arise from ryanodine receptors in the sarcoplasmic reticulum (SR). Here, an anomalous subdiffusion model is developed to explore Ca2+ spark formation in cardiac myocytes. Numerical simulations reproduce the brightness, the time course, and spatial size of a typical cardiac Ca2+ spark. It is suggested that the diffusion of Ca2+ spark in the cytoplasm may no longer obey Fickian second law, but the anomalous space subdiffusion. The physical reason is perhaps due to the effects of the electric field of the calcium ions and the viscoelasticity of the cytoplasm and its complex structures.

Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions.

PubMed

Mailloux, Ryan J; Xuan, Jian Ying; McBride, Skye; Maharsy, Wael; Thorn, Stephanie; Holterman, Chet E; Kennedy, Christopher R J; Rippstein, Peter; deKemp, Robert; da Silva, Jean; Nemer, Mona; Lou, Marjorie; Harper, Mary-Ellen

2014-05-23

Glutaredoxin-2 (Grx2) modulates the activity of several mitochondrial proteins in cardiac tissue by catalyzing deglutathionylation reactions. However, it remains uncertain whether Grx2 is required to control mitochondrial ATP output in heart. Here, we report that Grx2 plays a vital role modulating mitochondrial energetics and heart physiology by mediating the deglutathionylation of mitochondrial proteins. Deletion of Grx2 (Grx2(-/-)) decreased ATP production by complex I-linked substrates to half that in wild type (WT) mitochondria. Decreased respiration was associated with increased complex I glutathionylation diminishing its activity. Tissue glucose uptake was concomitantly increased. Mitochondrial ATP output and complex I activity could be recovered by restoring the redox environment to that favoring the deglutathionylated states of proteins. Grx2(-/-) hearts also developed left ventricular hypertrophy and fibrosis, and mice became hypertensive. Mitochondrial energetics from Grx2 heterozygotes (Grx2(+/-)) were also dysfunctional, and hearts were hypertrophic. Intriguingly, Grx2(+/-) mice were far less hypertensive than Grx2(-/-) mice. Thus, Grx2 plays a vital role in modulating mitochondrial metabolism in cardiac muscle, and Grx2 deficiency leads to pathology. As mitochondrial ATP production was restored by the addition of reductants, these findings may be relevant to novel redox-related therapies in cardiac disease. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Disseminated Skeletal Muscle and Cardiac Metastasis from Squamous Cell Carcinoma of the Lung Detected with FDG and FLT PET/CT.

PubMed

Jain, Tarun Kumar; Rayamajhi, Sampanna Jung; Basher, Rajender Kumar; Gupta, Dheeraj; Maturu, Venkata Nagarjuna; Mittal, Bhagwant Rai

2016-09-01

Lung cancer is one of the leading cancers all over the world. Positron emission tomography (PET) using 18F fluorodeoxyglucose (18F FDG) is useful for staging of the disease and decide the appropriate management. 3'-deoxy-3'-18 F-fluorothymidine (18F FLT) is a tracer being extensively evaluated currently and is said to represent tumor proliferation. Common sites of metastases from lung cancer include adrenal glands, bone, and brain. Muscle metastasis and cardiac metastasis are uncommon findings. We report a case of squamous cell carcinoma of the lung with metastases to multiple skeletal muscles and myocardium detected with both FDG and FLT PET/computed tomography (CT).

Myostatin as a Marker for Doxorubicin Induced Cardiac Damage.

PubMed

Kesik, Vural; Honca, Tevfik; Gulgun, Mustafa; Uysal, Bulent; Kurt, Yasemin Gulcan; Cayci, Tuncer; Babacan, Oguzhan; Gocgeldi, Ercan; Korkmazer, Nadir

2016-01-01

Doxorubicin (DXR) is an effective chemotherapeutic agent but causes severe cardiac failure over known doses. Thus, early detection and prevention of cardiac damage is important. Various markers have been tested for early detection of cardiac damage. Myostatin is a protein produced in skeletal muscle cells inhibits muscle differentiation and growth during myogenesis. We evaluated the role of myostatin as a marker for showing DXR induced cardiac damage and compared with well known cardiac markers like NT-proBNP, hs-TnT and CK in a rat model of chronic DXR cardiotoxicity. Myostatin, NT-proBNP, and hs-TnT but not CK rose significantly during DXR treatment. Myostatin can be used as an early marker of DXR induced cardiotoxicity. © 2016 by the Association of Clinical Scientists, Inc.

Living cardiac patch: the elixir for cardiac regeneration.

PubMed

Lakshmanan, Rajesh; Krishnan, Uma Maheswari; Sethuraman, Swaminathan

2012-12-01

A thorough understanding of the cellular and muscle fiber orientation in left ventricular cardiac tissue is of paramount importance for the generation of artificial cardiac patches to treat the ischemic myocardium. The major challenge faced during cardiac patch engineering is to choose a perfect combination of three entities; cells, scaffolds and signaling molecules comprising the tissue engineering triad for repair and regeneration. This review provides an overview of various scaffold materials, their mechanical properties and fabrication methods utilized in cardiac patch engineering. Stem cell therapies in clinical trials and the commercially available cardiac patch materials were summarized in an attempt to provide a recent perspective in the treatment of heart failure. Various tissue engineering strategies employed thus far to construct viable thick cardiac patches is schematically illustrated. Though many strategies have been proposed for fabrication of various cardiac scaffold materials, the stage and severity of the disease condition demands the incorporation of additional cues in a suitable scaffold material. The scaffold may be nanofibrous patch, hydrogel or custom designed films. Integration of stem cells and biomolecular cues along with the scaffold may provide the right microenvironment for the repair of unhealthy left ventricular tissue as well as promote its regeneration.

Lithium toxicity precipitated by thyrotoxicosis due to silent thyroiditis: cardiac arrest, quadriplegia, and coma.

PubMed

Sato, Yoshinori; Taki, Katsumi; Honda, Yuki; Takahashi, Shoichiro; Yoshimura, Ashio

2013-06-01

Lithium is widely used to treat bipolar disorders. Lithium toxicity is generally caused by inappropriately high doses of lithium or impaired lithium excretion. Most lithium is eliminated via the kidneys and, since thyroid hormone increases tubular reabsorption of lithium, thyrotoxicosis could contribute to the development of lithium toxicity. We report a case of severe lithium toxicity that was apparently precipitated by the onset of thyrotoxicosis resulting from silent thyroiditis and dehydration. The patient was a 64-year-old woman who was admitted for muscle weakness in the lower extremities, diarrhea, and palpitations. She had bipolar disorder and was being treated with lithium carbonate, which she discontinued one week before admission. Her circulating lithium levels had been monitored yearly. Early in her admission she was dehydrated and had febrile episodes, paroxysmal atrial fibrillation, and muscle weakness. Initially, fluid therapy was started, but she lost consciousness and had a cardiac arrest for 2 minutes due to prolonged sinus arrest. Chest compression and manual artificial ventilation were performed, and body surface pacing was started. Serum lithium was markedly elevated to 3.81 mEq/L (therapeutic range, 0.4-1.0 mEq/L), and thyroid hormone levels were increased (free triiodothyronine, 8.12 pg/mL; free thyroxine, 4.45 ng/dL), while thyrotropin (TSH) was suppressed (<0.01 μIU/mL). Hemodialysis was performed, and a temporary pacemaker was inserted for severe sinus bradycardia. The serum thyroglobulin was 4680 ng/mL (reference range, <32.7 ng/mL). A TSH receptor antibody test was negative. Glucocorticoid therapy and inorganic iodine (100 mg) were administered and continued until day 11. However, her neurological symptoms deteriorated with floppy quadriplegia and deep coma. She gradually recovered. On day 36, she was discharged without any neurological symptoms or thyrotoxicosis. A 64-year-old woman taking lithium for bipolar disorder

Cardiac Electrophysiology: Normal and Ischemic Ionic Currents and the ECG

ERIC Educational Resources Information Center

Klabunde, Richard E.

2017-01-01

Basic cardiac electrophysiology is foundational to understanding normal cardiac function in terms of rate and rhythm and initiation of cardiac muscle contraction. The primary clinical tool for assessing cardiac electrical events is the electrocardiogram (ECG), which provides global and regional information on rate, rhythm, and electrical…

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.

Tight glycemic control with insulin does not affect skeletal muscle degradation during the early post-operative period following pediatric cardiac surgery

PubMed Central

Fisher, Jeremy G.; Sparks, Eric A.; Khan, Faraz A.; Alexander, Jamin L.; Asaro, Lisa A.; Wypij, David; Gaies, Michael; Modi, Biren P.; Duggan, Christopher; Agus, Michael S.D.; Yu, Yong-Ming; Jaksic, Tom

2015-01-01

Objective Critical illness is associated with significant catabolism and persistent protein loss correlates with increased morbidity and mortality. Insulin is a potent anti-catabolic hormone; high-dose insulin decreases skeletal muscle protein breakdown in critically ill pediatric surgical patients. However, insulin's effect on protein catabolism when given at clinically utilized doses has not been studied. The objective was to evaluate the effect of post-operative tight glycemic control and clinically-dosed insulin on skeletal muscle degradation in children after cardiac surgery with cardiopulmonary bypass. Design Secondary analysis of a two-center, prospective randomized trial comparing tight glycemic control with standard care. Randomization was stratified by study center. Patients Children 0-36 months who were admitted to the ICU after cardiac surgery requiring cardiopulmonary bypass. Interventions In the tight glycemic control (TGC) arm, insulin was titrated to maintain blood glucose between 80-110 mg/dL. Patients in the control arm received standard care. Skeletal muscle breakdown was quantified by a ratio of urinary 3-methylhistidine to urinary creatinine (3MH:Cr). Main Results A total of 561 patients were included: 281 in the TGC arm and 280 receiving standard care. There was no difference in 3MH:Cr between groups (TGC 249 ± 127 vs. standard care 253 ± 112, mean ± standard deviation in μmol/g, P=0.72). In analyses restricted to the TGC patients, higher 3MH:Cr correlated with younger age as well as lower weight, weight-for-age z-score, length, and body surface area (P<0.005 for each), and lower post-operative day 3 serum creatinine (r=-0.17, P=0.02). Sex, prealbumin, and albumin were not associated with 3MH:Cr. During urine collection, 245 patients (87%) received insulin. However, any insulin exposure did not impact 3MH:Cr (t-test, P=0.45), and there was no dose-dependent effect of insulin on 3MH:Cr (r=-0.03, P=0.60). Conclusion Though high-dose insulin

Overview of the Muscle Cytoskeleton

PubMed Central

Henderson, Christine A.; Gomez, Christopher G.; Novak, Stefanie M.; Mi-Mi, Lei; Gregorio, Carol C.

2018-01-01

Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease. PMID:28640448

F-18 sodium fluoride PET/CT does not effectively image myocardial inflammation due to suspected cardiac sarcoidosis.

PubMed

Weinberg, Richard L; Morgenstern, Rachelle; DeLuca, Albert; Chen, Jennifer; Bokhari, Sabahat

2017-12-01

Sarcoidosis is an inflammatory disorder of unknown etiology that can involve the heart. While effective in imaging cardiac sarcoidosis, F-18 fluorodeoxyglucose (FDG) PET/CT often shows non-specific myocardial uptake. F-18 sodium fluoride (NaF) has been used to image inflammation in coronary artery plaques and has low background myocardial uptake. Here, we evaluated whether F-18 NaF can image myocardial inflammation due to clinically suspected cardiac sarcoidosis. We performed a single institution pilot study testing if F-18 NaF PET/CT can detect myocardial inflammation in patients with suspected cardiac sarcoidosis. Patients underwent cardiac PET/CT with F-18 FDG as part of their routine care and subsequently received an F-18 NaF PET/CT scan. Three patients underwent F-18 FDG and F-18 NaF imaging. In all patients, there was F-18 FDG uptake consistent with cardiac sarcoidosis. The F-18 NaF PET/CT scans showed no myocardial uptake. In this small preliminary study, PET/CT scan using F-18 NaF does not appear to detect myocardial inflammation caused by suspected cardiac sarcoidosis.

Disseminated Skeletal Muscle and Cardiac Metastasis from Squamous Cell Carcinoma of the Lung Detected with FDG and FLT PET/CT

PubMed Central

Jain, Tarun Kumar; Rayamajhi, Sampanna Jung; Basher, Rajender Kumar; Gupta, Dheeraj; Maturu, Venkata Nagarjuna; Mittal, Bhagwant Rai

2016-01-01

Lung cancer is one of the leading cancers all over the world. Positron emission tomography (PET) using 18F fluorodeoxyglucose (18F FDG) is useful for staging of the disease and decide the appropriate management. 3’-deoxy-3’-18 F-fluorothymidine (18F FLT) is a tracer being extensively evaluated currently and is said to represent tumor proliferation. Common sites of metastases from lung cancer include adrenal glands, bone, and brain. Muscle metastasis and cardiac metastasis are uncommon findings. We report a case of squamous cell carcinoma of the lung with metastases to multiple skeletal muscles and myocardium detected with both FDG and FLT PET/computed tomography (CT). PMID:27651747

Patient-Specific Simulation of Cardiac Blood Flow From High-Resolution Computed Tomography.

PubMed

Lantz, Jonas; Henriksson, Lilian; Persson, Anders; Karlsson, Matts; Ebbers, Tino

2016-12-01

Cardiac hemodynamics can be computed from medical imaging data, and results could potentially aid in cardiac diagnosis and treatment optimization. However, simulations are often based on simplified geometries, ignoring features such as papillary muscles and trabeculae due to their complex shape, limitations in image acquisitions, and challenges in computational modeling. This severely hampers the use of computational fluid dynamics in clinical practice. The overall aim of this study was to develop a novel numerical framework that incorporated these geometrical features. The model included the left atrium, ventricle, ascending aorta, and heart valves. The framework used image registration to obtain patient-specific wall motion, automatic remeshing to handle topological changes due to the complex trabeculae motion, and a fast interpolation routine to obtain intermediate meshes during the simulations. Velocity fields and residence time were evaluated, and they indicated that papillary muscles and trabeculae strongly interacted with the blood, which could not be observed in a simplified model. The framework resulted in a model with outstanding geometrical detail, demonstrating the feasibility as well as the importance of a framework that is capable of simulating blood flow in physiologically realistic hearts.

A collocation--Galerkin finite element model of cardiac action potential propagation.

PubMed

Rogers, J M; McCulloch, A D

1994-08-01

A new computational method was developed for modeling the effects of the geometric complexity, nonuniform muscle fiber orientation, and material inhomogeneity of the ventricular wall on cardiac impulse propagation. The method was used to solve a modification to the FitzHugh-Nagumo system of equations. The geometry, local muscle fiber orientation, and material parameters of the domain were defined using linear Lagrange or cubic Hermite finite element interpolation. Spatial variations of time-dependent excitation and recovery variables were approximated using cubic Hermite finite element interpolation, and the governing finite element equations were assembled using the collocation method. To overcome the deficiencies of conventional collocation methods on irregular domains, Galerkin equations for the no-flux boundary conditions were used instead of collocation equations for the boundary degrees-of-freedom. The resulting system was evolved using an adaptive Runge-Kutta method. Converged two-dimensional simulations of normal propagation showed that this method requires less CPU time than a traditional finite difference discretization. The model also reproduced several other physiologic phenomena known to be important in arrhythmogenesis including: Wenckebach periodicity, slowed propagation and unidirectional block due to wavefront curvature, reentry around a fixed obstacle, and spiral wave reentry. In a new result, we observed wavespeed variations and block due to nonuniform muscle fiber orientation. The findings suggest that the finite element method is suitable for studying normal and pathological cardiac activation and has significant advantages over existing techniques.

Polymer microfiber meshes facilitate cardiac differentiation of c-kit{sup +} human cardiac stem cells

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

Kan, Lijuan; Thayer, Patrick; Fan, Huimin

Electrospun microfiber meshes have been shown to support the proliferation and differentiation of many types of stem cells, but the phenotypic fate of c-kit{sup +} human cardiac stem cells (hCSCs) have not been explored. To this end, we utilized thin (~5 µm) elastomeric meshes consisting of aligned 1.7 µm diameter poly (ester-urethane urea) microfibers as substrates to examine their effect on hCSC viability, morphology, proliferation, and differentiation relative to cells cultured on tissue culture polystyrene (TCPS). The results showed that cells on microfiber meshes displayed an elongated morphology aligned in the direction of fiber orientation, lower proliferation rates, but increasedmore » expressions of genes and proteins majorly associated with cardiomyocyte phenotype. The early (NK2 homeobox 5, Nkx2.5) and late (cardiac troponin I, cTnI) cardiomyocyte genes were significantly increased on meshes (Nkx=2.5 56.2±13.0, cTnl=2.9±0.56,) over TCPS (Nkx2.5=4.2±0.9, cTnl=1.6±0.5, n=9, p<0.05 for both groups) after differentiation. In contrast, expressions of smooth muscle markers, Gata6 and myosin heavy chain (SM-MHC), were decreased on meshes. Immunocytochemical analysis with cardiac antibody exhibited the similar pattern of above cardiac differentiation. We conclude that aligned microfiber meshes are suitable for guiding cardiac differentiation of hCSCs and may facilitate stem cell-based therapies for treatment of cardiac diseases. - Highlights: • First study to characterize c-kit{sup +} human cardiac stem cells on microfiber meshes. • Microfiber meshes seem reducing cell proliferation, but no effect on cell viability. • Microfiber meshes facilitate the elongation of human cardiac stem cells in culture. • Cardiac but not smooth muscle differentiation were enhanced on microfiber meshes. • Microfiber meshes may be used as cardiac patches in cell-based cardiac therapy.« less

Orofacial pain of cardiac origin: Review literature and clinical cases

PubMed Central

Garcia-Vicente, Laia; Jané-Salas, Enric; Estrugo-Devesa, Albert; Chimenos-Küstner, Eduardo; Roca-Elias, Josep

2012-01-01

The most common types of orofacial pain originate at the dental or periodontal level or in the musculoskeletal structures. However, the patient may present pain in this region even though the source is located elsewhere in the body. One possible source of heterotopic pain is of cardiac origin. Objectives: Report two cases of orofacial pain of cardiac origin and review the clinical cases described in the literature. Study Design: Description of clinical cases and review of clinical cases. Results and conclusions: Nine cases of atypical pain of cardiac origin are recorded, which include 5 females and 4 males. In craniofacial structures, pain of cardiac origin is usually bilateral. At the craniofacial level, the most frequent location described is in the throat and jaw. Pain of cardiac origin is considered atypical due to its location, although roughly 10% of the cases of cardiac ischemia manifest primarily in craniofacial structures. Finally, the differential diagnosis of pain of odontogenic origin must be taken into account with pain of non-odontogenic origin (muscle, psychogenic, neuronal, cardiac, sinus and neurovascular pain) in order to avoid diagnostic errors in the dental practice as well as unnecessary treatments. Key words:Orofacial pain, ischemic heart disease, heterotopic pain, odontalgia. PMID:22322488

Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats

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

Yasuda, Yoshikazu; Fukushima, Yuji; Kaneki, Masao

Highlights: ► Propofol, as a model anesthetic drug, induced whole body insulin resistance. ► Propofol anesthesia decreased glucose infusion rate to maintain euglycemia. ► Propofol decreased insulin-mediated glucose uptake in skeletal and cardiac muscles. ► Propofol increased hepatic glucose output confirming hepatic insulin resistance. -- Abstract: Hyperglycemia together with hepatic and muscle insulin resistance are common features in critically ill patients, and these changes are associated with enhanced inflammatory response, increased susceptibility to infection, muscle wasting, and worsened prognosis. Tight blood glucose control by intensive insulin treatment may reduce the morbidity and mortality in intensive care units. Although some anestheticsmore » have been shown to cause insulin resistance, it remains unknown how and in which tissues insulin resistance is induced by anesthetics. Moreover, the effects of propofol, a clinically relevant intravenous anesthetic, also used in the intensive care unit for sedation, on insulin sensitivity have not yet been investigated. Euglycemic hyperinsulinemic clamp study was performed in rats anesthetized with propofol and conscious unrestrained rats. To evaluate glucose uptake in tissues and hepatic glucose output [{sup 3}H]glucose and 2-deoxy[{sup 14}C]glucose were infused during the clamp study. Anesthesia with propofol induced a marked whole-body insulin resistance compared with conscious rats, as reflected by significantly decreased glucose infusion rate to maintain euglycemia. Insulin-stimulated tissue glucose uptake was decreased in skeletal muscle and heart, and hepatic glucose output was increased in propofol anesthetized rats. Anesthesia with propofol induces systemic insulin resistance along with decreases in insulin-stimulated glucose uptake in skeletal and heart muscle and attenuation of the insulin-mediated suppression of hepatic glucose output in rats.« less

Distinct functions of the laminin β LN domain and collagen IV during cardiac extracellular matrix formation and stabilization of alary muscle attachments revealed by EMS mutagenesis in Drosophila

PubMed Central

2014-01-01

Background The Drosophila heart (dorsal vessel) is a relatively simple tubular organ that serves as a model for several aspects of cardiogenesis. Cardiac morphogenesis, proper heart function and stability require structural components whose identity and ways of assembly are only partially understood. Structural components are also needed to connect the myocardial tube with neighboring cells such as pericardial cells and specialized muscle fibers, the so-called alary muscles. Results Using an EMS mutagenesis screen for cardiac and muscular abnormalities in Drosophila embryos we obtained multiple mutants for two genetically interacting complementation groups that showed similar alary muscle and pericardial cell detachment phenotypes. The molecular lesions underlying these defects were identified as domain-specific point mutations in LamininB1 and Cg25C, encoding the extracellular matrix (ECM) components laminin β and collagen IV α1, respectively. Of particular interest within the LamininB1 group are certain hypomorphic mutants that feature prominent defects in cardiac morphogenesis and cardiac ECM layer formation, but in contrast to amorphic mutants, only mild defects in other tissues. All of these alleles carry clustered missense mutations in the laminin LN domain. The identified Cg25C mutants display weaker and largely temperature-sensitive phenotypes that result from glycine substitutions in different Gly-X-Y repeats of the triple helix-forming domain. While initial basement membrane assembly is not abolished in Cg25C mutants, incorporation of perlecan is impaired and intracellular accumulation of perlecan as well as the collagen IV α2 chain is detected during late embryogenesis. Conclusions Assembly of the cardiac ECM depends primarily on laminin, whereas collagen IV is needed for stabilization. Our data underscore the importance of a correctly assembled ECM particularly for the development of cardiac tissues and their lateral connections. The mutational

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

Decrease in coronary vascular volume in systole augments cardiac contraction.

PubMed

Willemsen, M J; Duncker, D J; Krams, R; Dijkman, M A; Lamberts, R R; Sipkema, P; Westerhof, N

2001-08-01

Coronary arterial inflow is impeded and venous outflow is increased as a result of the decrease in coronary vascular volume due to cardiac contraction. We evaluated whether cardiac contraction is influenced by interfering with the changes of the coronary vascular volume over the heart cycle. Length-tension relationships were determined in Tyrode-perfused rat papillary muscle and when coronary vascular volume changes were partly inhibited by filling it with congealed gelatin or perfusing it with a high viscosity dextran buffer. Also, myocyte thickening during contraction was reduced by placing a silicon tube around the muscle. Increasing perfusion pressure from 8 to 80 cmH2O, increased developed tension by approximately 40%. When compared with the low perfusion state, developed tension of the gelatin-filled vasculature was reduced to 43 +/- 6% at the muscle length where the muscle generates the largest developed tension (n = 5, means +/- SE). Dextran reduced developed tension to 73 +/- 6% (n = 6). The silicon tube, in low perfusion state, reduced the developed tension to 83 +/- 7% (n = 4) of control. Time-control and oxygen-lowering experiments show that the findings are based on mechanical effects. Thus interventions to prevent myocyte thickening reduce developed tension. We hypothesize that when myocyte thickening is prevented, intracellular pressure increases and counteracts the force produced by the contractile apparatus. We conclude that emptying of the coronary vasculature serves a physiological purpose by facilitating cardiomyocyte thickening thereby augmenting force development.

Molecular and immunohistochemical analyses of cardiac troponin T during cardiac development in the Mexican axolotl, Ambystoma mexicanum.

PubMed

Zhang, C; Pietras, K M; Sferrazza, G F; Jia, P; Athauda, G; Rueda-de-Leon, E; Rveda-de-Leon, E; Maier, J A; Dube, D K; Lemanski, S L; Lemanski, L F

2007-01-01

The Mexican axolotl, Ambystoma mexicanum, is an excellent animal model for studying heart development because it carries a naturally occurring recessive genetic mutation, designated gene c, for cardiac nonfunction. The double recessive mutants (c/c) fail to form organized myofibrils in the cardiac myoblasts resulting in hearts that fail to beat. Tropomyosin expression patterns have been studied in detail and show dramatically decreased expression in the hearts of homozygous mutant embryos. Because of the direct interaction between tropomyosin and troponin T (TnT), and the crucial functions of TnT in the regulation of striated muscle contraction, we have expanded our studies on this animal model to characterize the expression of the TnT gene in cardiac muscle throughout normal axolotl development as well as in mutant axolotls. In addition, we have succeeded in cloning the full-length cardiac troponin T (cTnT) cDNA from axolotl hearts. Confocal microscopy has shown a substantial, but reduced, expression of TnT protein in the mutant hearts when compared to normal during embryonic development. 2006 Wiley-Liss, Inc.

Effects of testosterone and nandrolone on cardiac function: a randomized, placebo-controlled study.

PubMed

Chung, T; Kelleher, S; Liu, P Y; Conway, A J; Kritharides, L; Handelsman, D J

2007-02-01

Androgens have striking effects on skeletal muscle, but the effects on human cardiac muscle function are not well defined, neither has the role of metabolic activation (aromatization, 5alpha reduction) of testosterone on cardiac muscle been directly studied. To assess the effects of testosterone and nandrolone, a non-amplifiable and non-aromatizable pure androgen, on cardiac muscle function in healthy young men. Double-blind, randomized, placebo-controlled, three-arm parallel group clinical trial. Ambulatory care research centre. Healthy young men randomized into three groups of 10 men. Weekly intramuscular injections of testosterone (200 mg mixed esters), nandrolone (200 mg nandrolone decanoate) or matching (2 ml arachis oil vehicle) placebo for 4 weeks. Comprehensive measures of cardiac muscle function involving transthoracic cardiac echocardiography measuring myocardial tissue velocity, peak systolic strain and strain rates, and bioimpedance measurement of cardiac output and systematic vascular resistance. Left ventricular (LV) function (LV ejection fraction, LV modified TEI index), right ventricular (RV) function (ejection area, tricuspid annular systolic planar motion, RV modified TEI index) as well as cardiac afterload (mean arterial pressure, systemic vascular resistance) and overall cardiac contractility (stroke volume, cardiac output) were within age- and gender-specific reference ranges and were not significantly (P < 0.05) altered by either androgen or placebo over 4 weeks of treatment. Minor changes remaining within normal range were observed solely within the testosterone group for: increased LV end-systolic diameter (30 +/- 7 vs. 33 +/- 5 mm, P = 0.04) and RV end-systolic area (12.8 +/- 1.3 vs. 14.6 +/- 3.3 cm(2), P = 0.04), reduced LV diastolic septal velocity (Em, 9.5 +/- 2.6 vs. 8.7 +/- 2.0 cm/s, P = 0.006), increased LV filling pressure (E/Em ratio, 7.1 +/- 1.6 vs. 8.3 +/- 1.8, P = 0.02) and shortened PR interval on the electrocardiogram (167

Cardiac Expression of ms1/STARS, a Novel Gene Involved in Cardiac Development and Disease, Is Regulated by GATA4

PubMed Central

Kobayashi, Satoru; Peterson, Richard E.; He, Aibin; Motterle, Anna; Samani, Nilesh J.; Menick, Donald R.; Pu, William T.; Liang, Qiangrong

2012-01-01

Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), α, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, α and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease. PMID:22431517

Albumin fiber scaffolds for engineering functional cardiac tissues.

PubMed

Fleischer, Sharon; Shapira, Assaf; Regev, Omri; Nseir, Nora; Zussman, Eyal; Dvir, Tal

2014-06-01

In recent years attempts to engineer contracting cardiac patches were focused on recapitulation of the myocardium extracellular microenvironment. We report here on our work, where for the first time, a three-dimensional cardiac patch was fabricated from albumin fibers. We hypothesized that since albumin fibers' mechanical properties resemble those of cardiac tissue extracellular matrix (ECM) and their biochemical character enables their use as protein carriers, they can support the assembly of cardiac tissues capable of generating strong contraction forces. Here, we have fabricated aligned and randomly oriented electrospun albumin fibers and investigated their structure, mechanical properties, and chemical nature. Our measurements showed that the scaffolds have improved elasticity as compared to synthetic electrospun PCL fibers, and that they are capable of adsorbing serum proteins, such as laminin leading to strong cell-matrix interactions. Moreover, due to the functional groups on their backbone, the fibers can be chemically modified with essential biomolecules. When seeded with rat neonatal cardiac cells the engineered scaffolds induced the assembly of aligned cardiac tissues with high aspect ratio cardiomyocytes and massive actinin striation. Compared to synthetic fibrous scaffolds, cardiac cells cultured within aligned or randomly oriented scaffolds formed functional tissues, exhibiting significantly improved function already on Day 3, including higher beating rate (P = 0.0002 and P < 0.0001, respectively), and higher contraction amplitude (P = 0.009 and P = 0.003, respectively). Collectively, our results suggest that albumin electrospun scaffolds can play a key role in contributing to the ex vivo formation of a contracting cardiac muscle tissue. © 2014 Wiley Periodicals, Inc.

Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats

PubMed Central

Dolinsky, Vernon W; Jones, Kelvin E; Sidhu, Robinder S; Haykowsky, Mark; Czubryt, Michael P; Gordon, Tessa; Dyck, Jason R B

2012-01-01

Exercise training (ET) improves endurance capacity by increasing both skeletal muscle mitochondrial number and function, as well as contributing to favourable cardiac remodelling. Interestingly, some of the benefits of regular exercise can also be mimicked by the naturally occurring polyphenol, resveratrol (RESV). However, it is not known whether RESV enhances physiological adaptations to ET. To investigate this, male Wistar rats were randomly assigned to a control chow diet or a chow diet that contained RESV (4 g kg−1 of diet) and subsequently subjected to a programme of progressive treadmill running for 12 weeks. ET-induced improvements in exercise performance were enhanced by 21% (P < 0.001) by the addition of RESV to the diet. In soleus muscle, ET + RESV increased both the twitch (1.8-fold; P < 0.05) and tetanic (1.2-fold; P < 0.05) forces generated during isometric contraction, compared to ET alone. In vivo echocardiography demonstrated that ET + RESV also increased the resting left ventricular ejection fraction by 10% (P < 0.05), and reduced left ventricular wall stress compared to ET alone. These functional changes were accompanied by increased cardiac fatty acid oxidation (1.2-fold; P < 0.05) and favourable changes in cardiac gene expression and signal transduction pathways that optimized the utilization of fatty acids in ET + RESV compared to ET alone. Overall, our findings provide evidence that the capacity for fatty acid oxidation is augmented by the addition of RESV to the diet during ET, and that this may contribute to the improved physical performance of rats following ET. PMID:22473781

Effects of age and inactivity due to prolonged bed rest on atrophy of trunk muscles.

PubMed

Ikezoe, Tome; Mori, Natsuko; Nakamura, Masatoshi; Ichihashi, Noriaki

2012-01-01

This study investigated the effects of age and inactivity due to being chronically bedridden on atrophy of trunk muscles. The subjects comprised 33 young women (young group) and 41 elderly women who resided in nursing homes or chronic care institutions. The elderly subjects were divided into two groups: independent elderly group who were able to perform activities of daily living involving walking independently (n = 28) and dependent elderly group who were chronically bedridden (n = 13). The thickness of the following six trunk muscles was measured by B-mode ultrasound: the rectus abdominis, external oblique, internal oblique, transversus abdominis, thoracic erector spinae (longissimus) and lumbar multifidus muscles. All muscles except for the transversus abdominis and lumbar multifidus muscles were significantly thinner in the independent elderly group compared with those in the young group. The thicknesses of all muscles in the dependent elderly group was significantly smaller than that in the young group, whereas there were no differences between the dependent elderly and independent elderly groups in the muscle thicknesses of the rectus abdominis and internal oblique muscles. In conclusion, our results suggest that: (1) age-related atrophy compared with young women was less in the deep antigravity trunk muscles than the superficial muscles in the independent elderly women; (2) atrophy associated with chronic bed rest was more marked in the antigravity muscles, such as the back and transversus abdominis.

Computational approaches to understand cardiac electrophysiology and arrhythmias

PubMed Central

Roberts, Byron N.; Yang, Pei-Chi; Behrens, Steven B.; Moreno, Jonathan D.

2012-01-01

Cardiac rhythms arise from electrical activity generated by precisely timed opening and closing of ion channels in individual cardiac myocytes. These impulses spread throughout the cardiac muscle to manifest as electrical waves in the whole heart. Regularity of electrical waves is critically important since they signal the heart muscle to contract, driving the primary function of the heart to act as a pump and deliver blood to the brain and vital organs. When electrical activity goes awry during a cardiac arrhythmia, the pump does not function, the brain does not receive oxygenated blood, and death ensues. For more than 50 years, mathematically based models of cardiac electrical activity have been used to improve understanding of basic mechanisms of normal and abnormal cardiac electrical function. Computer-based modeling approaches to understand cardiac activity are uniquely helpful because they allow for distillation of complex emergent behaviors into the key contributing components underlying them. Here we review the latest advances and novel concepts in the field as they relate to understanding the complex interplay between electrical, mechanical, structural, and genetic mechanisms during arrhythmia development at the level of ion channels, cells, and tissues. We also discuss the latest computational approaches to guiding arrhythmia therapy. PMID:22886409

Cardiac elastography: detecting pathological changes in myocardium tissues

NASA Astrophysics Data System (ADS)

Konofagou, Elisa E.; Harrigan, Timothy; Solomon, Scott

2003-05-01

Estimation of the mechanical properties of the cardiac muscle has been shown to play a crucial role in the detection of cardiovascular disease. Elastography was recently shown feasible on RF cardiac data in vivo. In this paper, the role of elastography in the detection of ischemia/infarct is explored with simulations and in vivo experiments. In finite-element simulations of a portion of the cardiac muscle containing an infarcted region, the cardiac cycle was simulated with successive compressive and tensile strains ranging between -30% and 20%. The incremental elastic modulus was also mapped uisng adaptive methods. We then demonstrated this technique utilizing envelope-detected sonographic data (Hewlett-Packard Sonos 5500) in a patient with a known myocardial infarction. In cine-loop and M-Mode elastograms from both normal and infarcted regions in simulations and experiments, the infarcted region was identifed by the up to one order of magnitude lower incremental axial displacements and strains, and higher modulus. Information on motion, deformation and mechanical property should constitute a unique tool for noninvasive cardiac diagnosis.

Constitutive properties of adult mammalian cardiac muscle cells

NASA Technical Reports Server (NTRS)

Zile, M. R.; Richardson, K.; Cowles, M. K.; Buckley, J. M.; Koide, M.; Cowles, B. A.; Gharpuray, V.; Cooper, G. 4th

1998-01-01

BACKGROUND: The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction. METHODS AND RESULTS: Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (sigma), and resultant changes in cell strain (epsilon) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the sigma on the agarose gel at a constant rate to define the cardiocyte sigma-versus-epsilon relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte sigma-versus-epsilon relationship during an increase and then a decrease in sigma. In both protocols, myofilament activation was minimized by a reduction in [Ca2+]i. Myofilament activation effects were assessed in protocol C by defining cardiocyte sigma versus epsilon during an increase in sigma with physiological [Ca2+]i. In protocol A, the cardiocyte sigma-versus-epsilon relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the sigma-versus-epsilon relation in hypertrophied cardiocytes was shifted to the left compared with normal cells. CONCLUSIONS: Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction.

Cardiac function in muscular dystrophy associates with abdominal muscle pathology.

PubMed

Gardner, Brandon B; Swaggart, Kayleigh A; Kim, Gene; Watson, Sydeaka; McNally, Elizabeth M

The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients.

Elevated Cardiac Troponin T in Patients With Skeletal Myopathies.

PubMed

Schmid, Johannes; Liesinger, Laura; Birner-Gruenberger, Ruth; Stojakovic, Tatjana; Scharnagl, Hubert; Dieplinger, Benjamin; Asslaber, Martin; Radl, Roman; Beer, Meinrad; Polacin, Malgorzata; Mair, Johannes; Szolar, Dieter; Berghold, Andrea; Quasthoff, Stefan; Binder, Josepha S; Rainer, Peter P

2018-04-10

Cardiac troponins are often elevated in patients with skeletal muscle disease who have no evidence of cardiac disease. The goal of this study was to characterize cardiac troponin concentrations in patients with myopathies and derive insights regarding the source of elevated troponin T measurements. Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) concentrations were determined by using high sensitivity assays in 74 patients with hereditary and acquired skeletal myopathies. Patients underwent comprehensive cardiac evaluation, including 12-lead electrocardiogram, 24-h electrocardiogram, cardiac magnetic resonance imaging, and coronary artery computed tomography. cTnT and cTnI protein expression was determined in skeletal muscle samples of 9 patients and in control tissues derived from autopsy using antibodies that are used in commercial assays. Relevant Western blot bands were subjected to liquid chromatography tandem mass spectrometry for protein identification. Levels of cTnT (median: 24 ng/l; interquartile range: 11 to 54 ng/l) were elevated (>14 ng/l) in 68.9% of patients; cTnI was elevated (>26 ng/l) in 4.1% of patients. Serum cTnT levels significantly correlated with creatine kinase and myoglobin (r = 0.679 and 0.786, respectively; both p < 0.001). Based on cTnT serial testing, 30.1% would have fulfilled current rule-in criteria for myocardial infarction. Noncoronary cardiac disease was present in 23%. Using cTnT antibodies, positive bands were found in both diseased and healthy skeletal muscle at molecular weights approximately 5 kDa below cTnT. Liquid chromatography tandem mass spectrometry identified the presence of skeletal troponin T isoforms in these bands. Measured cTnT concentrations were chronically elevated in the majority of patients with skeletal myopathies, whereas cTnI elevation was rare. Our data indicate that cross-reaction of the cTnT immunoassay with skeletal muscle troponin isoforms was the likely cause. Copyright © 2018 The

Selective muscle fiber loss and molecular compensation in mitochondrial myopathy due to TK2 deficiency.

PubMed

Vilà, Maya R; Villarroya, Joan; García-Arumí, Elena; Castellote, Amparo; Meseguer, Anna; Hirano, Michio; Roig, Manuel

2008-04-15

A 12-year-old patient with mitochondrial DNA (mtDNA) depletion syndrome due to TK2 gene mutations has been evaluated serially over the last 10 years. We observed progressive muscle atrophy with selective loss of type 2 muscle fibers and, despite severe depletion of mtDNA, normal activities of respiratory chain (RC) complexes and levels of COX II mitochondrial protein in the remaining muscle fibers. These results indicate that compensatory mechanisms account for the slow progression of the disease. Identification of factors that ameliorate mtDNA depletion may reveal new therapeutic targets for these devastating disorders.

Temperature-dependence of isometric tension and cross-bridge kinetics of cardiac muscle fibers reconstituted with a tropomyosin internal deletion mutant.

PubMed

Lu, Xiaoying; Tobacman, Larry S; Kawai, Masataka

2006-12-01

The effect of temperature on isometric tension and cross-bridge kinetics was studied with a tropomyosin (Tm) internal deletion mutant AS-Delta23Tm (Ala-Ser-Tm Delta(47-123)) in bovine cardiac muscle fibers by using the thin filament extraction and reconstitution technique. The results are compared with those from actin reconstituted alone, cardiac muscle-derived control acetyl-Tm, and recombinant control AS-Tm. In all four reconstituted muscle groups, isometric tension and stiffness increased linearly with temperature in the range 5-40 degrees C for fibers activated in the presence of saturating ATP and Ca(2+). The slopes of the temperature-tension plots of the two controls were very similar, whereas the slope derived from fibers with actin alone had approximately 40% the control value, and the slope from mutant Tm had approximately 36% the control value. Sinusoidal analysis was performed to study the temperature dependence of cross-bridge kinetics. All three exponential processes A, B, and C were identified in the high temperature range (30-40 degrees C); only processes B and C were identified in the mid-temperature range (15-25 degrees C), and only process C was identified in the low temperature range (5-10 degrees C). At a given temperature, similar apparent rate constants (2pia, 2pib, 2pic) were observed in all four muscle groups, whereas their magnitudes were markedly less in the order of AS-Delta23Tm < Actin < AS-Tm approximately Acetyl-Tm groups. Our observations are consistent with the hypothesis that Tm enhances hydrophobic and stereospecific interactions (positive allosteric effect) between actin and myosin, but Delta23Tm decreases these interactions (negative allosteric effect). Our observations further indicate that tension/cross-bridge is increased by Tm, but is diminished by Delta23Tm. We conclude that Tm affects the conformation of actin so as to increase the area of hydrophobic interaction between actin and myosin molecules.

Atomic force microscope observation of branching in single transcript molecules derived from human cardiac muscle

NASA Astrophysics Data System (ADS)

Reed, Jason; Hsueh, Carlin; Mishra, Bud; Gimzewski, James K.

2008-09-01

We have used an atomic force microscope to examine a clinically derived sample of single-molecule gene transcripts, in the form of double-stranded cDNA, (c: complementary) obtained from human cardiac muscle without the use of polymerase chain reaction (PCR) amplification. We observed a log-normal distribution of transcript sizes, with most molecules being in the range of 0.4-7.0 kilobase pairs (kb) or 130-2300 nm in contour length, in accordance with the expected distribution of mRNA (m: messenger) sizes in mammalian cells. We observed novel branching structures not previously known to exist in cDNA, and which could have profound negative effects on traditional analysis of cDNA samples through cloning, PCR and DNA sequencing.

Cardiac Trauma.

PubMed

Gosavi, Sucheta; Tyroch, Alan H; Mukherjee, Debabrata

2016-11-01

Cardiac trauma is a leading cause of death in the United States and occurs mostly due to motor vehicle accidents. Blunt cardiac trauma and penetrating chest injuries are most common, and both can lead to aortic injuries. Timely diagnosis and early management are the key to improve mortality. Cardiac computed tomography and cardiac ultrasound are the 2 most important diagnostic modalities. Mortality related to cardiac trauma remains high despite improvement in diagnosis and management.

3D bioprinted functional and contractile cardiac tissue constructs.

PubMed

Wang, Zhan; Lee, Sang Jin; Cheng, Heng-Jie; Yoo, James J; Atala, Anthony

2018-04-01

oxygen supply to the cardiac muscle, resulting in permanent cardiac cell death. Eventually, scar tissue formed in the damaged cardiac muscle that cannot conduct electrical or mechanical stimuli thus leading to a reduction in the pumping efficiency of the heart. The therapeutic options available for end-stage heart failure is to undergo heart transplantation or the use of mechanical ventricular assist devices (VADs). However, many patients die while being on a waiting list, due to the organ shortage and limitation of VADs, such as surgical complications, infection, thrombogenesis, and failure of the electrical motor and hemolysis. Ultimately, 3D bioprinting strategy aims to create clinically applicable tissue constructs that can be immediately implanted in the body. To date, the focus on replicating complex and heterogeneous tissue constructs continues to increase as 3D bioprinting technologies advance. In this study, we demonstrated the feasibility of 3D bioprinting strategy to bioengineer the functional cardiac tissue that possesses a highly organized structure with unique physiological and biomechanical properties similar to native cardiac tissue. This bioprinting strategy has great potential to precisely generate functional cardiac tissues for use in pharmaceutical and regenerative medicine applications. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

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.

Characterization of muscle ankyrin repeat proteins in human skeletal muscle.

PubMed

Wette, Stefan G; Smith, Heather K; Lamb, Graham D; Murphy, Robyn M

2017-09-01

Muscle ankyrin repeat proteins (MARPs) are a family of titin-associated, stress-response molecules and putative transducers of stretch-induced signaling in skeletal muscle. In cardiac muscle, cardiac ankyrin repeat protein (CARP) and diabetes-related ankyrin repeat protein (DARP) reportedly redistribute from binding sites on titin to the nucleus following a prolonged stretch. However, it is unclear whether ankyrin repeat domain protein 2 (Ankrd 2) shows comparable stretch-induced redistribution to the nucleus. We measured the following in rested human skeletal muscle: 1 ) the absolute amount of MARPs and 2 ) the distribution of Ankrd 2 and DARP in both single fibers and whole muscle preparations. In absolute amounts, Ankrd 2 is the most abundant MARP in human skeletal muscle, there being ~3.1 µmol/kg, much greater than DARP and CARP (~0.11 and ~0.02 µmol/kg, respectively). All DARP was found to be tightly bound at cytoskeletal (or possibly nuclear) sites. In contrast, ~70% of the total Ankrd 2 is freely diffusible in the cytosol [including virtually all of the phosphorylated (p)Ankrd 2-Ser99 form], ~15% is bound to non-nuclear membranes, and ~15% is bound at cytoskeletal sites, likely at the N2A region of titin. These data are not consistent with the proposal that Ankrd 2, per se, or pAnkrd 2-Ser99 mediates stretch-induced signaling in skeletal muscle, dissociating from titin and translocating to the nucleus, because the majority of these forms of Ankrd 2 are already free in the cytosol. It will be necessary to show that the titin-associated Ankrd 2 is modified by stretch in some as-yet-unidentified way, distinct from the diffusible pool, if it is to act as a stretch-sensitive signaling molecule. Copyright © 2017 the American Physiological Society.

Management of cardiac involvement in muscular dystrophies: paediatric versus adult forms.

PubMed

Palladino, Alberto; D'Ambrosio, Paola; Papa, Andrea Antonio; Petillo, Roberta; Orsini, Chiara; Scutifero, Marianna; Nigro, Gerardo; Politano, Luisa

2016-12-01

Muscular dystrophies are a group of genetic disorders characterized by muscle degeneration and consequent substitution by fat and fibrous tissue. Cardiac involvement is an almost constant feature in a great part of these diseases, as both primary myocardial involvement and secondary involvement due to respiratory insufficiency, pulmonary hypertension or reduced mobility. Primary myocardial involvement usually begins more precociously compared to the secondary involvement. In fact the first signs of cardiomyopathy can be observed in the first decade of life in muscular dystrophies with childhood onset and later in adult form of muscular dystrophies as myotonic dystrophy type 1. At least an annual cardiac follow-up is recommended in these patients including clinical and instrumental examination (ECG, 24h Holter monitoring, ECHO), to detect cardiac involvement. A more frequent monitoring may be required according to the type of cardiomyopathy and the patient's needs. In this short review practical guide-lines are shown for physicians routinely involved in the management of these patients.

Peptide-enhanced mRNA transfection in cultured mouse cardiac fibroblasts and direct reprogramming towards cardiomyocyte-like cells

PubMed Central

Lee, Kunwoo; Yu, Pengzhi; Lingampalli, Nithya; Kim, Hyun Jin; Tang, Richard; Murthy, Niren

2015-01-01

The treatment of myocardial infarction is a major challenge in medicine due to the inability of heart tissue to regenerate. Direct reprogramming of endogenous cardiac fibroblasts into functional cardiomyocytes via the delivery of transcription factor mRNAs has the potential to regenerate cardiac tissue and to treat heart failure. Even though mRNA delivery to cardiac fibroblasts has the therapeutic potential, mRNA transfection in cardiac fibroblasts has been challenging. Herein, we develop an efficient mRNA transfection in cultured mouse cardiac fibroblasts via a polyarginine-fused heart-targeting peptide and lipofectamine complex, termed C-Lipo and demonstrate the partial direct reprogramming of cardiac fibroblasts towards cardiomyocyte cells. C-Lipo enabled the mRNA-induced direct cardiac reprogramming due to its efficient transfection with low toxicity, which allowed for multiple transfections of Gata4, Mef2c, and Tbx5 (GMT) mRNAs for a period of 2 weeks. The induced cardiomyocyte-like cells had α-MHC promoter-driven GFP expression and striated cardiac muscle structure from α-actinin immunohistochemistry. GMT mRNA transfection of cultured mouse cardiac fibroblasts via C-Lipo significantly increased expression of the cardiomyocyte marker genes, Actc1, Actn2, Gja1, Hand2, and Tnnt2, after 2 weeks of transfection. Moreover, this study provides the first direct evidence that the stoichiometry of the GMT reprogramming factors influence the expression of cardiomyocyte marker genes. Our results demonstrate that mRNA delivery is a potential approach for cardiomyocyte generation. PMID:25834424

Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles

PubMed Central

Thomas, Melissa M.; Wang, David C.; D'Souza, Donna M.; Krause, Matthew P.; Layne, Andrew S.; Criswell, David S.; O'Neill, Hayley M.; Connor, Michael K.; Anderson, Judy E.; Kemp, Bruce E.; Steinberg, Gregory R.; Hawke, Thomas J.

2014-01-01

AMP-activated protein kinase (AMPK) is a master regulator of metabolism. While muscle-specific AMPK β1β2 double-knockout (β1β2M-KO) mice display alterations in metabolic and mitochondrial capacity, their severe exercise intolerance suggested a secondary contributor to the observed phenotype. We find that tibialis anterior (TA), but not soleus, muscles of sedentary β1β2M-KO mice display a significant myopathy (decreased myofiber areas, increased split and necrotic myofibers, and increased centrally nucleated myofibers. A mitochondrial- and fiber-type-specific etiology to the myopathy was ruled out. However, β1β2M-KO TA muscles displayed significant (P<0.05) increases in platelet aggregation and apoptosis within myofibers and surrounding interstitium (P<0.05). These changes correlated with a 45% decrease in capillary density (P<0.05). We hypothesized that the β1β2M-KO myopathy in resting muscle resulted from impaired AMPK-nNOSμ signaling, causing increased platelet aggregation, impaired vasodilation, and, ultimately, ischemic injury. Consistent with this hypothesis, AMPK-specific phosphorylation (Ser1446) of nNOSμ was decreased in β1β2M-KO compared to wild-type (WT) mice. The AMPK-nNOSμ relationship was further demonstrated by administration of 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) to β1β2-MKO muscles and C2C12 myotubes. AICAR significantly increased nNOSμ phosphorylation and nitric oxide production (P<0.05) within minutes of administration in WT muscles and C2C12 myotubes but not in β1β2M-KO muscles. These findings highlight the importance of the AMPK-nNOSμ pathway in resting skeletal muscle.—Thomas, M. M., Wang, D. C., D'Souza, D. M., Krause, M. P., Layne, A. S., Criswell, D. S., O'Neill, H. M., Connor, M. K., Anderson, J. E., Kemp, B. E., Steinberg, G. R., and Hawke, T. J. Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles. PMID:24522207

Superoxide anion radical-triggered Ca2+ release from cardiac sarcoplasmic reticulum through ryanodine receptor Ca2+ channel.

PubMed

Kawakami, M; Okabe, E

1998-03-01

The ryanodine receptor Ca2+ channel (RyRC) constitutes the Ca2+-release pathway in sarcoplasmic reticulum (SR) of cardiac muscle. A direct mechanical and a Ca2+-triggered mechanism (Ca2+-induced Ca2+ release) have been proposed to explain the in situ activation of Ca2+ release in cardiac muscle. A variety of chemical oxidants have been shown to activate RyRC; however, the role of modification induced by oxygen-derived free radicals in pathological states of the muscle remains to be elucidated. It has been hypothesized that oxygen-derived free radicals initiate Ca2+-mediated functional changes in or damage to cardiac muscle by acting on the SR and promoting an increase in Ca2+ release. We confirmed that superoxide anion radical (O2-) generated from hypoxanthine-xanthine oxidase reaction decreases calmodulin content and increases 45Ca2+ efflux from the heavy fraction of canine cardiac SR vesicles; hypoxanthine-xanthine oxidase also decreases Ca2+ free within the intravesicular space of the SR with no effect on Ca2+-ATPase activity. Current fluctuations through single Ca2+-release channels have been monitored after incorporation into planar phospholipid bilayers. We demonstrate that activation of the channel by O2- is dependent of the presence of calmodulin and identified calmodulin as a functional mediator of O2--triggered Ca2+ release through the RyRC. For the first time, we show that O2- stimulates Ca2+ release from heavy SR vesicles and suggest the importance of accessory proteins such as calmodulin in modulating the effect of O2-. The decreased calmodulin content induced by oxygen-derived free radicals, especially O2-, is a likely mechanism of accumulation of cytosolic Ca2+ (due to increased Ca2+ release from SR) after reperfusion of the ischemic heart.

[Overactive muscles: it can be more serious than common myalgia or cramp].

PubMed

Molenaar, Joery P F; Snoeck, Marc M J; Voermans, Nicol C; van Engelen, Baziel G M

2016-01-01

Positive muscle phenomena are due to muscle overactivity. Examples are cramp, myalgia, and stiffness. These manifestations have mostly acquired causes, e.g. side-effects of medication, metabolic disorders, vitamin deficiency, excessive caffeine intake or neurogenic disorders. We report on three patients with various positive muscle phenomena, to illustrate the clinical signs that indicate an underlying myopathy. Patient A, a 56-year-old man, was diagnosed with muscle cramp in the context of excessive coffee use and previous lumbosacral radiculopathy. Patient B, a 71-year-old man, was shown to have RYR1-related myopathy. Patient C, a 42-year-old man, suffered from Brody myopathy. We propose for clinicians to look out for a number of 'red flags' that can point to an underlying myopathy, and call for referral to neurology if indicated. Red flags include second wind phenomenon, familial occurrence of similar complaints, marked muscle stiffness, myotonia, muscle weakness, muscle hypertrophy, and myoglobinuria. Establishing a correct diagnosis is important for proper treatment. Certain myopathies call for cardiac or respiratory screening.

Speed of sound in muscle for use in sonomicrometry.

PubMed

Marsh, Richard L

2016-12-08

Converting ultrasound transit time into a measure of distance when using sonomicrometry requires that the speed of sound be known. A number of different values for the speed of sound in muscle have been assumed in studies of skeletal and cardiac muscle, and in some cases the effect of temperature has been ignored. The speed of ultrasound with frequencies greater than 1MHz in skeletal and cardiac muscle is briefly reviewed, including the effects of temperature and contractile state. A simplified equation for the speed of sound in pure water is presented for the temperature range from 0-50°C. This equation can be used when calibrating sonomicrometer transducers in water. The data available indicate that the speed of sound in both cardiac and skeletal muscle can be approximated by multiplying the speed of sound in pure water at the measurement temperature by 1.045. Differences in the speed of sound in the longitudinal and transverse directions and changes with contractile state appear to be small and in most cases can probably be safely ignored. The normal variation in muscle composition does not greatly affect the speed of ultrasound in muscle, but investigators placing sonomicrometer transducers near tendons should be conscious of the much greater speed of sound in tendon and variation with loading. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biomarker evaluation of skeletal muscle toxicity following clofibrate administration in rats.

PubMed

Bodié, Karen; Buck, Wayne R; Pieh, Julia; Liguori, Michael J; Popp, Andreas

2016-05-01

The use of sensitive biomarkers to monitor skeletal muscle toxicity in preclinical toxicity studies is important for the risk assessment in humans during the development of a novel compound. Skeletal muscle toxicity in Sprague Dawley Rats was induced with clofibrate at different dose levels for 7 days to compare standard clinical pathology assays with novel skeletal muscle and cardiac muscle biomarkers, gene expression and histopathological changes. The standard clinical pathology assays aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) enzyme activity were compared to novel biomarkers fatty acid binding protein 3 (Fabp3), myosin light chain 3 (Myl3), muscular isoform of CK immunoreactivity (three isoforms CKBB, CKMM, CKMB), parvalbumin (Prv), skeletal troponin I (sTnI), cardiac troponin T (cTnT), cardiac troponin I (cTnI), CKMM, and myoglobin (Myo). The biomarker elevations were correlated to histopathological findings detected in several muscles and gene expression changes. Clofibrate predominantly induced skeletal muscle toxicity of type I fibers of low magnitude. Useful biomarkers for skeletal muscle toxicity were AST, Fabp3, Myl3, (CKMB) and sTnI. Measurements of CK enzyme activity by a standard clinical assay were not useful for monitoring clofibrate-induced skeletal muscle toxicity in the rat at the doses used in this study. Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.

Short-term effects of β2-AR blocker ICI 118,551 on sarcoplasmic reticulum SERCA2a and cardiac function of rats with heart failure.

PubMed

Gong, Haibin; Li, Yanfei; Wang, Lei; Lv, Qian; Wang, Xiuli

2016-09-01

The study was conducted to examine the effects of ICI 118,551 on the systolic function of cardiac muscle cells of rats in heart failure and determine the molecular mechanism of selective β2-adrenergic receptor (β2-AR) antagonist on these cells. The chronic heart failure model for rats was prepared through abdominal aortic constriction and separate cardiac muscle cells using the collagenase digestion method. The rats were then divided into Sham, HF and HF+ICI 50 nM goups and cultivated for 48 h. β2-AR, Gi/Gs and sarcoplasmic reticulum Ca 2+ -ATPase (SERCA2a) protein expression levels in the cardiac muscle cells were evaluated by western blotting and changes in the systolic function of cardiac muscle cells based on the boundary detection system of contraction dynamics for individual cells was measured. The results showed that compared with the Sham group, the survival rate, percentage of basic contraction and maximum contraction amplitude percentage of cardiac muscle cells with heart failure decreased, Gi protein expression increased while Gs and SERCA2a protein expression decreased. Compared with the HF group, the maximum contraction amplitude percentage of cardiac muscle cells in group HF+ICI 50 nM decreased, the Gi protein expression level increased while the SERCA2a protein expression level decreased. Following the stimulation of Ca 2+ and ISO, the maximum contraction amplitude percentage of cardiac muscle cells in the HF+ICI 50 nM group was lower than that in group HF. This indicated that ICI 118,551 has negative inotropic effects on cardiac muscle cells with heart failure, which may be related to Gi protein. Systolic function of cardiac muscle cells with heart failure can therefore be reduced by increasing Gi protein expression and lowering SERCA2a protein expression.

Nandrolone decanoate negatively reverses the beneficial effects of exercise on cardiac muscle via sarcolemmal, but not mitochondrial K(ATP) channel.

PubMed

Bayat, Gholamreza; Javan, Mohammad; Safari, Fatemeh; Khalili, Azadeh; Shokri, Saeed; Goudarzvand, Mahdi; Salimi, Mehdi; Hajizadeh, Sohrab

2016-03-01

ATP-sensitive potassium channels are supposed to have a substantial role in improvement of cardiac performance. This study was performed to evaluate whether nandrolone decanoate (ND) and (or) exercise training could affect the expression of cardiac K(ATP) channel subunits. Thirty-five male albino Wistar rats were randomly divided into 5 groups, including sedentary control (SC), sedentary vehicle (SV), sedentary ND (SND), exercise control (EC), and exercise and ND (E+ND). Exercise training was performed on a treadmill 5 times per week. ND was injected (10 mg/kg/week, i.m.) to the rats in the SND and E+ND groups. Following cardiac isolation, the expression of both sarcolemmal and mitochondrial subunits of K(ATP) channel was measured using Western blot method. The expression of sarcolemmal, but not mitochondrial, subunits of K(ATP) channel (Kir6.2 and SUR2) of EC group was significantly higher compared with SC group while ND administration (SND group) did not show any change in their expression. In the E+ND group, ND administration led to decrease of the over-expression of sarcolemmal Kir6.2 and SUR2 which was previously induced by exercise. There was no significant association between the mitochondrial expression of either Kir6.2 or SUR2 proteins and administration of ND or exercise. Supra-physiological dosage of ND negatively reverses the effects of exercise on the cardiac muscle expression of sarcolemmal, but not mitochondrial, K(ATP) channel subunits.

Discovery and progress of direct cardiac reprogramming.

PubMed

Kojima, Hidenori; Ieda, Masaki

2017-06-01

Cardiac disease remains a major cause of death worldwide. Direct cardiac reprogramming has emerged as a promising approach for cardiac regenerative therapy. After the discovery of MyoD, a master regulator for skeletal muscle, other single cardiac reprogramming factors (master regulators) have been sought. Discovery of cardiac reprogramming factors was inspired by the finding that multiple, but not single, transcription factors were needed to generate induced pluripotent stem cells (iPSCs) from fibroblasts. We first reported a combination of cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (GMT), that could convert mouse fibroblasts into cardiomyocyte-like cells, which were designated as induced cardiomyocyte-like cells (iCMs). Following our first report of cardiac reprogramming, many researchers, including ourselves, demonstrated an improvement in cardiac reprogramming efficiency, in vivo direct cardiac reprogramming for heart regeneration, and cardiac reprogramming in human cells. However, cardiac reprogramming in human cells and adult fibroblasts remains inefficient, and further efforts are needed. We believe that future research elucidating epigenetic barriers and molecular mechanisms of direct cardiac reprogramming will improve the reprogramming efficiency, and that this new technology has great potential for clinical applications.

Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification.

PubMed

Pillai, Indulekha C L; Li, Shen; Romay, Milagros; Lam, Larry; Lu, Yan; Huang, Jie; Dillard, Nathaniel; Zemanova, Marketa; Rubbi, Liudmilla; Wang, Yibin; Lee, Jason; Xia, Ming; Liang, Owen; Xie, Ya-Hong; Pellegrini, Matteo; Lusis, Aldons J; Deb, Arjun

2017-02-02

Mammalian tissues calcify with age and injury. Analogous to bone formation, osteogenic cells are thought to be recruited to the affected tissue and induce mineralization. In the heart, calcification of cardiac muscle leads to conduction system disturbances and is one of the most common pathologies underlying heart blocks. However the cell identity and mechanisms contributing to pathological heart muscle calcification remain unknown. Using lineage tracing, murine models of heart calcification and in vivo transplantation assays, we show that cardiac fibroblasts (CFs) adopt an osteoblast cell-like fate and contribute directly to heart muscle calcification. Small-molecule inhibition of ENPP1, an enzyme that is induced upon injury and regulates bone mineralization, significantly attenuated cardiac calcification. Inhibitors of bone mineralization completely prevented ectopic cardiac calcification and improved post injury heart function. Taken together, these findings highlight the plasticity of fibroblasts in contributing to ectopic calcification and identify pharmacological targets for therapeutic development. Copyright © 2017 Elsevier Inc. All rights reserved.

Tandospirone reduces wasting and improves cardiac function in experimental cancer cachexia.

PubMed

Elkina, Yulia; Palus, Sandra; Tschirner, Anika; Hartmann, Kai; von Haehling, Stephan; Doehner, Wolfram; Mayer, Ulrike; Coats, Andrew J S; Beadle, John; Anker, Stefan D; Springer, Jochen

2013-12-10

Cancer cachexia is thought to be the cause of >20% of cancer related deaths. Symptoms of cancer cachexia patients include depression and anorexia significantly worsening their quality of life. Moreover, in rodent models of cancer cachexia atrophy of the heart has been shown to impair cardiac function. Here, we characterize the effects of the antidepressant and anxiolytic drug tandospirone on wasting, cardiac function and survival in experimental cancer cachexia. The well-established Yoshida hepatoma rat model was used and tumor-bearing rats were treated with 1mg/kg/d (LD), 10mg/kg/d (HD) tandospirone or placebo. Weight, body composition (NMR), cardiac function (echocardiography), activity and food intake were assessed. Noradrenalin and cortisol were measured in plasma and caspase activity in skeletal muscle. Ten mg/kg/d tandospirone decreased the loss of body weight (p=0.0003) compared to placebo animals, mainly due to preservation of muscle mass (p<0.001), while 1mg/kg/d tandospirone was not effective. Locomotor activity (p=0.0007) and food intake (p=0.0001) were increased by HD tandospirone. The weight (p=0.0277) and function of heart (left ventricular mass, fractional shortening, stroke volume, ejection fraction, all p<0.05) were significantly improved. In the HD tandospirone group, plasma levels of noradrenalin and cortisol were significantly reduced by 49% and 52%, respectively, which may have contributed to the lower caspase activity in the gastrocnemius muscle. Most importantly, HD tandospirone significantly improved survival compared to placebo rats (HR: 0.34; 95% CI: 0.13-0.86; p=0.0495). Tandospirone showed significant beneficial effects in the Yoshida hepatoma cancer cachexia model and should be further examined as a prospective drug for this syndrome. © 2013.

Sudden perinatal death due to rupture of congenital cardiac diverticulum. Pathological findings and medico-legal investigations in malpractice charge.

PubMed

Marchesi, Matteo; Boracchi, Michele; Gentile, Guendalina; Maghin, Francesca; Zoja, Riccardo

2017-09-01

Congenital diverticula of the left ventricle, very rare malformations, are determined by an abnormal embryonic development of the ventricular wall and can be isolated or associated to other cardiac anomalies. In most of the cases, these pathologies are not symptomatic and in some patients can be associated to ventricular arrhythmia, cardiac rupture with tamponade and sudden death. Authors are presenting the case of a sudden death in an 8-weeks-old newborn due to rupture of a cardiac congenital diverticulum of the left ventricle, discovered only at the moment of the autopsic examination. The parents of the victim pressed charges against the medical staff that was appointed to the cares, blaming them with malpractice. The missed diagnosis of a cardiac congenital diverticulum of the left ventricle, a rare pathology, reflects the trickiness of the medical management that can lead to medico-legal controversies and, even though such rare conditions must be always taken into consideration when investigating possible dysfunction causing the death, diagnostic difficulties, in the case in exam, justify the missed diagnosis intra-vitam of cardiac ventricular diverticulum. Copyright © 2017 Elsevier B.V. All rights reserved.

From Syncitium to Regulated Pump: A Cardiac Muscle Cellular Update

ERIC Educational Resources Information Center

Korzick, Donna H.

2011-01-01

The primary purpose of this article is to present a basic overview of some key teaching concepts that should be considered for inclusion in an six- to eight-lecture introductory block on the regulation of cardiac performance for graduate students. Within the context of cardiac excitation-contraction coupling, this review incorporates information…

MURC, a Muscle-Restricted Coiled-Coil Protein That Modulates the Rho/ROCK Pathway, Induces Cardiac Dysfunction and Conduction Disturbance▿

PubMed Central

Ogata, Takehiro; Ueyama, Tomomi; Isodono, Koji; Tagawa, Masashi; Takehara, Naofumi; Kawashima, Tsuneaki; Harada, Koichiro; Takahashi, Tomosaburo; Shioi, Tetsuo; Matsubara, Hiroaki; Oh, Hidemasa

2008-01-01

We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias. PMID:18332105

MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance.

PubMed

Ogata, Takehiro; Ueyama, Tomomi; Isodono, Koji; Tagawa, Masashi; Takehara, Naofumi; Kawashima, Tsuneaki; Harada, Koichiro; Takahashi, Tomosaburo; Shioi, Tetsuo; Matsubara, Hiroaki; Oh, Hidemasa

2008-05-01

We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias.

Effects of dietary omega-3 on dystrophic cardiac and diaphragm muscles as evaluated by 1H magnetic resonance spectroscopy: Metabolic profile and calcium-related proteins.

PubMed

Maurício, Adriana Fogagnolo; de Carvalho, Samara Camaçari; Santo Neto, Humberto; Marques, Maria Julia

2017-08-01

Duchenne muscular dystrophy (DMD) is characterized by the absence of dystrophin and muscle degeneration. Calcium dysregulation and oxidative stress also contribute to the disease progression. We evaluated the potential therapeutic benefits of supplementation with omega-3 on the metabolic profile, calcium-related proteins and oxidative stress response in the heart and diaphragm (DIA) of the mdx mouse model of DMD at later stages of the disease (13 months). Mdx mice (8 months old) received omega-3 via a dietary supplement for 5 months. Metabolites were analyzed by 1 H magnetic resonance spectroscopy. Muscle total calcium was evaluated by inductively coupled plasma-optical emission spectrometry. Calsequestrin, TRPC1 and 4-HNE were determined via Western blot. Omega-3 decreased the metabolites taurine (related to calcium regulation and oxidative stress), aspartate (related to inflammation) and oxypurinol (related to oxidative stress) in the heart (aspartate) and DIA (taurine, aspartate and oxypurinol). Omega-3 also significantly decreased total calcium and TRPC1 levels in cardiac and DIA muscles and increased the levels of calsequestrin (cardiac and skeletal) and decreased the oxidative stress marker 4-HNE. The current study suggests that supplementation with omega-3 may generate therapeutic benefits on dystrophy progression, at later stages of the disease, with changes in the metabolic profile that may be correlated to omega-3 therapy. Copyright © 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

Electrical stimulation as a biomimicry tool for regulating muscle cell behavior

PubMed Central

Ahadian, Samad; Ostrovidov, Serge; Hosseini, Vahid; Kaji, Hirokazu; Ramalingam, Murugan; Bae, Hojae; Khademhosseini, Ali

2013-01-01

There is a growing need to understand muscle cell behaviors and to engineer muscle tissues to replace defective tissues in the body. Despite a long history of the clinical use of electric fields for muscle tissues in vivo, electrical stimulation (ES) has recently gained significant attention as a powerful tool for regulating muscle cell behaviors in vitro. ES aims to mimic the electrical environment of electroactive muscle cells (e.g., cardiac or skeletal muscle cells) by helping to regulate cell-cell and cell-extracellular matrix (ECM) interactions. As a result, it can be used to enhance the alignment and differentiation of skeletal or cardiac muscle cells and to aid in engineering of functional muscle tissues. Additionally, ES can be used to control and monitor force generation and electrophysiological activity of muscle tissues for bio-actuation and drug-screening applications in a simple, high-throughput, and reproducible manner. In this review paper, we briefly describe the importance of ES in regulating muscle cell behaviors in vitro, as well as the major challenges and prospective potential associated with ES in the context of muscle tissue engineering. PMID:23823664

Electrical stimulation as a biomimicry tool for regulating muscle cell behavior.

PubMed

Ahadian, Samad; Ostrovidov, Serge; Hosseini, Vahid; Kaji, Hirokazu; Ramalingam, Murugan; Bae, Hojae; Khademhosseini, Ali

2013-01-01

There is a growing need to understand muscle cell behaviors and to engineer muscle tissues to replace defective tissues in the body. Despite a long history of the clinical use of electric fields for muscle tissues in vivo, electrical stimulation (ES) has recently gained significant attention as a powerful tool for regulating muscle cell behaviors in vitro. ES aims to mimic the electrical environment of electroactive muscle cells (e.g., cardiac or skeletal muscle cells) by helping to regulate cell-cell and cell-extracellular matrix (ECM) interactions. As a result, it can be used to enhance the alignment and differentiation of skeletal or cardiac muscle cells and to aid in engineering of functional muscle tissues. Additionally, ES can be used to control and monitor force generation and electrophysiological activity of muscle tissues for bio-actuation and drug-screening applications in a simple, high-throughput, and reproducible manner. In this review paper, we briefly describe the importance of ES in regulating muscle cell behaviors in vitro, as well as the major challenges and prospective potential associated with ES in the context of muscle tissue engineering.

Exercise-induced changes of MCT1 in cardiac and skeletal muscles of diabetic rats induced by high-fat diet and STZ.

PubMed

Nikooie, Rohollah; Rajabi, Hamid; Gharakhanlu, Reza; Atabi, Fereshteh; Omidfar, Kobra; Aveseh, Malihe; Larijani, Bagher

2013-12-01

We hypothesized that a part of therapeutic effects of endurance training on insulin resistance is mediated by increase in cardiac and skeletal muscle mitochondrial lactate transporter, monocarboxylate transporter 1 (MCT1). Therefore, we examined the effect of 7 weeks endurance training on the mRNA and protein expression of MCT1 and MCT4 and their chaperon, CD147, on both sarcolemmal and mitochondrial membrane, separately, in healthy and type 2 diabetic rats. Diabetes was induced by injection of low dose of streptozotocin and feeding with high-fat diet. Insulin resistance was confirmed by homeostasis model assessment-estimated insulin resistance index and accuracy of two membranes separation was confirmed by negative control markers (glucose transporter 1 and cytochrome c oxidase. Real-time PCR and western blotting were used for mRNA and protein expression, respectively. Diabetes dramatically reduced MCT1 and MCT4 mRNA and their expression on sarcolemmal membrane whereas the reduction in MCT1 expression was less in mitochondrial membrane. Training increased the MCT1 mRNA and protein expression in both membranes and decreased insulin resistance as an adaptive consequence. In both tissues increase in CD147 mRNA was only parallel to MCT1 expression. The response of MCT1 on sarcolemmal and mitochondrial membranes was different between cardiac and skeletal muscles which indicate that intracellular lactate kinetic is tissue specific that allows a tissue to coordinate whole organism metabolism.

Chiral recognition of pinacidil and its 3-pyridyl isomer by canine cardiac and smooth muscle: Antagonism by sulfonylureas

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

Steinberg, M.I.; Wiest, S.A.; Zimmerman, K.M.

1991-01-01

Pinacidil, a potassium channel opener (PCO), relaxes vascular smooth muscle by increasing potassium ion membrane conductance, thereby causing membrane hyperpolarization. PCOs also act on cardiac muscle to decrease action potential duration (APD) selectively. To examine the enantiomeric selectivity of pinacidil, the stereoisomers of pinacidil (a 4-pyridylcyanoguanidine) and its 3-pyridyl isomer (LY222675) were synthesized and studied in canine Purkinje fibers and cephalic veins. The (-)-enantiomers of both pinacidil and LY222675 were more potent in relaxing phenylephrine-contracted cephalic veins and decreasing APD than were their corresponding (+)-enantiomers. The EC50 values for (-)-pinacidil and (-)-LY222675 in relaxing cephalic veins were 0.44 and 0.09more » microM, respectively. In decreasing APD, the EC50 values were 3.2 microM for (-)-pinacidil and 0.43 microM for (-)-LY222675. The eudismic ratio was greater for the 3-pyridyl isomer than for pinacidil in both cardiac (71 vs. 22) and vascular (53 vs. 17) tissues. (-)-LY222675 and (-)-pinacidil (0.1-30 microM) also increased 86Rb efflux from cephalic veins to a greater extent than did their respective optical antipodes. The antidiabetic sulfonylurea, glyburide (1-30 microM), shifted the vascular concentration-response curve of (-)-pinacidil to the right by a similar extent at each inhibitor concentration. Glipizide also antagonized the response to (-)-pinacidil, but was about 1/10 as potent with a maximal shift occurring at 10 and 30 microM. Glyburide antagonized the vascular relaxant effects of 0.3 microM (-)-LY222675 (EC50, 2.3 microM) and reversed the decrease in APD caused by 3 microM (-)-LY222675 (EC50, 1.9 microM). Nitroprusside did not alter 86Rb efflux, and vascular relaxation induced by sodium nitroprusside was unaffected by sulfonylureas.« less

Ultrastructure and cytochemistry of cardiac intramitochondrial glycogen.

PubMed

Sótonyi, P; Somogyi, E; Nemes, A; Juhász-Nagy, S

1976-01-01

Authors have observed abnormalities of glycogen localization in cardiac muscle, after normothermic cardiac arrest. The identification of these intramitrochondrial particles as glycogen was confirmed by selective staining with periodic acid-lead citrat, periodic acid-thiosemicarbazide protein methods and by their selective removal from tissue sections by alfa-amylase. The intramitochondrial glycogen particles were of beta-type. Some intramitochondrial particles were surrounded by paired membranes which resulted from protrusion of parts of mitochondrial membrane.

Effects of Trichothecenes on Cardiac Cell Electrical Function

DTIC Science & Technology

1985-12-16

toxic effects . These studies demonstrated unequivocal reversible effects of certain mycotoxins on heart cell electrical activity. Preliminary studies...muscle cells shown in Figure 8 illustrate the typical effects of trichothecene mycotoxins in canine ventricular cells. T-2 tetraol, for 3xample...false tendon cells and V ventricular muscle cells (shown in Figure 8) illustrate the typical effects of trichothecene mycotoxins in canine cardiac

Cervical outlet syndrome due to an accessory part of the trapezius muscle in the posterior triangle of the neck.

PubMed

Hug, U; Burg, D; Meyer, V E

2000-06-01

A 48-year-old man presented with pain and sensory impairment radiating from the neck to the thumb and forefinger of the right hand when lifting weights and turning or tilting the head. The symptoms were due to an anomalous accessory part of the trapezius muscle crossing the upper part of the brachial plexus. Excision of the anomalous muscle and release of the clavicular part of the sternocleidomastoid muscle abolished the complaints.

Distinct contributions of the thin and thick filaments to length-dependent activation in heart muscle.

PubMed

Zhang, Xuemeng; Kampourakis, Thomas; Yan, Ziqian; Sevrieva, Ivanka; Irving, Malcolm; Sun, Yin-Biao

2017-02-23

The Frank-Starling relation is a fundamental auto-regulatory property of the heart that ensures the volume of blood ejected in each heartbeat is matched to the extent of venous filling. At the cellular level, heart muscle cells generate higher force when stretched, but despite intense efforts the underlying molecular mechanism remains unknown. We applied a fluorescence-based method, which reports structural changes separately in the thick and thin filaments of rat cardiac muscle, to elucidate that mechanism. The distinct structural changes of troponin C in the thin filaments and myosin regulatory light chain in the thick filaments allowed us to identify two aspects of the Frank-Starling relation. Our results show that the enhanced force observed when heart muscle cells are maximally activated by calcium is due to a change in thick filament structure, but the increase in calcium sensitivity at lower calcium levels is due to a change in thin filament structure.

[Cardiac arrest in chronic metabolic alkalosis due to sodium bicarbonate abuse].

PubMed

Niewiński, Grzegorz; Korta, Teresa; Debowska, Małgorzata; Kosiński, Cezary; Kubik, Tomasz; Romanik, Wojciech; Kański, Andrzej

2008-01-01

Moderate metabolic alkalosis has not been considered as a life-threatening situation by many authors, but when it persists and pH increases above 7.65, the situation may become critical. We present a case of a 61-yr-old alcoholic male patient, who had been consuming approximately 200 g of sodium bicarbonate daily for twenty years, due to persisitent heartburn and abdominal pains. The patient was admitted to the ITU after home cardiac arrest and resuscitation. On admission he was unconscious and in respiratory distress, with a GCS of 5. Blood gases revealed that his pH was 7.64, HCO3 44 mmol L(-1), K+ 2.4 mmol L(-1)l, Cl- 44 mmol L(-1), and lactate concentration over 15 mmol L(-1). He was treated with controlled hypercapnia, up to a PaCO2 of 63 mm Hg, sedation, and administration of a large amount of chloride (864 mmol during the first day). The patient regained consciousness after 48 h, was extubated and transferred to the internal medicine department where he died 3 days later. Chronic alkali abuse can lead to various metabolic disturbances, neurologic disturbances and cardiovascular compromise. In the described case, the exact cause of cardiac arrest remained unknown, but may have been caused by alkalosis combined with hypoxia, hypokalemia and poor general condition. The extreme metabolic alkalosis (pH 7.8) could also have been enhanced by the administration of i.v. sodium bicarbonate during resuscitation. The treatment of choice in such cases should consist of vigorous chloride containing fluid resuscitation, ammonium chloride and hemodialysis.

[Case of acute ischemic stroke due to cardiac myxoma treated by intravenous thrombolysis and endovascular therapy].

PubMed

Kamiya, Yuki; Ichikawa, Hiroo; Mizuma, Keita; Itaya, Kazuhiro; Shimizu, Yuki; Kawamura, Mitsuru

2014-01-01

A 48-year-old woman with no previous neurological diseases was transferred to our hospital because of sudden-onset unconsciousness. On arrival, she showed consciousness disturbance (E1V1M3 on the Glasgow Coma Scale), tetraplegia, right conjugate deviation and bilateral pathological reflexes. These symptoms resulted in a NIH stroke scale score of 32. Brain diffusion-weighted MR imaging (DWI) showed multiple hyper-intense lesions, and MR angiography revealed occlusions of the basilar artery (BA) and superior branch of the right middle cerebral artery (MCA). Transthoracic echocardiography disclosed a 51 × 24 mm myxoma in the left atrium. These findings led to diagnosis of acute ischemic stroke due to embolization from cardiac myxoma. Thrombolytic therapy with intravenous tissue plasminogen activator (IV tPA) was started 120 min after onset because there were no contraindications for this treatment. However, the symptoms did not resolve, and thus endovascular therapy was performed immediately after IV tPA. Angiography of the left vertebral artery initially showed BA occlusion, but a repeated angiogram resulted in spontaneous recanalization of the BA. However, the left posterior cerebral artery remained occluded by a residual embolus. Subsequently, occlusion found in the superior branch of the right MCA was treated by intra-arterial local thrombolysis using urokinase and thrombectomy with a foreign body retrieval device, but the MCA remained occluded. DWI after endovascular therapy showed new hyper-intense lesions in the bilateral medial thalamus and left occipital cortex. Clinically, neurological status did not improve, with a score of 5 on the modified Rankin Scale. IV tPA can be used for stroke due to cardiac myxoma, but development of brain aneurysms and metastases caused by myxoma is a concern. Given the difficulty of predicting an embolus composite from a thrombus or tumor particle, aspiration thrombectomy may be safer and more effective for stroke due to cardiac

Purification of cardiac myocytes from human heart biopsies for gene expression analysis.

PubMed

Kosloski, L M; Bales, I K; Allen, K B; Walker, B L; Borkon, A M; Stuart, R S; Pak, A F; Wacker, M J

2009-09-01

The collection of gene expression data from human heart biopsies is important for understanding the cellular mechanisms of arrhythmias and diseases such as cardiac hypertrophy and heart failure. Many clinical and basic research laboratories conduct gene expression analysis using RNA from whole cardiac biopsies. This allows for the analysis of global changes in gene expression in areas of the heart, while eliminating the need for more complex and technically difficult single-cell isolation procedures (such as flow cytometry, laser capture microdissection, etc.) that require expensive equipment and specialized training. The abundance of fibroblasts and other cell types in whole biopsies, however, can complicate gene expression analysis and the interpretation of results. Therefore, we have designed a technique to quickly and easily purify cardiac myocytes from whole cardiac biopsies for RNA extraction. Human heart tissue samples were collected, and our purification method was compared with the standard nonpurification method. Cell imaging using acridine orange staining of the purified sample demonstrated that >98% of total RNA was contained within identifiable cardiac myocytes. Real-time RT-PCR was performed comparing nonpurified and purified samples for the expression of troponin T (myocyte marker), vimentin (fibroblast marker), and alpha-smooth muscle actin (smooth muscle marker). Troponin T expression was significantly increased, and vimentin and alpha-smooth muscle actin were significantly decreased in the purified sample (n = 8; P < 0.05). Extracted RNA was analyzed during each step of the purification, and no significant degradation occurred. These results demonstrate that this isolation method yields a more purified cardiac myocyte RNA sample suitable for downstream applications, such as real-time RT-PCR, and allows for more accurate gene expression changes in cardiac myocytes from heart biopsies.

Cardiac function and exercise adaptation in 8 children with LPIN1 mutations.

PubMed

Legendre, Antoine; Khraiche, Diala; Ou, Phalla; Mauvais, François-Xavier; Madrange, Marine; Guemann, Anne-Sophie; Jais, Jean-Philippe; Bonnet, Damien; Hamel, Yamina; de Lonlay, Pascale

2018-03-01

Lipin-1 deficiency is a major cause of rhabdomyolysis that are precipitated by febrile illness. The prognosis is poor, with one-third of patients dying from cardiac arrest during a crisis episode. Apart from acute rhabdomyolysis, most patients are healthy, showing normal clinical and cardiac ultrasound parameters. We report cardiac and exercise examinations of 8 children carrying two LPIN1 mutations. The examinations were performed outside of a myolysis episode, but one patient presented with fever during one examination. All but one patient displayed normal resting cardiac function, as determined by echocardiography. One patient exhibited slight left ventricular dysfunction at rest and a lack of increased stroke volume during cycle ramp exercise. During exercise, peripheral muscle adaptation was impaired in 2 patients compared to healthy controls: they presented an abnormal increase in cardiac output relative to oxygen uptake: dQ/dVO 2 =8.2 and 9.5 (>2DS of controls population). One patient underwent 2 exercise tests; during one test, the patient was febrile, leading to acute rhabdomyolysis in the following hours. He exhibited changes in recovery muscle reoxygenation parameters and an increased dQ/dVO 2 during exercise compared with that under normothermia (7.9 vs 6), which did not lead to acute rhabdomyolysis. The four patients assessed by cardiac 1 H-magnetic resonance spectroscopy exhibited signs of intracardiac steatosis. We observed abnormal haemodynamic profiles during exercise in 3/8 patients with lipin-1 deficiency, suggesting impaired muscle oxidative phosphorylation during exercise. Fever appeared to be an aggravating factor. One patient exhibited moderate cardiac dysfunction, which was possibly related to intracardiac stored lipid toxicity. Copyright © 2018 Elsevier Inc. All rights reserved.

Duchenne Muscular Dystrophy Gene Expression in Normal and Diseased Human Muscle

NASA Astrophysics Data System (ADS)

Oronzi Scott, M.; Sylvester, J. E.; Heiman-Patterson, T.; Shi, Y.-J.; Fieles, W.; Stedman, H.; Burghes, A.; Ray, P.; Worton, R.; Fischbeck, K. H.

1988-03-01

A probe for the 5' end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers.

Integration of multiple cell-matrix interactions into alginate scaffolds for promoting cardiac tissue regeneration.

PubMed

Sapir, Yulia; Kryukov, Olga; Cohen, Smadar

2011-03-01

Cardiac tissue engineering aims to repair damaged myocardial tissues by applying heart patches created in vitro. Herein, we explored the possible role of a combination of two matrix-attached peptides, the adhesion peptide G(4)RGDY and heparin-binding peptide G(4)SPPRRARVTY (HBP) in cardiac tissue regeneration. Neonatal rat cardiac cells were seeded into unmodified, single peptide or double peptide-attached alginate scaffolds, all having the same physical features of porosity, hydrogel forming and matrix stiffness. The cardiac tissue developed in the HBP/RGD-attached scaffolds revealed the best features of a functional muscle tissue, as judged by all studied parameters, i.e., immunostaining of cardiac cell markers, histology, western blot of protein expressions and metabolic activity. By day 7, well-developed myocardial fibers were observed in these cell constructs. At 14 days the HBP/RGD-attached constructs presented an isotropic myofiber arrangement, while no such arrangement was seen in the other constructs. The expression levels of α-actinin, N-cadherin and Connexin-43, showing preservation and an increase in Connexin-43 expression (Cx-43) with time, further supported the formation a contractile muscle tissue in the HBP/RGD-attached scaffolds. Collectively, the attachment of combinatorial peptides representing different signaling in ECM-cell interactions proved to play a key role, contributing to the formation of a functional cardiac muscle tissue, in vitro. Copyright © 2010 Elsevier Ltd. All rights reserved.

Fiber-type differences in muscle mitochondrial profiles.

PubMed

Leary, S C; Lyons, C N; Rosenberger, A G; Ballantyne, J S; Stillman, J; Moyes, C D

2003-10-01

Although striated muscles differ in mitochondrial content, the extent of fiber-type specific mitochondrial specializations is not well known. To address this issue, we compared mitochondrial structural and functional properties in red muscle (RM), white muscle (WM), and cardiac muscle of rainbow trout. Overall preservation of the basic relationships between oxidative phosphorylation complexes among fiber types was confirmed by kinetic analyses, immunoblotting of native holoproteins, and spectroscopic measurements of cytochrome content. Fiber-type differences in mitochondrial properties were apparent when parameters were expressed per milligram mitochondrial protein. However, the differences diminished when expressed relative to cytochrome oxidase (COX), possibly a more meaningful denominator than mitochondrial protein. Expressed relative to COX, there were no differences in oxidative phosphorylation enzyme activities, pyruvate-based respiratory rates, H2O2 production, or state 4 proton leak respiration. These data suggest most mitochondrial qualitative properties are conserved across fiber types. However, there remained modest differences ( approximately 50%) in stoichiometries of selected enzymes of the Krebs cycle, beta-oxidation, and antioxidant enzymes. There were clear differences in membrane fluidity (RM > cardiac, WM) and proton conductance (H+/min/mV/U COX: WM > RM > cardiac). The pronounced differences in mitochondrial content between fiber types could be attributed to a combination of differences in myonuclear domain and modest effects on the expression of nuclear- and mitochondrially encoded respiratory genes. Collectively, these studies suggest constitutive pathways that transcend fiber types are primarily responsible for determining most quantitative and qualitative properties of mitochondria.

Plakins in striated muscle.

PubMed

Boyer, Justin G; Bernstein, Marija A; Boudreau-Larivière, Céline

2010-03-01

Striated muscle cells contain numerous architectural proteins that contribute to the function of muscle as generators of mechanical force. Among these proteins are crosslinkers belonging to the plakin family, namely plectin, microtubule-actin crosslinking factor (ACF7/MACF1), bullous pemphigoid antigen 1 (Bpag1/dystonin), and desmoplakin. These plakin family members, in particular plectin and Bpag1/dystonin, exist as several isoforms. The domain organization of these plakin variants dictates their subcellular location and the proteins with which they interact. Several studies suggest that plakins exert unique functions within various compartments of the muscle cell including the sarcolemma, the sarcomere, both neuromuscular and myotendinous junctions in skeletal muscle, and the intercalated discs in cardiac muscle. Plakins may also regulate the cellular placement and function of specific organelles, notably the nucleus, mitochondria, Golgi apparatus, and sarcoplasmic reticulum. Here we review and summarize our current knowledge of the function of plakins in striated muscle cells.

Standard magnetic resonance-based measurements of the Pi→ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles

PubMed Central

Ugurbil, Kamil

2011-01-01

Magnetic resonance spectroscopy-based magnetization transfer techniques (MT) are commonly used to assess the rate of oxidative (i.e., mitochondrial) ATP synthesis in intact tissues. Physiologically appropriate interpretation of MT rate data depends on accurate appraisal of the biochemical events that contribute to a specific MT rate measurement. The relative contributions of the specific enzymatic reactions that can contribute to a MT Pi→ATP rate measurement are tissue dependent; nonrecognition of this fact can bias the interpretation of MT Pi→ATP rate data. The complexities of MT-based measurements of mitochondrial ATP synthesis rates made in striated muscle and other tissues are reviewed, following which, the adverse impacts of erroneous Pi→ATP rate data analyses on the physiological inferences presented in selected published studies of cardiac and skeletal muscle are considered. PMID:21368294

Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis.

PubMed

Nakano, Haruko; Minami, Itsunari; Braas, Daniel; Pappoe, Herman; Wu, Xiuju; Sagadevan, Addelynn; Vergnes, Laurent; Fu, Kai; Morselli, Marco; Dunham, Christopher; Ding, Xueqin; Stieg, Adam Z; Gimzewski, James K; Pellegrini, Matteo; Clark, Peter M; Reue, Karen; Lusis, Aldons J; Ribalet, Bernard; Kurdistani, Siavash K; Christofk, Heather; Nakatsuji, Norio; Nakano, Atsushi

2017-12-12

The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy.

Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis

PubMed Central

Nakano, Haruko; Minami, Itsunari; Braas, Daniel; Pappoe, Herman; Wu, Xiuju; Sagadevan, Addelynn; Vergnes, Laurent; Fu, Kai; Morselli, Marco; Dunham, Christopher; Ding, Xueqin; Stieg, Adam Z; Gimzewski, James K; Pellegrini, Matteo; Clark, Peter M; Reue, Karen; Lusis, Aldons J; Ribalet, Bernard; Kurdistani, Siavash K; Christofk, Heather; Nakatsuji, Norio

2017-01-01

The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy. PMID:29231167

Cardiac Niche Influences the Direct Reprogramming of Canine Fibroblasts into Cardiomyocyte-Like Cells

PubMed Central

Palazzolo, Giacomo; Quattrocelli, Mattia; Toelen, Jaan; Dominici, Roberto; Tettamenti, Guido; Barthelemy, Inès; Blot, Stephane; Gijsbers, Rik; Cassano, Marco

2016-01-01

The Duchenne and Becker muscular dystrophies are caused by mutation of dystrophin gene and primarily affect skeletal and cardiac muscles. Cardiac involvement in dystrophic GRMD dogs has been demonstrated by electrocardiographic studies with the onset of a progressive cardiomyopathy similar to the cardiac disease in DMD patients. In this respect, GRMD is a useful model to explore cardiac and skeletal muscle pathogenesis and for developing new therapeutic protocols. Here we describe a protocol to convert GRMD canine fibroblasts isolated from heart and skin into induced cardiac-like myocytes (ciCLMs). We used a mix of transcription factors (GATA4, HAND2, TBX5, and MEF2C), known to be able to differentiate mouse and human somatic cells into ciCLMs. Exogenous gene expression was obtained using four lentiviral vectors carrying transcription factor genes and different resistance genes. Our data demonstrate a direct switch from fibroblast into ciCLMs with no activation of early cardiac genes. ciCLMs were unable to contract spontaneously, suggesting, differently from mouse and human cells, an incomplete differentiation process. However, when transplanted in neonatal hearts of SCID/Beige mice, ciCLMs participate in cardiac myogenesis. PMID:26681949

Cardiac Niche Influences the Direct Reprogramming of Canine Fibroblasts into Cardiomyocyte-Like Cells.

PubMed

Palazzolo, Giacomo; Quattrocelli, Mattia; Toelen, Jaan; Dominici, Roberto; Anastasia, Luigi; Tettamenti, Guido; Barthelemy, Inès; Blot, Stephane; Gijsbers, Rik; Cassano, Marco; Sampaolesi, Maurilio

2016-01-01

The Duchenne and Becker muscular dystrophies are caused by mutation of dystrophin gene and primarily affect skeletal and cardiac muscles. Cardiac involvement in dystrophic GRMD dogs has been demonstrated by electrocardiographic studies with the onset of a progressive cardiomyopathy similar to the cardiac disease in DMD patients. In this respect, GRMD is a useful model to explore cardiac and skeletal muscle pathogenesis and for developing new therapeutic protocols. Here we describe a protocol to convert GRMD canine fibroblasts isolated from heart and skin into induced cardiac-like myocytes (ciCLMs). We used a mix of transcription factors (GATA4, HAND2, TBX5, and MEF2C), known to be able to differentiate mouse and human somatic cells into ciCLMs. Exogenous gene expression was obtained using four lentiviral vectors carrying transcription factor genes and different resistance genes. Our data demonstrate a direct switch from fibroblast into ciCLMs with no activation of early cardiac genes. ciCLMs were unable to contract spontaneously, suggesting, differently from mouse and human cells, an incomplete differentiation process. However, when transplanted in neonatal hearts of SCID/Beige mice, ciCLMs participate in cardiac myogenesis.

MUSCLEMOTION: A Versatile Open Software Tool to Quantify Cardiomyocyte and Cardiac Muscle Contraction In Vitro and In Vivo.

PubMed

Sala, Luca; van Meer, Berend J; Tertoolen, Leon G J; Bakkers, Jeroen; Bellin, Milena; Davis, Richard P; Denning, Chris; Dieben, Michel A E; Eschenhagen, Thomas; Giacomelli, Elisa; Grandela, Catarina; Hansen, Arne; Holman, Eduard R; Jongbloed, Monique R M; Kamel, Sarah M; Koopman, Charlotte D; Lachaud, Quentin; Mannhardt, Ingra; Mol, Mervyn P H; Mosqueira, Diogo; Orlova, Valeria V; Passier, Robert; Ribeiro, Marcelo C; Saleem, Umber; Smith, Godfrey L; Burton, Francis L; Mummery, Christine L

2018-02-02

There are several methods to measure cardiomyocyte and muscle contraction, but these require customized hardware, expensive apparatus, and advanced informatics or can only be used in single experimental models. Consequently, data and techniques have been difficult to reproduce across models and laboratories, analysis is time consuming, and only specialist researchers can quantify data. Here, we describe and validate an automated, open-source software tool (MUSCLEMOTION) adaptable for use with standard laboratory and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes, and pharmacological responses. MUSCLEMOTION allowed rapid and easy measurement of movement from high-speed movies in (1) 1-dimensional in vitro models, such as isolated adult and human pluripotent stem cell-derived cardiomyocytes; (2) 2-dimensional in vitro models, such as beating cardiomyocyte monolayers or small clusters of human pluripotent stem cell-derived cardiomyocytes; (3) 3-dimensional multicellular in vitro or in vivo contractile tissues, such as cardiac "organoids," engineered heart tissues, and zebrafish and human hearts. MUSCLEMOTION was effective under different recording conditions (bright-field microscopy with simultaneous patch-clamp recording, phase contrast microscopy, and traction force microscopy). Outcomes were virtually identical to the current gold standards for contraction measurement, such as optical flow, post deflection, edge-detection systems, or manual analyses. Finally, we used the algorithm to quantify contraction in in vitro and in vivo arrhythmia models and to measure pharmacological responses. Using a single open-source method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell, animal, and human models. © 2017 The Authors.

[An autopsy case of progressive generalized muscle atrophy over 14 years due to post-polio syndrome].

PubMed

Oki, Ryosuke; Uchino, Akiko; Izumi, Yuishin; Ogawa, Hirohisa; Murayama, Shigeo; Kaji, Ryuji

2016-01-01

We report the case of a 72-year-old man who had contracted acute paralytic poliomyelitis in his childhood. Thereafter, he had suffered from paresis involving the left lower limb, with no relapse or progression of the disease. He began noticing slowly progressive muscle weakness and atrophy in the upper and lower extremities in his 60s. At the age of 72, muscle weakness developed rapidly, and he demonstrated dyspnea on exertion and dysphagia. He died after about 14 years from the onset of muscle weakness symptoms. Autopsy findings demonstrated motoneuron loss and glial scars not only in the plaque-like lesions in the anterior horns, which were sequelae of old poliomyelitis, but also throughout the spine. No Bunina bodies, TDP-43, and ubiquitin inclusions were found. Post-polio syndrome is rarely fatal due to rapid progressive dyspnea and dysphagia. Thus, the pathological findings in the patient are considered to be related to the development of muscle weakness.

Molecular and functional analyses of the contractile apparatus in lymphatic muscle

NASA Technical Reports Server (NTRS)

Muthuchamy, Mariappan; Gashev, Anatoliy; Boswell, Niven; Dawson, Nancy; Zawieja, David; Delp, Z. (Principal Investigator)

2003-01-01

Lymphatics are necessary for the generation and regulation of lymph flow. Lymphatics use phasic contractions and extrinsic compressions to generate flow; tonic contractions alter resistance. Lymphatic muscle exhibits important differences from typical vascular smooth muscle. In this study, the thoracic duct exhibited significant functional differences from mesenteric lymphatics. To understand the molecular basis for these differences, we examined the profiles of contractile proteins and their messages in mesenteric lymphatics, thoracic duct, and arterioles. Results demonstrated that mesenteric lymphatics express only SMB smooth muscle myosin heavy chain (SM-MHC), whereas thoracic duct and arterioles expressed both SMA and SMB isoforms. Both SM1 and SM2 isoforms of SM-MHC were detected in arterioles and mesenteric and thoracic lymphatics. In addition, the fetal cardiac/skeletal slow-twitch muscle-specific beta-MHC message was detected only in mesenteric lymphatics. All four actin messages, cardiac alpha-actin, vascular alpha-actin, enteric gamma-actin, and skeletal alpha-actin, were present in both mesenteric lymphatics and arterioles. However, in thoracic duct, predominantly cardiac alpha-actin and vascular alpha-actin were found. Western blot and immunohistochemical analyses corroborated the mRNA studies. However, in arterioles only vascular alpha-actin protein was detected. These data indicate that lymphatics display genotypic and phenotypic characteristics of vascular, cardiac, and visceral myocytes, which are needed to fulfill the unique roles of the lymphatic system.

Localized intracellular calcium signaling in muscle: calcium sparks and calcium quarks.

PubMed

Niggli, E

1999-01-01

Subcellularly localized Ca2+ signals in cardiac and skeletal muscle have recently been identified as elementary Ca2+ signaling events. The signals, termed Ca2+ sparks and Ca2+ quarks, represent openings of Ca2+ release channels located in the membrane of the sarcoplasmic reticulum (SR). In cardiac muscle, the revolutionary discovery of Ca2+ sparks has allowed the development of a fundamentally different concept for the amplification of Ca2+ signals by Ca(2+)-induced Ca2+ release. In such a system, a graded amplification of the triggering Ca2+ signal entering the myocyte via L-type Ca2+ channels is accomplished by a recruitment process whereby individual SR Ca2+ release units are locally controlled by L-type Ca2+ channels. In skeletal muscle, the initial SR Ca2+ release is governed by voltage-sensors but subsequently activates additional Ca2+ sparks by Ca(2+)-induced Ca2+ release from the SR. Results from studies on elementary Ca2+ release events will improve our knowledge of muscle Ca2+ signaling at all levels of complexity, from the molecule to normal cellular function, and from the regulation of cardiac and skeletal muscle force to the pathophysiology of excitation-contraction coupling.

The heart and cardiac pacing in Steinert disease.

PubMed

Nigro, Gerardo; Papa, Andrea Antonio; Politano, Luisa

2012-10-01

Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert's disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment.

microRNA-133: expression, function and therapeutic potential in muscle diseases and cancer.

PubMed

Yu, Hao; Lu, Yinhui; Li, Zhaofa; Wang, Qizhao

2014-01-01

microRNAs (miRNAs) are a class of small non-coding RNAs that are 18-25 nucleotides (nt) in length and negatively regulate gene expression post-transcriptionally. miRNAs are known to mediate myriad processes and pathways. While many miRNAs are expressed ubiquitously, some are expressed in a tissue specific manner. miR-133 is one of the most studied and best characterized miRNAs to date. Specifically expressed in muscles, it has been classified as myomiRNAs and is necessary for proper skeletal and cardiac muscle development and function. Genes encoding miR-133 (miR-133a-1, miR-133a-2 and miR-133b) are transcribed as bicistronic transcripts together with miR-1-2, miR-1-1, and miR-206, respectively. However, they exhibit opposing impacts on muscle development. miR-133 gets involved in muscle development by targeting a lot of genes, including SFR, HDAC4, cyclin D2 and so on. Its aberrant expression has been linked to many diseases in skeletal muscle and cardiac muscle such as cardiac hypertrophy, muscular dystrophy, heart failure, cardiac arrhythmia. Beyond the study in muscle, miR-133 has been implicated in cancer and identified as a key factor in cancer development, including bladder cancer, prostate cancer and so on. Much more attention has been drawn to the versatile molecular functions of miR-133, making it a truly valuable therapeutic gene in miRNA-based gene therapy. In this review, we identified and summarized the results of studies of miR-133 with emphasis on its function in human diseases in muscle and cancer, and highlighted its therapeutic value. It might provide researchers a new insight into the biological significance of miR-133.

Cardiac atrophy after bed rest and spaceflight.

PubMed

Perhonen, M A; Franco, F; Lane, L D; Buckey, J C; Blomqvist, C G; Zerwekh, J E; Peshock, R M; Weatherall, P T; Levine, B D

2001-08-01

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity

Cardiac atrophy after bed rest and spaceflight

NASA Technical Reports Server (NTRS)

Perhonen, M. A.; Franco, F.; Lane, L. D.; Buckey, J. C.; Blomqvist, C. G.; Zerwekh, J. E.; Peshock, R. M.; Weatherall, P. T.; Levine, B. D.

2001-01-01

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity

Cardiac Fibroblast: The Renaissance Cell

PubMed Central

Souders, Colby A.; Bowers, Stephanie L.K.; Baudino, Troy A.

2012-01-01

The permanent cellular constituents of the heart include cardiac fibroblasts, myocytes, endothelial cells and vascular smooth muscle cells. Previous studies have demonstrated that there are undulating changes in cardiac cell populations during embryonic development, through neonatal development and into the adult. Transient cell populations include lymphocytes, mast cells and macrophages, which can interact with these permanent cell types to affect cardiac function. It has also been observed that there are marked differences in the makeup of the cardiac cell populations depending on the species, which may be important when examining myocardial remodeling. Current dogma states that the fibroblast makes up the largest cell population of the heart; however, this appears to vary for different species, especially mice. Cardiac fibroblasts play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as myocardial infarct and hypertension. These cells have numerous functions, including synthesis and deposition of extracellular matrix, cell-cell communication with myocytes, cell-cell signaling with other fibroblasts, as well as with endothelial cells. These contacts affect the electrophysiological properties, secretion of growth factors and cytokines, as well as potentiating blood vessel formation. While a plethora of information is known about several of these processes, relatively little is understood about fibroblasts and their role in angiogenesis during development or cardiac remodeling. In this review we provide insight into the various properties of cardiac fibroblasts that helps illustrate their importance in maintaining proper cardiac function, as well as their critical role in the remodeling heart. PMID:19959782

The Molecular Basis of Cardiac Mechanics: Regulation of Motor Unit Recruitment

DTIC Science & Technology

2001-10-25

sensitivity, Cooperativity. I. INTRODUCTION The biological linear motor, that produces cardiac and skeletal muscle contraction , is by far smaller than...who have described the role of the mechanical initial loading condition (Preload) on muscle contraction and by Fenn (1923) who has showed that the...2437, 1982. [4] E. Eisenberg, and T. L. Hill. Muscle contraction and energy transduction in biological system. Science 227: 999-1006, 1985. [5

MicroRNA-133 mediates cardiac diseases: Mechanisms and clinical implications.

PubMed

Liu, Yi; Liang, Yan; Zhang, Jin-Fang; Fu, Wei-Ming

2017-05-15

MicroRNAs (miRNAs) belong to the family of small non-coding RNAs that mediate gene expression by post-transcriptional regulation. Increasing evidence have demonstrated that miR-133 is enriched in muscle tissues and myogenic cells, and its aberrant expression could induce the occurrence and development of cardiac disorders, such as cardiac hypertrophy, heart failure, etc. In this review, we summarized the regulatory roles of miR-133 in cardiac disorders and the underlying mechanisms, which suggest that miR-133 may be a potential diagnostic and therapeutic tool for cardiac disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of nutritional supplementation with l-arginine on repair of injuries due to muscle strain: experimental study on rats☆

PubMed Central

Couto, Lauren Izabel Medeiros; Wuicik, William Luiz; Kuhn, Ivan; Capriotti, Juan Rodolfo Vilela; Repka, João Carlos

2015-01-01

Objective To evaluate the influence of oral supplementation with arginine on regeneration of injuries due to straining of the anterior tibial muscle of rats. Methods Twenty-four Wistar rats of weight 492.5 ± 50.45 g were used. Injuries were induced through straining the anterior tibial muscles. The rats were separated into three groups of eight rats each. In the untreated group (UTG), after induction of injuries, the rats were observed for 24 h. In the simulation group (SG) and the arginine group (AG) respectively, the rats received isotonic saline solution and arginine solution via direct gavage, over a seven-day period. At the end of the period, blood samples were collected for serum evaluations of creatine kinase (CK), lactic dehydrogenase (LDH), aspartate aminotransferase (AST) and C-reactive protein (CRP). The right and left anterior tibial muscles were resected for histopathological evaluations on the muscle injuries, investigating edema, hemorrhage and disorganization or morphometric alteration of the muscle fibers. The tissue repair was investigated in terms of proliferation of adipose tissue, angiogenesis and collagen fibers. The ANOVA and Student's t methods were used and p ≤ 0.05 was taken to be statistically significant. Results In the serum evaluations, the AG showed lower CK assay values and higher AST values. In the histopathological evaluation, the UTG presented edema and hemorrhage compatible with injuries due to strain; the SG presented edema and hemorrhage with proliferation of adipose tissue and collagen fibers; and the AG presented not only the findings of the SG but also, especially, intense angiogenesis. Conclusion Oral supplementation with arginine did not cause any significant metabolic alterations that would contraindicate its use and it induced angiogenesis during the repair of muscles injured due to strain. PMID:26401505

Within-summer variation in out-of-hospital cardiac arrest due to extremely long sunshine duration.

PubMed

Onozuka, Daisuke; Hagihara, Akihito

2017-03-15

Although several studies have reported the impacts of extremely high temperatures on cardiovascular diseases, no studies have examined whether variation in out-of-hospital cardiac arrest (OHCA) due to extremely long sunshine duration changes during the summer. We obtained daily data on all cases of OHCA and weather variations for all 47 prefectures of Japan during the summer (June to September) between 2005 and 2014. A distributed lag non-linear model combined with a quasi-Poisson regression model was used to estimate within-summer variation in OHCA due to extremely long sunshine duration for each prefecture. Then, multivariate random-effects meta-analysis was performed to derive overall effect estimates of sunshine duration at the national level. A total of 166,496 OHCAs of presumed cardiac origin met the inclusion criteria. The minimum morbidity percentile (MMP) was the 0th percentile of sunshine duration at the national level. The overall cumulative relative risk (RR) at the 99th percentile vs. the MMP was 1.15 (95% CI: 1.05-1.27) during the summer. The effect of extremely long sunshine duration on OHCA in early summer was acute and did not persist, whereas an identical effect was observed in late summer, but it was delayed and lasted for several days. During summer periods, excessive sunshine duration could increase the risk of OHCA. Timely preventive measures to reduce the OHCA risk due to extremely long sunshine duration are important in early summer, whereas these measures could include a wider time window of several days to reduce the risk in late summer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Short-duration transcutaneous electrical nerve stimulation in the postoperative period of cardiac surgery.

PubMed

Gregorini, Cristie; Cipriano Junior, Gerson; Aquino, Leticia Moraes de; Branco, João Nelson Rodrigues; Bernardelli, Graziella França

2010-03-01

Respiratory muscle strength has been related to the postoperative outcome of cardiac surgeries. The main documented therapeutic purpose of transcutaneous electrical nerve stimulation (TENS) is the reduction of pain, which could bring secondary benefits to the respiratory muscles and, consequently, to lung capacities and volumes. The objective of the present study was to evaluate the effectiveness of short-duration transcutaneous electrical nerve stimulation (TENS) in the reduction of pain and its possible influence on respiratory muscle strength and lung capacity and volumes of patients in the postoperative period of cardiac surgery. Twenty five patients with mean age of 59.9 +/- 10.3 years, of whom 72% were men, and homogeneous as regards weight and height, were randomly assigned to two groups. One group received therapeutic TENS (n = 13) and the other, placebo TENS (n = 12), for four hours on the third postoperative day of cardiac surgery. Pain was analyzed by means of a visual analogue scale, and of respiratory muscle strength as measured by maximum respiratory pressures and lung capacity and volumes before and after application of TENS. Short-duration TENS significantly reduced pain of patients in the postoperative period (p < 0.001). Respiratory muscle strength (p < 0.001), tidal volume (p < 0.001) and vital capacity (p < 0.05) significantly improved after therapeutic TENS, unlike in the placebo group. Short-duration TENS proved effective for the reduction of pain and improvement of respiratory muscle strength, as well as of lung volumes and capacity.

Perfusion-induced changes in cardiac contractility depend on capillary perfusion.

PubMed

Dijkman, M A; Heslinga, J W; Sipkema, P; Westerhof, N

1998-02-01

The perfusion-induced increase in cardiac contractility (Gregg phenomenon) is especially found in heart preparations that lack adequate coronary autoregulation and thus protection of changes in capillary pressure. We determined in the isolated perfused papillary muscle of the rat whether cardiac muscle contractility is related to capillary perfusion. Oxygen availability of this muscle is independent of internal perfusion, and perfusion may be varied or even stopped without loss of function. Muscles contracted isometrically at 27 degrees C (n = 7). During the control state stepwise increases in perfusion pressure resulted in all muscles in a significant increase in active tension. Muscle diameter always increased with increased perfusion pressure, but muscle segment length was unaffected. Capillary perfusion was then obstructed by plastic microspheres (15 microns). Flow, at a perfusion pressure of 66.6 +/- 26.2 cmH2O, reduced from 17.6 +/- 5.4 microliters/min in the control state to 3.2 +/- 1.3 microliters/min after microspheres. Active tension developed by the muscle in the unperfused condition before microspheres and after microspheres did not differ significantly (-12.8 +/- 29.4% change). After microspheres similar perfusion pressure steps as in control never resulted in an increase in active tension. Even at the two highest perfusion pressures (89.1 +/- 28.4 and 106.5 +/- 31.7 cmH2O) that were applied a significant decrease in active tension was found. We conclude that the Gregg phenomenon is related to capillary perfusion.

Application of the principles of systems biology and Wiener's cybernetics for analysis of regulation of energy fluxes in muscle cells in vivo.

PubMed

Guzun, Rita; Saks, Valdur

2010-03-08

The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener's cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener's cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures - intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations of

Ubiquinol reduces muscle wasting but not fatigue in tumor-bearing mice.

PubMed

Clark, Yvonne Y; Wold, Loren E; Szalacha, Laura A; McCarthy, Donna O

2015-05-01

Fatigue is the most common and distressing symptom reported by cancer patients during and after treatment. Tumor growth increases oxidative stress and cytokine production, which causes skeletal muscle wasting and cardiac dysfunction. The purpose of this study was to determine whether treatment with the antioxidant ubiquinol improves muscle mass, cardiac function, and behavioral measures of fatigue in tumor-bearing mice. Adult female mice were inoculated with colon26 tumor cells. Half the control and tumor-bearing mice were administered ubiquinol (500 mg/kg/day) in their drinking water. Voluntary wheel running (i.e., voluntary running activity [VRA]) and grip strength were measured at Days 0, 8, 14, and 17 of tumor growth. Cardiac function was measured using echocardiography on Day 18 or 19. Biomarkers of inflammation, protein degradation, and oxidative stress were measured in serum and heart and gastrocnemius tissue. VRA and grip strength progressively declined in tumor-bearing mice. Muscle mass and myocardial diastolic function were decreased, and expression of proinflammatory cytokines was increased in serum and muscle and heart tissue on Day 19 of tumor growth. Oxidative stress was present only in the heart, while biomarkers of protein degradation were increased only in the gastrocnemius muscle. Ubiquinol increased muscle mass in the tumor-bearing and control animals but had no effect on the expression of biomarkers of inflammation, protein degradation, or oxidative stress or on behavioral measures of fatigue. © The Author(s) 2014.

High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II

PubMed Central

Sverdlov, Aaron L.; Elezaby, Aly; Behring, Jessica B.; Bachschmid, Markus M.; Luptak, Ivan; Tu, Vivian H.; Siwik, Deborah A.; Miller, Edward J.; Liesa, Marc; Shirihai, Orian S; Pimentel, David R.; Cohen, Richard A.; Colucci, Wilson S.

2014-01-01

Background Diet-induced obesity leads to metabolic heart disease (MHD) characterized by increased oxidative stress that may cause oxidative post-translational modifications (OPTM) of cardiac mitochondrial proteins. The functional consequences of OPTM of cardiac mitochondrial proteins in MHD are unknown. Our objective was to determine whether cardiac mitochondrial dysfunction in MHD due to diet-induced obesity is associated with cysteine OPTM. Methods and results Male C57Bl/6J mice were fed either a high-fat, high-sucrose (HFHS) or control diet for 8 months. Cardiac mitochondria from HFHS-fed mice (vs. control diet) had an increased rate of H2O2 production, a decreased GSH/GSSG ratio, a decreased rate of complex II substrate-driven ATP synthesis and decreased complex II activity. Complex II substrate-driven ATP synthesis and complex II activity were partially restored ex-vivo by reducing conditions. A biotin switch assay showed that HFHS feeding increased cysteine OPTM in complex II subunits A (SDHA) and B (SDHB). Using iodo-TMT multiplex tags we found that HFHS feeding is associated with reversible oxidation of cysteines 89 and 231 in SDHA, and 100, 103 and 115 in SDHB. Conclusions MHD due to consumption of a HFHS “Western” diet causes increased H2O2 production and oxidative stress in cardiac mitochondria associated with decreased ATP synthesis and decreased complex II activity. Impaired complex II activity and ATP production are associated with reversible cysteine OPTM of complex II. Possible sites of reversible cysteine OPTM in SDHA and SDHB were identified by iodo-TMT tag labeling. Mitochondrial ROS may contribute to the pathophysiology of MHD by impairing the function of complex II. PMID:25109264

Coiled fiber scaffolds embedded with gold nanoparticles improve the performance of engineered cardiac tissues

NASA Astrophysics Data System (ADS)

Fleischer, Sharon; Shevach, Michal; Feiner, Ron; Dvir, Tal

2014-07-01

Coiled perimysial fibers within the heart muscle provide it with the ability to contract and relax efficiently. Here, we report on a new nanocomposite scaffold for cardiac tissue engineering, integrating coiled electrospun fibers with gold nanoparticles. Cultivation of cardiac cells within the hybrid scaffolds promoted cell organization into elongated and aligned tissues generating a strong contraction force, high contraction rate and low excitation threshold.Coiled perimysial fibers within the heart muscle provide it with the ability to contract and relax efficiently. Here, we report on a new nanocomposite scaffold for cardiac tissue engineering, integrating coiled electrospun fibers with gold nanoparticles. Cultivation of cardiac cells within the hybrid scaffolds promoted cell organization into elongated and aligned tissues generating a strong contraction force, high contraction rate and low excitation threshold. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr00300d

Modulating Beta-Cardiac Myosin Function at the Molecular and Tissue Levels

PubMed Central

Tang, Wanjian; Blair, Cheavar A.; Walton, Shane D.; Málnási-Csizmadia, András; Campbell, Kenneth S.; Yengo, Christopher M.

2017-01-01

Inherited cardiomyopathies are a common form of heart disease that are caused by mutations in sarcomeric proteins with beta cardiac myosin (MYH7) being one of the most frequently affected genes. Since the discovery of the first cardiomyopathy associated mutation in beta-cardiac myosin, a major goal has been to correlate the in vitro myosin motor properties with the contractile performance of cardiac muscle. There has been substantial progress in developing assays to measure the force and velocity properties of purified cardiac muscle myosin but it is still challenging to correlate results from molecular and tissue-level experiments. Mutations that cause hypertrophic cardiomyopathy are more common than mutations that lead to dilated cardiomyopathy and are also often associated with increased isometric force and hyper-contractility. Therefore, the development of drugs designed to decrease isometric force by reducing the duty ratio (the proportion of time myosin spends bound to actin during its ATPase cycle) has been proposed for the treatment of hypertrophic cardiomyopathy. Para-Nitroblebbistatin is a small molecule drug proposed to decrease the duty ratio of class II myosins. We examined the impact of this drug on human beta cardiac myosin using purified myosin motor assays and studies of permeabilized muscle fiber mechanics. We find that with purified human beta-cardiac myosin para-Nitroblebbistatin slows actin-activated ATPase and in vitro motility without altering the ADP release rate constant. In permeabilized human myocardium, para-Nitroblebbistatin reduces isometric force, power, and calcium sensitivity while not changing shortening velocity or the rate of force development (ktr). Therefore, designing a drug that reduces the myosin duty ratio by inhibiting strong attachment to actin while not changing detachment can cause a reduction in force without changing shortening velocity or relaxation. PMID:28119616

Augmented sphingosine 1 phosphate receptor-1 signaling in cardiac fibroblasts induces cardiac hypertrophy and fibrosis through angiotensin II and interleukin-6

PubMed Central

Ohkura, Sei-ichiro; Takashima, Shin-ichiro; Yoshioka, Kazuaki; Okamoto, Yasuo; Inagaki, Yutaka; Sugimoto, Naotoshi; Kitano, Teppei; Takamura, Masayuki; Wada, Takashi; Kaneko, Shuichi; Takuwa, Yoh

2017-01-01

Background: Cardiac fibroblasts, together with cardiomyocytes, occupy the majority of cells in the myocardium and are involved in myocardial remodeling. The lysophospholipid mediator sphigosine-1-phosphate (S1P) regulates functions of cardiovascular cells through multiple receptors including S1PR1–S1PR3. S1PR1 but not other S1P receptors was upregulated in angiotensin II-induced hypertrophic hearts. Therefore, we investigated a role of S1PR1 in fibroblasts for cardiac remodeling by employing transgenic mice that overexpressed S1PR1 under the control of α-smooth muscle actin promoter. In S1PR1-transgenic mouse heart, fibroblasts and/or myofibroblasts were hyperplastic, and those cells as well as vascular smooth muscle cells overexpressed S1PR1. Transgenic mice developed bi-ventricular hypertrophy by 12-week-old and diffuse interstitial fibrosis by 24-week-old without hemodynamic stress. Cardiac remodeling in transgenic mice was associated with greater ERK phosphorylation, upregulation of fetal genes, and systolic dysfunction. Transgenic mouse heart showed increased mRNA expression of angiotensin-converting enzyme and interleukin-6 (IL-6). Isolated fibroblasts from transgenic mice exhibited enhanced generation of angiotensin II, which in turn stimulated IL-6 release. Either an AT1 blocker or angiotensin-converting enzyme inhibitor prevented development of cardiac hypertrophy and fibrosis, systolic dysfunction and increased IL-6 expression in transgenic mice. Finally, administration of anti-IL-6 antibody abolished an increase in tyrosine phosphorylation of STAT3, a major signaling molecule downstream of IL-6, in the transgenic mouse heart and prevented development of cardiac hypertrophy in transgenic mice. These results demonstrate a promoting role of S1PR1 in cardiac fibroblasts for cardiac remodeling, in which angiotensin II—AT1 and IL-6 are involved. PMID:28771545

Mathematical Models of Cardiac Pacemaking Function

NASA Astrophysics Data System (ADS)

Li, Pan; Lines, Glenn T.; Maleckar, Mary M.; Tveito, Aslak

2013-10-01

Over the past half century, there has been intense and fruitful interaction between experimental and computational investigations of cardiac function. This interaction has, for example, led to deep understanding of cardiac excitation-contraction coupling; how it works, as well as how it fails. However, many lines of inquiry remain unresolved, among them the initiation of each heartbeat. The sinoatrial node, a cluster of specialized pacemaking cells in the right atrium of the heart, spontaneously generates an electro-chemical wave that spreads through the atria and through the cardiac conduction system to the ventricles, initiating the contraction of cardiac muscle essential for pumping blood to the body. Despite the fundamental importance of this primary pacemaker, this process is still not fully understood, and ionic mechanisms underlying cardiac pacemaking function are currently under heated debate. Several mathematical models of sinoatrial node cell membrane electrophysiology have been constructed as based on different experimental data sets and hypotheses. As could be expected, these differing models offer diverse predictions about cardiac pacemaking activities. This paper aims to present the current state of debate over the origins of the pacemaking function of the sinoatrial node. Here, we will specifically review the state-of-the-art of cardiac pacemaker modeling, with a special emphasis on current discrepancies, limitations, and future challenges.

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.

A fetal human heart cardiac-inducing RNA (CIR) promotes the differentiation of stem cells into cardiomyocytes.

PubMed

Kochegarov, Andrei; Moses-Arms, Ashley; Lemanski, Larry F

2015-08-01

A specific human fetal heart RNA has been discovered, which has the ability to induce myocardial cell formation from mouse embryonic and human-induced pluripotent stem cells in culture. In this study, commercially obtained RNA from human fetal heart was cloned, sequenced, and synthesized using standard laboratory approaches. Molecular analyses of the specific fetal cardiac-inducing RNA (CIR), revealed that it is a fragment of N-sulfoglucosaminesulfohydrolase and the caspase recruitment domain family member 14 precursor. Stem cells transfected with CIRs often form into spindle-shaped cells characteristic of cardiomyocytes,and express the cardiac-specific contractile protein marker, troponin-T, in addition to tropomyosin and α-actinin as detected by immunohistochemical staining. Expression of these contractile proteins showed organization into sarcomeric myofibrils characteristic of striated cardiac muscle cells. Computer analyses of the RNA secondary structures of the active CIR show significant similarities to a RNA from salamander or myofibril-inducing RNA (MIR), which also promotes non-muscle cells to differentiate into cardiac muscle. Thus, these two RNAs, salamander MIR and the newly discovered human-cloned CIR reported here, appear to have evolutionarily conserved secondary structures suggesting that both play major roles in vertebrate heart development and, particularly, in the differentiation of cardiomyocytes from non-muscle cells during development.

Top-down Mass Spectrometry of Cardiac Myofilament Proteins in Health and Disease

PubMed Central

Ying, Peng; Serife, Ayaz-Guner; Deyang, Yu; Ying, Ge

2014-01-01

Myofilaments are composed of thin and thick filaments which coordinate with each other to regulate muscle contraction and relaxation. Posttranslational modifications (PTMs) together with genetic variations and alternative splicing of the myofilament proteins play essential roles in regulating cardiac contractility in health and disease. Therefore, a comprehensive characterization of the myofilament proteins in physiological and pathological conditions is essential for better understanding the molecular basis of cardiac function and dysfunction. Due to the vast complexity and dynamic nature of proteins, it is challenging to obtain a holistic view of myofilament protein modifications. In recent years, top-down mass spectrometry (MS) has emerged as a powerful approach to study isoform composition and PTMs of proteins owing to its advantage of complete sequence coverage and its ability to identify PTMs and sequence variants without a priori knowledge. In this review, we will discuss the application of top-down MS to study cardiac myofilaments and highlight the insights it provides into the understanding of molecular mechanisms in contractile dysfunction of heart failure. Particularly, recent results of cardiac troponin and tropomyosin modifications will be elaborated. The limitations and perspectives on the use of top-down MS for myofilament protein characterization will also be briefly discussed. PMID:24945106

Application of the Principles of Systems Biology and Wiener’s Cybernetics for Analysis of Regulation of Energy Fluxes in Muscle Cells in Vivo

PubMed Central

Guzun, Rita; Saks, Valdur

2010-01-01

The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener’s cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener’s cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures – intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations

Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features.

PubMed

Maggi, Lorenzo; Carboni, Nicola; Bernasconi, Pia

2016-08-11

LMNA-related disorders are caused by mutations in the LMNA gene, which encodes for the nuclear envelope proteins, lamin A and C, via alternative splicing. Laminopathies are associated with a wide range of disease phenotypes, including neuromuscular, cardiac, metabolic disorders and premature aging syndromes. The most frequent diseases associated with mutations in the LMNA gene are characterized by skeletal and cardiac muscle involvement. This review will focus on genetics and clinical features of laminopathies affecting primarily skeletal muscle. Although only symptomatic treatment is available for these patients, many achievements have been made in clarifying the pathogenesis and improving the management of these diseases.

Skeletal, cardiac, and respiratory muscle function and histopathology in the P448Lneo- mouse model of FKRP-deficient muscular dystrophy.

PubMed

Yu, Qing; Morales, Melissa; Li, Ning; Fritz, Alexander G; Ruobing, Ren; Blaeser, Anthony; Francois, Ershia; Lu, Qi-Long; Nagaraju, Kanneboyina; Spurney, Christopher F

2018-04-06

Fukutin-related protein (FKRP) mutations are the most common cause of dystroglycanopathies known to cause both limb girdle and congenital muscular dystrophy. The P448Lneo- mouse model has a knock-in mutation in the FKRP gene and develops skeletal, respiratory, and cardiac muscle disease. We studied the natural history of the P448Lneo- mouse model over 9 months and the effects of twice weekly treadmill running. Forelimb and hindlimb grip strength (Columbus Instruments) and overall activity (Omnitech Electronics) assessed skeletal muscle function. Echocardiography was performed using VisualSonics Vevo 770 (FujiFilm VisualSonics). Plethysmography was performed using whole body system (ADInstruments). Histological evaluations included quantification of inflammation, fibrosis, central nucleation, and fiber size variation. P448Lneo- mice had significantly increased normalized tissue weights compared to controls at 9 months of age for the heart, gastrocnemius, soleus, tibialis anterior, quadriceps, and triceps. There were no significant differences seen in forelimb or hindlimb grip strength or activity monitoring in P448Lneo- mice with or without exercise compared to controls. Skeletal muscles demonstrated increased inflammation, fibrosis, central nucleation, and variation in fiber size compared to controls (p < 0.05) and worsened with exercise. Plethysmography showed significant differences in respiratory rates and decreased tidal and minute volumes in P448Lneo- mice (p < 0.01). There was increased fibrosis in the diaphragm compared to controls (p < 0.01). Echocardiography demonstrated decreased systolic function in 9-month-old mutant mice (p < 0.01). There was increased myocardial wall thickness and mass (p < 0.001) with increased fibrosis in 9-month-old P448Lneo- mice compared to controls (p < 0.05). mRNA expression for natriuretic peptide type A (Nppa) was significantly increased in P448Lneo- mice compared to controls at 6 months (p < 0.05) and

Nuclear accumulation of myocyte muscle LIM protein is regulated by heme oxygenase 1 and correlates with cardiac function in the transition to failure

PubMed Central

Paudyal, Anju; Dewan, Sukriti; Ikie, Cindy; Whalley, Benjamin J; de Tombe, Pieter P.

2016-01-01

Key points The present study investigated the mechanism associated with impaired cardiac mechanosensing that leads to heart failure by examining the factors regulating muscle LIM protein subcellular distribution in myocytes.In myocytes, muscle LIM protein subcellular distribution is regulated by cell contractility rather than passive stretch via heme oxygenase‐1 and histone deacetylase signalling. The result of the present study provide new insights into mechanotransduction in cardiac myocytes.Myocyte mechanosensitivity, as indicated by the muscle LIM protein ratio, is also correlated with cardiac function in the transition to failure in a guinea‐pig model of disease. This shows that the loss mechanosensitivity plays an important role during the transition to failure in the heart.The present study provides the first indication that mechanosensing could be modified pharmacologically during the transition to heart failure. Abstract Impaired mechanosensing leads to heart failure and a decreased ratio of cytoplasmic to nuclear CSRP3/muscle LIM protein (MLP ratio) is associated with a loss of mechanosensitivity. In the present study, we tested whether passive or active stress/strain was important in modulating the MLP ratio and determined whether this correlated with heart function during the transition to failure. We exposed cultured neonatal rat myocytes to a 10% cyclic mechanical stretch at 1 Hz, or electrically paced myocytes at 6.8 V (1 Hz) for 48 h. The MLP ratio decreased by 50% (P < 0.05, n = 4) only in response to electrical pacing, suggesting impaired mechanosensitivity. Inhibition of contractility with 10 μm blebbistatin resulted in an ∼3‐fold increase in the MLP ratio (n = 8, P < 0.05), indicating that myocyte contractility regulates nuclear MLP. Inhibition of histone deacetylase (HDAC) signalling with trichostatin A increased nuclear MLP following passive stretch, suggesting that HDACs block MLP nuclear accumulation. Inhibition of heme

[Cardiac cachexia].

PubMed

Miján, Alberto; Martín, Elvira; de Mateo, Beatriz

2006-05-01

Chronic heart failure (CHF), especially affecting the right heart, frequently leads to malnutrition. If the latter is severe and is combined to other factors, it may lead to cardiac cachexia. This one is associated to increased mortality and lower survival of patients suffering from it. The causes of cardiac cachexia are diverse, generally associated to maintenance of a negative energy balance, with increasing evidence of its multifactorial origin. Neurohumoral, inflammatory, immunological, and metabolic factors, among others, are superimposed in the patient with CHF, leading to involvement and deterioration of several organs and systems, since this condition affects both lean (or active cellular) mass and adipose and bone tissue osteoporosis. Among all, the most pronounced deterioration may be seen at skeletal muscle tissue, at both structural and functional levels, the heart not being spared. As for treatment, it should be based on available scientific evidence. Assessment of nutritional status of any patient with CHF is a must, with the requirement of nutritional intervention in case of malnutrition. In this situation, especially if accompanied by cardiac cachexia, it is required to modify energy intake and oral diet quality, and to consider the indication of specific complementary or alternative artificial nutrition. Besides, the causal relationship of the beneficial role of moderate physical exertion is increasing, as well as modulation of metabolic and inflammatory impairments observed in cardiac cachexia with several drugs, leading to a favorable functional and structural response in CHF patients.

Artificial aortic valve dysfunction due to pannus and thrombus - different methods of cardiac surgical management.

PubMed

Ostrowski, Stanisław; Marcinkiewicz, Anna; Kośmider, Anna; Walczak, Andrzej; Zwoliński, Radosław; Jaszewski, Ryszard

2015-09-01

Approximately 60 000 prosthetic valves are implanted annually in the USA. The risk of prosthesis dysfunction ranges from 0.1% to 4% per year. Prosthesis valve dysfunction is usually caused by a thrombus obstructing the prosthetic discs. However, 10% of prosthetic valves are dysfunctional due to pannus formation, and 12% of prostheses are damaged by both fibrinous and thrombotic components. The authors present two patients with dysfunctional aortic prostheses who were referred for cardiac surgery. Different surgical solutions were used in the treatment of each case. The first patient was a 71-year-old woman whose medical history included arterial hypertension, stable coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and hypercholesterolemia; she had previously undergone left-sided mastectomy and radiotherapy. The patient was admitted to the Cardiac Surgery Department due to aortic prosthesis dysfunction. Transthoracic echocardiography revealed complete obstruction of one disc and a severe reduction in the mobility of the second. The mean transvalvular gradient was very high. During the operation, pannus covering the discs' surface was found. A biological aortic prosthesis was reimplanted without complications. The second patient was an 87-year-old woman with arterial hypertension, persistent atrial fibrillation, and COPD, whose past medical history included gastric ulcer disease and ischemic stroke. As in the case of the first patient, she was admitted due to valvular prosthesis dysfunction. Preoperative transthoracic echocardiography revealed an obstruction of the posterior prosthetic disc and significant aortic regurgitation. Transesophageal echocardiography and fluoroscopy confirmed the prosthetic dysfunction. During the operation, a thrombus growing around a minor pannus was found. The thrombus and pannus were removed, and normal functionality of the prosthetic valve was restored. Precise and modern diagnostic methods

High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II.

PubMed

Sverdlov, Aaron L; Elezaby, Aly; Behring, Jessica B; Bachschmid, Markus M; Luptak, Ivan; Tu, Vivian H; Siwik, Deborah A; Miller, Edward J; Liesa, Marc; Shirihai, Orian S; Pimentel, David R; Cohen, Richard A; Colucci, Wilson S

2015-01-01

Diet-induced obesity leads to metabolic heart disease (MHD) characterized by increased oxidative stress that may cause oxidative post-translational modifications (OPTM) of cardiac mitochondrial proteins. The functional consequences of OPTM of cardiac mitochondrial proteins in MHD are unknown. Our objective was to determine whether cardiac mitochondrial dysfunction in MHD due to diet-induced obesity is associated with cysteine OPTM. Male C57BL/6J mice were fed either a high-fat, high-sucrose (HFHS) or control diet for 8months. Cardiac mitochondria from HFHS-fed mice (vs. control diet) had an increased rate of H2O2 production, a decreased GSH/GSSG ratio, a decreased rate of complex II substrate-driven ATP synthesis and decreased complex II activity. Complex II substrate-driven ATP synthesis and complex II activity were partially restored ex-vivo by reducing conditions. A biotin switch assay showed that HFHS feeding increased cysteine OPTM in complex II subunits A (SDHA) and B (SDHB). Using iodo-TMT multiplex tags we found that HFHS feeding is associated with reversible oxidation of cysteines 89 and 231 in SDHA, and 100, 103 and 115 in SDHB. MHD due to consumption of a HFHS "Western" diet causes increased H2O2 production and oxidative stress in cardiac mitochondria associated with decreased ATP synthesis and decreased complex II activity. Impaired complex II activity and ATP production are associated with reversible cysteine OPTM of complex II. Possible sites of reversible cysteine OPTM in SDHA and SDHB were identified by iodo-TMT tag labeling. Mitochondrial ROS may contribute to the pathophysiology of MHD by impairing the function of complex II. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease". Copyright © 2014 Elsevier Ltd. All rights reserved.

Cardiac mitochondrial oxidative capacity is partly preserved after cryopreservation with dimethyl sulfoxide.

PubMed

Meyer, A; Charles, A L; Singh, F; Zoll, J; Talha, S; Enache, I; Chaarloux, A; Inser-Horobeti, M E; Geny, B

2016-01-01

Cardiac muscle cryopreservation is a challenge for both diagnostic procedure requiring viable tissues and therapeutic advance in regenerative medicine. Mitochondria are targets of both direct and indirect damages, secondary to congelation per se and/or to cryoprotectant's toxic effects, which participate to diminution of viability and/or functioning of cells after freezing. At the cardiac muscle level, only one study had investigated mitochondrial respiration after cryopreservation. To determine the effect of cryopreservation on mitochondrial respiration of cardiac muscle. We recorded mitochondrial respiration through complexes I, II, III and IV along with mitochondrial coupling in fresh and cryopreserved rat left ventricles samples and assessed difference of the means, correlation and agreement between the measures in all samples. Mitochondrial respiration was partly maintained up to 70% in cryopreserved samples whatever the substrate. A significant correlation was observed between fresh and cryopreserved samples (r = 0.71, p < 0.0001). However, mitochondrial coupling significantly decreased after cryopreservation (- 1.44 ± 0.15; p < 0.005) suggesting that mitochondrial intactness was not totally preserved by cryopreservation. Further, the fluctuations around the mean difference were wide (-14.06, +5.08 µmol/min/g), increasing with respiration rates (p < 0.0001). Thus, fresh samples extemporaneous analysis should be preferred when available despite the fact that cryopreservation using DMSO partly protect cardiac mitochondrial respiration and coupling. These data support the interest to further refine cryopreservation methods.

The clinical significance of the atrial subendocardial smooth muscle layer and cardiac myofibroblasts in human atrial tissue with valvular atrial fibrillation.

PubMed

Park, Jae Hyung; Pak, Hui-Nam; Lee, Sak; Park, Han Ki; Seo, Jeong-Wook; Chang, Byung-Chul

2013-01-01

The existence of myofibroblasts (MFBs) and the role of subendocardial smooth muscle (SSM) layer of human atrial tissue in atrial fibrillation (AF) have not yet been elucidated. We hypothesized that the SSM layer and MFB play some roles in atrial structural remodeling and maintenance of valvular AF in patients who undergo cardiac surgery. We analyzed immunohistochemical staining of left atrial (LA) appendage tissues taken from 17 patients with AF and 15 patients remaining in sinus rhythm (SR) who underwent cardiac surgery (male 50.0%, 54.1 ± 14.2 years old, valve surgery 87.5%). SSM was quantified by α-smooth muscle actin (α-SMA) stain excluding vascular structure. MFB was defined as α-SMA+ cells with disorganized Connexin 43-positive gap junctions in Sirius red-positive fibrotic area. The SSM layer of atrium was significantly thicker in patients with AF than in those with SR (P=.0091). Patients with SSM layer ≥ 14 μm had a larger LA size (P=.0006) and greater fibrotic area (P=.0094) than those patients whose SSM layer <14 μm. MFBs were found in 7 of 17 (41.2%) patients with AF and 2 of 15 (13.3%) in SR group (P=.0456) in SSM area, colocalized with Periodic Acid-Schiff (PAS) stain-positive glycogen storage cells (95.5%). SSM layer was closely related to the existence of AF, degrees of atrial remodeling, and fibrosis in patients who underwent open heart surgery. We found that MFB does exist in SSM layer of human atrial tissue co-localized with PAS-positive cells. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Lack of UCP3 does not affect skeletal muscle mitochondrial function under lipid-challenged conditions, but leads to sudden cardiac death.

PubMed

Nabben, Miranda; van Bree, Bianca W J; Lenaers, Ellen; Hoeks, Joris; Hesselink, Matthijs K C; Schaart, Gert; Gijbels, Marion J J; Glatz, Jan F C; da Silva, Gustavo J J; de Windt, Leon J; Tian, Rong; Mike, Elise; Skapura, Darlene G; Wehrens, Xander H T; Schrauwen, Patrick

2014-01-01

UCP3's exact physiological function in lipid handling in skeletal and cardiac muscle remains unknown. Interestingly, etomoxir, a fat oxidation inhibitor and strong inducer of UCP3, is proposed for treating both diabetes and heart failure. We hypothesize that the upregulation of UCP3 upon etomoxir serves to protect mitochondria against lipotoxicity. To evaluate UCP3's role in skeletal muscle (skm) and heart under lipid-challenged conditions, the effect of UCP3 ablation was examined in a state of dysbalance between fat availability and oxidative capacity. Wild type (WT) and UCP3(-/-) mice were subjected to high-fat feeding for 14 days. From day 6 onwards, they were given either saline or etomoxir. Etomoxir treatment induced an increase in markers of lipotoxicity in skm compared to saline. This increase upon etomoxir was similar for both, WT and UCP3(-/-) mice, suggesting that UCP3 does not play a role in protection against lipotoxicity. Interestingly, we observed 25 % mortality in UCP3(-/-)s upon etomoxir administration vs. 11 % in WTs. This increased mortality in UCP3(-/-) compared to WT mice could not be explained by differences in cardiac lipotoxicity, apoptosis, fibrosis (histology, immunohistochemistry), oxidative capacity (respirometry) or function (echocardiography). Electrophysiology demonstrated, however, prolonged QRS and QTc intervals and greater susceptibility to ventricular tachycardia upon programmed electrical stimulation in etomoxir-treated UCP3(-/-)s versus WTs. Isoproterenol administration after pacing resulted in 75 % mortality in UCP3(-/-)s vs. 14 % in WTs. Our results argue against a protective role for UCP3 on skm metabolism under lipid overload, but suggest UCP3 to be crucial in prevention of arrhythmias upon lipid-challenged conditions.

Heterogeneity of adult masseter muscle satellite cells with cardiomyocyte differentiation potential.

PubMed

Huang, Wei; Liang, Jialiang; Feng, Yuliang; Jia, Zhanfeng; Jiang, Lin; Cai, Wenfeng; Paul, Christian; Gu, Jianguo G; Stambrook, Peter J; Millard, Ronald W; Zhu, Xiao-Lan; Zhu, Ping; Wang, Yigang

2018-05-26

Although resident cardiac stem cells have been reported, regeneration of functional cardiomyocytes (CMs) remains a challenge. The present study identifies an alternative progenitor source for CM regeneration without the need for genetic manipulation or invasive heart biopsy procedures. Unlike limb skeletal muscles, masseter muscles (MM) in the mouse head are developed from Nkx2-5 mesodermal progenitors. Adult masseter muscle satellite cells (MMSCs) display heterogeneity in developmental origin and cell phenotypes. The heterogeneous MMSCs that can be characterized by cell sorting based on stem cell antigen-1 (Sca1) show different lineage potential. While cardiogenic potential is preserved in Sca1 + MMSCs as shown by expression of cardiac progenitor genes (including Nkx2-5), skeletal myogenic capacity is maintained in Sca1 - MMSCs with Pax7 expression. Sca1 + MMSC-derived beating cells express cardiac genes and exhibit CM-like morphology. Electrophysiological properties of MMSC-derived CMs are demonstrated by calcium transients and action potentials. These findings show that MMSCs could serve as a novel cell source for cardiomyocyte replacement. Copyright © 2018. Published by Elsevier Inc.

A 3-D Cardiac Muscle Construct for Exploring Adult Marrow Stem Cell Based Myocardial Regeneration

PubMed Central

Valarmathi, Mani T.; Goodwin, Richard L.; Fuseler, John W.; Davis, Jeffrey M.; Yost, Michael J.; Potts, Jay D.

2010-01-01

Adult bone marrow stromal cells (BMSCs) are capable of differentiating into cardiomyocyte-like cells in vitro and contribute to myocardial regeneration in vivo. Consequently, BMSCs may potentially play a vital role in cardiac repair and regeneration. However, this concept has been limited by inadequate and inconsistent differentiation of BMSCs into cardiomyocytes along with poor survival and integration of neo-cardiomyocytes after implantation into ischemic myocardium. In order to overcome these barriers and to explore adult stem cell based myocardial regeneration, we have developed an in vitro model of three-dimensional (3-D) cardiac muscle using rat ventricular embryonic cardiomyocytes (ECMs) and BMSCs. When ECMs and BMSCs were seeded sequentially onto a 3-D tubular scaffold engineered from topographically aligned type I collagen fibers and cultured in basal medium for 7, 14, 21, or 28 days, the maturation and co-differentiation into a cardiomyocyte lineage was observed. Phenotypic induction was characterized at morphological, immunological, biochemical and molecular levels. The observed expression of transcripts coding for cardiomyocyte phenotypic markers and the immunolocalization of cardiomyogenic lineage-associated proteins revealed typical expression patterns of neo-cardiomyogenesis. At the biochemical level differentiating cells exhibited appropriate metabolic activity and at the ultrastructural level myofibrillar and sarcomeric organization were indicative of an immature phenotype. Our 3-D co-culture system sustains the ECMs in vitro continuum of differentiation process and simultaneously induces the maturation and differentiation of BMSCs into cardiomyocyte-like cells. Thus, this novel 3-D co-culture system provides a useful in vitro model to investigate the functional role and interplay of developing ECMs and BMSCs during cardiomyogenic differentiation. PMID:20129663

Muscle and bone follow similar temporal patterns of recovery from muscle-induced disuse due to botulinum toxin injection.

PubMed

Manske, Sarah L; Boyd, Steven K; Zernicke, Ronald F

2010-01-01

If muscle force is a primary source for triggering bone adaptation, with disuse and reloading, bone changes should follow muscle changes. We examined the timing and magnitude of changes in muscle cross-sectional area (MCSA) and bone architecture in response to muscle inactivity following botulinum toxin (BTX) injection. We hypothesized that MCSA would return to baseline levels sooner than bone properties following BTX injection. Female BALB mice (15 weeks old) were injected with 20 muL of BTX (1 U/100 g body mass, n=18) or saline (SAL, n=18) into the posterior calf musculature of one limb. The contralateral limb (CON) served as an internal control. MCSA and bone properties were assessed at baseline, 2, 4, 8, 12, and 16 weeks post-injection using in vivo micro-CT at the tibia proximal metaphysis (bone only) and diaphysis. Muscles were dissected and weighed after sacrifice. Significant GroupxLegxTime interactions indicated that the maximal decrease in MCSA (56%), proximal metaphyseal BV/TV (38%) and proximal diaphyseal Ct.Ar (7%) occurred 4 weeks after injection. There was no delay prior to bone recovery as both muscle and bone properties began to recover after this time, but MCSA and BV/TV remained 15% and 20% lower, respectively, in the BTX-injected leg than the BTX-CON leg 16 weeks post-injection. Gastrocnemius mass (primarily fast-twitch) was 14% lower in the BTX-injected leg than the SAL-injected leg, while soleus mass (primarily slow-twitch) was 15% greater in the BTX group than the SAL group. Our finding that muscle size and bone began to recover at similar times after BTX injection was unexpected. This suggested that partial weight-bearing and/or return of slow-twitch muscle activity in the BTX leg may have been sufficient to stimulate bone recovery. Alternatively, muscle function may have recovered sooner than MCSA. Our results indicated that muscle cross-sectional area, while important, may not be the primary factor associated with bone loss and recovery

Cardiac Auscultation for Noncardiologists: Application in Cardiac Rehabilitation Programs: PART I: PATIENTS AFTER ACUTE CORONARY SYNDROMES AND HEART FAILURE.

PubMed

Compostella, Leonida; Compostella, Caterina; Russo, Nicola; Setzu, Tiziana; Iliceto, Sabino; Bellotto, Fabio

2017-09-01

During outpatient cardiac rehabilitation after an acute coronary syndrome or after an episode of congestive heart failure, a careful, periodic evaluation of patients' clinical and hemodynamic status is essential. Simple and traditional cardiac auscultation could play a role in providing useful prognostic information.Reduced intensity of the first heart sound (S1), especially when associated with prolonged apical impulse and the appearance of added sounds, may help identify left ventricular (LV) dysfunction or conduction disturbances, sometimes associated with transient myocardial ischemia. If both S1 and second heart sound (S2) are reduced in intensity, a pericardial effusion may be suspected, whereas an increased intensity of S2 may indicate increased pulmonary artery pressure. The persistence of a protodiastolic sound (S3) after an acute coronary syndrome is an indicator of severe LV dysfunction and a poor prognosis. In patients with congestive heart failure, the association of an S3 and elevated heart rate may indicate impending decompensation. A presystolic sound (S4) is often associated with S3 in patients with LV failure, although it could also be present in hypertensive patients and in patients with an LV aneurysm. Careful evaluation of apical systolic murmurs could help identifying possible LV dysfunction or mitral valve pathology, and differentiate them from a ruptured papillary muscle or ventricular septal rupture. Friction rubs after an acute myocardial infarction, due to reactive pericarditis or Dressler syndrome, are often associated with a complicated clinical course.During cardiac rehabilitation, periodic cardiac auscultation may provide useful information about the clinical-hemodynamic status of patients and allow timely detection of signs, heralding possible complications in an efficient and low-cost manner.

Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants

PubMed Central

Zhou, Zhiqun; Huang, Wenrui; Liang, Jingsheng; Szczesna-Cordary, Danuta

2016-01-01

The homozygous appearance of the intronic mutation (IVS6-1) in the MYL2 gene encoding for myosin ventricular/slow-twitch skeletal regulatory light chain (RLC) was recently linked to the development of slow skeletal muscle fiber type I hypotrophy and early cardiac death. The IVS6-1 (c403-1G>C) mutation resulted from a cryptic splice site in MYL2 causing a frameshift and replacement of the last 32 codons by 19 different amino acids in the RLC mutant protein. Infants who were IVS6-1+∕+-positive died between 4 and 6 months of age due to cardiomyopathy and heart failure. In this report we have investigated the molecular mechanism and functional consequences associated with the IVS6-1 mutation using recombinant human cardiac IVS6-1 and wild-type (WT) RLC proteins. Recombinant proteins were reconstituted into RLC-depleted porcine cardiac muscle preparations and subjected to enzymatic and functional assays. IVS6-1-RLC showed decreased binding to the myosin heavy chain (MHC) compared with WT, and IVS6-1-reconstituted myosin displayed reduced binding to actin in rigor. The IVS6-1 myosin demonstrated a significantly lower Vmax of the actin-activated myosin ATPase activity compared with WT. In stopped-flow experiments, IVS6-1 myosin showed slower kinetics of the ATP induced dissociation of the acto-myosin complex and a significantly reduced slope of the kobs-[MgATP] relationship compared to WT. In skinned porcine cardiac muscles, RLC-depleted and IVS6-1 reconstituted muscle strips displayed a significant decrease in maximal contractile force and a significantly increased Ca2+ sensitivity, both hallmarks of hypertrophic cardiomyopathy-associated mutations in MYL2. Our results showed that the amino-acid changes in IVS6-1 were sufficient to impose significant conformational alterations in the RLC protein and trigger a series of abnormal protein-protein interactions in the cardiac muscle sarcomere. Notably, the mutation disrupted the RLC-MHC interaction and the steady-state and

Comparative analysis of nitric oxide and SALMFamide neuropeptides as general muscle relaxants in starfish.

PubMed

Melarange, Richard; Elphick, Maurice R

2003-03-01

Previous studies have established that the gaseous signalling molecule nitric oxide (NO) and the SALMFamide neuropeptides S1 and S2 cause cardiac stomach relaxation in the starfish Asterias rubens. Here we show that S1, S2 and the NO donor SNAP also cause relaxation of two other preparations from Asterias - tube feet and the apical muscle of the body wall. The rank order of effectiveness as muscle relaxants when tested at a concentration of 10 micro mol l(-1) was SNAP>S2>S1 for both tube feet and apical muscle whereas for cardiac stomach it was S2>S1>SNAP. Significantly, these data indicate that NO and SALMFamide neuropeptides function as general muscle relaxants in starfish but vary in their relative importance in different organ systems. The molecular mechanisms by which NO and SALMFamides cause muscle relaxation in starfish are not known, but previous pharmacological studies on the cardiac stomach using the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazol[4,3-a]quinoxalin-1-one (ODQ) indicate that the cyclic nucleotide second messenger cGMP may mediate effects of NO. Consistent with this hypothesis, here we report that ODQ also causes partial inhibition of the relaxing effect of SNAP on tube foot and apical muscle preparations. To further investigate the involvement of cyclic nucleotides as mediators of the effects of NO and SALMFamides on starfish muscle, we have measured both cGMP and cAMP in cardiac stomach and in apical muscle after treatment with S1, S2 or SNAP. However, no significant changes in cyclic nucleotide content were observed compared with controls. Further experiments were performed on apical muscle tissue in the presence of the cyclic-nucleotide-phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), a drug that also causes cardiac stomach relaxation in starfish. Treatment with IBMX caused a 2-3-fold increase above basal levels for cGMP and cAMP, but co-treatment with IBMX and S1 or S2 or SNAP resulted in no significant further

Cardiac autonomic modulation and sleepiness: physiological consequences of sleep deprivation due to 40 h of prolonged wakefulness.

PubMed

Glos, Martin; Fietze, Ingo; Blau, Alexander; Baumann, Gert; Penzel, Thomas

2014-02-10

The autonomic nervous system (ANS) is modulated by sleep and wakefulness. Noninvasive assessment of cardiac ANS with heart rate variability (HRV) analysis is a window for monitoring malfunctioning of cardiovascular autonomic modulation due to sleep deprivation. This study represents the first investigation of dynamic ANS effects and of electrophysiological and subjective sleepiness, in parallel, during 40 h of prolonged wakefulness under constant routine (CR) conditions. In eleven young male healthy subjects, ECG, EEG, EOG, and EMG chin recordings were performed during baseline sleep, during 40 h of sleep deprivation, and during recovery sleep. After sleep deprivation, slow-wave sleep and sleep efficiency increased, whereas HRV - global variability and HRV sympathovagal balance - was reduced (all p<0.05). Sleep-stage-dependent analysis revealed reductions in the sympathovagal balance only for NREM sleep stages (all p<0.05). Comparison of the daytime pattern of CR day one (CR baseline) with that of CR day two (CR sleep deprivation) disclosed an increase in subjective sleepiness, in the amount of unintended sleep, and in HRV sympathovagal balance, with accompaniment by increased EEG alpha attenuation (all p<0.05). Circadian rhythm analysis revealed the strongest influence on heart rate, with less influence on HRV sympathovagal balance. Hour-by-hour analysis disclosed the difference between CR sleep deprivation and CR baseline for subjective sleepiness at almost every single hour and for unintended sleep particularly in the morning and afternoon (both p<0.05). These findings indicate that 40 h of prolonged wakefulness lead in the following night to sleep-stage-dependent reduction in cardiac autonomic modulation. During daytime, an increased occurrence of behavioral and physiological signs of sleepiness was accompanied by diminished cardiac autonomic modulation. The observed changes are an indicator of autonomic stress due to sleep deprivation - which, if chronic

An investigation of fatigue phenomenon in the upper limb muscle due to short duration pulses in an FES system

NASA Astrophysics Data System (ADS)

Naeem, Jannatul; Wong Azman, Amelia; Khan, Sheroz; Mohd Mustafah, Yasir

2013-12-01

Functional Electrical Stimulation (FES) is a method of artificially stimulating muscles or nerves in order to result in contraction or relaxation of muscles. Many studies have shown that FES system has helped patients to live a better lives especially those who are suffering from physical mobility. Unfortunately, one of the main limitations of an FES system besides of its high cost is largely due to muscle fatigue. Muscle fatigue will affect the training duration which could delay patients' recovery rate. In this paper, we analyzed the occurrence of this fatigue phenomenon in terms of stimulator parameters such as amplitude, frequency, pulse width and pulse shape. The objective of this investigation is to identify other key features of the FES system parameters in order to prolong the training duration among patients. The experiment has been done on a healthy person for the duration of one minute and later the muscles response will be observed. Resultant muscle response is recorded as force using force resistive sensor. The experimental results show muscles will get fatigue at a different rate as the frequency increases. The experiment also shows that the duty cycle is reciprocal to the resultant force.

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

Cardiac tissue engineering: state of the art.

PubMed

Hirt, Marc N; Hansen, Arne; Eschenhagen, Thomas

2014-01-17

The engineering of 3-dimensional (3D) heart muscles has undergone exciting progress for the past decade. Profound advances in human stem cell biology and technology, tissue engineering and material sciences, as well as prevascularization and in vitro assay technologies make the first clinical application of engineered cardiac tissues a realistic option and predict that cardiac tissue engineering techniques will find widespread use in the preclinical research and drug development in the near future. Tasks that need to be solved for this purpose include standardization of human myocyte production protocols, establishment of simple methods for the in vitro vascularization of 3D constructs and better maturation of myocytes, and, finally, thorough definition of the predictive value of these methods for preclinical safety pharmacology. The present article gives an overview of the present state of the art, bottlenecks, and perspectives of cardiac tissue engineering for cardiac repair and in vitro testing.

Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function.

PubMed

Sommese, Ruth F; Sung, Jongmin; Nag, Suman; Sutton, Shirley; Deacon, John C; Choe, Elizabeth; Leinwand, Leslie A; Ruppel, Kathleen; Spudich, James A

2013-07-30

Cardiovascular disorders are the leading cause of morbidity and mortality in the developed world, and hypertrophic cardiomyopathy (HCM) is among the most frequently occurring inherited cardiac disorders. HCM is caused by mutations in the genes encoding the fundamental force-generating machinery of the cardiac muscle, including β-cardiac myosin. Here, we present a biomechanical analysis of the HCM-causing mutation, R453C, in the context of human β-cardiac myosin. We found that this mutation causes a ∼30% decrease in the maximum ATPase of the human β-cardiac subfragment 1, the motor domain of myosin, and a similar percent decrease in the in vitro velocity. The major change in the R453C human β-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type, with no appreciable change in the stroke size, as observed with a dual-beam optical trap. These results predict that the overall force of the ensemble of myosin molecules in the muscle should be higher in the R453C mutant compared with wild type. Loaded in vitro motility assay confirms that the net force in the ensemble is indeed increased. Overall, this study suggests that the R453C mutation should result in a hypercontractile state in the heart muscle.

Heart rate at the onset of muscle contraction and during passive muscle stretch in humans: a role for mechanoreceptors

PubMed Central

Gladwell, V F; Coote, J H

2002-01-01

Previous evidence suggests that the heart rate (HR) increase observed with isometric exercise is dependent on different afferent mechanisms to those eliciting the increase in blood pressure (BP). Central command and muscle metaboreceptors have been shown to contribute to this differential effect. However, in experimental animals passive stretch of the hindlimb increases HR suggesting that small fibre mechanoreceptors could also have a role. This has not been previously shown in humans and was investigated in this study. Healthy human volunteers were instrumented to record BP, ECG, respiration, EMG of rectus femoris and gastrocnemius and contraction force of triceps surae. Voluntary isometric contraction of triceps surae elicited a significant HR change in the first three respiratory cycles at 40 % of maximum voluntary contraction whereas BP did not change significantly until after 30 s. This suggests that different mechanisms are involved in the initiation of the cardiovascular changes. Sustained passive stretch of triceps surae for 1 min, by dorsiflexion of the foot, caused a significant (P < 0.05) increase in HR (5 ± 2.6 beats min−1) with no significant change in BP. A time domain measure of cardiac vagal activity was reduced significantly during passive stretch from 69.7 ± 12.9 to 49.6 ± 8.9 ms. Rapid rhythmic passive stretch (0.5 Hz for 1 min) was without significant effect suggesting that large muscle proprioreceptors are not involved. We conclude that in man small fibre muscle mechanoreceptors responding to stretch, inhibit cardiac vagal activity and thus increase HR. These afferents could contribute to the initial cardiac acceleration in response to muscle contraction. PMID:11986394

Mild therapeutic hypothermia in patients after out-of-hospital cardiac arrest due to acute ST-segment elevation myocardial infarction undergoing immediate percutaneous coronary intervention.

PubMed

Wolfrum, Sebastian; Pierau, Christian; Radke, Peter W; Schunkert, Heribert; Kurowski, Volkhard

2008-06-01

Mild therapeutic hypothermia (MTH) has been integrated into international resuscitation guidelines. In the majority of patients, sudden cardiac arrest is caused by myocardial infarction. This study investigated whether a combination of MTH with primary percutaneous coronary intervention (PCI) is feasible, safe, and potentially beneficial in patients after cardiac arrest due to acute myocardial infarction. Single-center observational study with a historical control group. University clinic. Thirty-three patients after cardiac arrest with ventricular fibrillation as initial rhythm and restoration of spontaneous circulation who remained unconscious at admission and presented with acute ST elevation myocardial infarction (STEMI). In 16 consecutive patients (2005-2006), MTH was initiated immediately after admission and continued during primary PCI. Seventeen consecutive patients who were treated in a similar 2-yr observation interval before implementation of MTH (2003-2004) served as a control group. Feasibility, safety, mortality, and neurologic outcome were documented. Initiation of MTH did not result in longer door-to-balloon times compared with the control group (82 vs. 85 mins), indicating that implementation of MTH did not delay the onset of primary PCI. Target temperature (32-34 degrees C) in the MTH group was reached within 4 hrs, consistent with previous trials and suggesting that primary PCI did not affect the velocity of cooling. Despite a tendency to increased bleeding complications and infections, patients treated with MTH tended to have a lower mortality after 6 months (25% vs. 35%, p = .71) and an improved neurologic outcome as determined by a Glasgow-Pittsburgh Cerebral Performance Scale score of 1 or 2 (69% vs. 47% in the control group, p = .30). MTH in combination with primary PCI is feasible and safe in patients resuscitated after cardiac arrest due to acute myocardial infarction. A combination of these therapeutic procedures should be strongly

Radio electric conveyed fields directly reprogram human dermal skin fibroblasts toward cardiac, neuronal, and skeletal muscle-like lineages.

PubMed

Maioli, Margherita; Rinaldi, Salvatore; Santaniello, Sara; Castagna, Alessandro; Pigliaru, Gianfranco; Gualini, Sara; Cavallini, Claudia; Fontani, Vania; Ventura, Carlo

2013-01-01

Somatic cells can be directly reprogrammed to alternative differentiated fates without first becoming stem/progenitor cells. Nevertheless, the initial need for viral-mediated gene delivery renders this strategy unsafe in humans. Here, we provide evidence that exposure of human skin fibroblasts to a Radio Electric Asymmetric Conveyer (REAC), an innovative device delivering radio electric conveyed fields at a radiofrequency of 2.4 GHz, afforded remarkable commitment toward cardiac, neuronal, and skeletal muscle lineages. REAC induced the transcription of tissue-restricted genes, including Mef2c, Tbx5, GATA4, Nkx2.5, and prodynorphin for cardiac reprogramming, as well as myoD, and neurogenin 1 for skeletal myogenesis and neurogenesis, respectively. Conversely, REAC treatment elicited a biphasic effect on a number of stemness-related genes, leading to early transcriptional increase of Oct4, Sox2, cMyc, Nanog, and Klf4 within 6-20 h, followed by a downregulation at later times. The REAC action bypassed a persistent reprogramming toward an induced pluripotent stem cell-like state and involved the transcriptional induction of the NADPH oxidase subunit Nox4. Our results show for the first time the feasibility of using a physical stimulus to afford the expression of pluripotentiality in human adult somatic cells up to the attainment of three major target lineages for regenerative medicine.

Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features

PubMed Central

Maggi, Lorenzo; Carboni, Nicola; Bernasconi, Pia

2016-01-01

LMNA-related disorders are caused by mutations in the LMNA gene, which encodes for the nuclear envelope proteins, lamin A and C, via alternative splicing. Laminopathies are associated with a wide range of disease phenotypes, including neuromuscular, cardiac, metabolic disorders and premature aging syndromes. The most frequent diseases associated with mutations in the LMNA gene are characterized by skeletal and cardiac muscle involvement. This review will focus on genetics and clinical features of laminopathies affecting primarily skeletal muscle. Although only symptomatic treatment is available for these patients, many achievements have been made in clarifying the pathogenesis and improving the management of these diseases. PMID:27529282

Chronic effects of losartan on the muscles and the serologic profiles of mdx mice.

PubMed

Lee, Eun-Mi; Kim, Dae-Yong; Kim, Ah-Young; Lee, Eun-Joo; Kim, Sang-Hyeob; Lee, Myeong-Mi; Sung, Soo-Eun; Park, Jin-Kyu; Jeong, Kyu-Shik

2015-12-15

Losartan, an angiotensin II type 1 receptor blocker, attenuates transforming growth factor-β (TGF-β) signaling, which inhibits myogenic regeneration. Although many researchers have demonstrated that losartan has anti-fibrotic and protective effects on cardiac and skeletal muscles, for long-term administration to treat dystrophic disorders, it is essential to demonstrate not only the therapeutic effects of losartan on muscles but also its effects on other organs and on blood biochemistry. Mdx mice, an animal model of Duchenne muscular dystrophy (DMD), were fed losartan dissolved in tap water. After 44weeks, the skeletal (gastrocnemius), cardiac, and diaphragm muscles of mdx mice were removed. Tissue and blood samples were collected from all experimental animals. Effects of losartan on muscle regeneration, fibrosis, and blood enzymatic profiles were evaluated. In histopathological findings and serum biochemistry analyses, chronic losartan administration showed muscular protective effects and inhibited fibrosis in skeletal (gastrocnemius), cardiac, and diaphragmatic muscles. In addition, losartan had no effects on other solid organs. Interestingly, losartan had beneficial effects on serum HDL ratio. This study demonstrates the therapeutic effects of losartan on muscles and its effects on other organs and on blood biochemistry. In conclusion, our results provide useful information for consideration of chronic losartan administration be as a treatment of DMD. Copyright © 2015 Elsevier Inc. All rights reserved.

Cell differentiation in cardiac myxomas: confocal microscopy and gene expression analysis after laser capture microdissection.

PubMed

Pucci, Angela; Mattioli, Claudia; Matteucci, Marco; Lorenzini, Daniele; Panvini, Francesca; Pacini, Simone; Ippolito, Chiara; Celiento, Michele; De Martino, Andrea; Dolfi, Amelio; Belgio, Beatrice; Bortolotti, Uberto; Basolo, Fulvio; Bartoloni, Giovanni

2018-05-22

Cardiac myxomas are rare tumors with a heterogeneous cell population including properly neoplastic (lepidic), endothelial and smooth muscle cells. The assessment of neoplastic (lepidic) cell differentiation pattern is rather difficult using conventional light microscopy immunohistochemistry and/or whole tissue extracts for mRNA analyses. In a preliminary study, we investigated 20 formalin-fixed and paraffin-embedded cardiac myxomas by means of conventional immunohistochemistry; in 10/20 cases, cell differentiation was also analyzed by real-time RT-PCR after laser capture microdissection of the neoplastic cells, whereas calretinin and endothelial antigen CD31 immunoreactivity was localized in 4/10 cases by double immunofluorescence confocal microscopy. Gene expression analyses of α-smooth muscle actin, endothelial CD31 antigen, alpha-cardiac actin, matrix metalloprotease-2 (MMP2) and tissue inhibitor of matrix metalloprotease-1 (TIMP1) was performed on cDNA obtained from either microdissected neoplastic cells or whole tumor sections. We found very little or absent CD31 and α-Smooth Muscle Actin expression in the microdissected cells as compared to the whole tumors, whereas TIMP1 and MMP2 genes were highly expressed in both ones, greater levels being found in patients with embolic phenomena. α-Cardiac Actin was not detected. Confocal microscopy disclosed two different signals corresponding to calretinin-positive myxoma cells and to endothelial CD31-positive cells, respectively. In conclusion, the neoplastic (lepidic) cells showed a distinct gene expression pattern and no consistent overlapping with endothelial and smooth muscle cells or cardiac myocytes; the expression of TIMP1 and MMP2 might be related to clinical presentation; larger series studies using also systematic transcriptome analysis might be useful to confirm the present results.

Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy.

PubMed

Noguchi, Satoru; Ogawa, Megumu; Malicdan, May Christine; Nonaka, Ikuya; Nishino, Ichizo

2017-02-01

Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders with a broad spectrum of clinical presentation and are caused by mutations in one of COL6A1-3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. In this study, we define critical events that contribute to muscle weakness and fibrosis in a mouse model with collagen VI deficiency. The Col6a1 GT/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1 GT/GT mice have high numbers of interstitial skeletal muscle mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI deficient muscular dystrophy, and more importantly, provide the insights on the therapeutic strategies for collagen VI deficiency. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Establishing Early Functional Perfusion and Structure in Tissue Engineered Cardiac Constructs

PubMed Central

Wang, Bo; Patnaik, Sourav S.; Brazile, Bryn; Butler, J. Ryan; Claude, Andrew; Zhang, Ge; Guan, Jianjun; Hong, Yi; Liao, Jun

2016-01-01

Myocardial infarction (MI) causes massive heart muscle death and remains a leading cause of death in the world. Cardiac tissue engineering aims to replace the infarcted tissues with functional engineered heart muscles or revitalize the infarcted heart by delivering cells, bioactive factors, and/or biomaterials. One major challenge of cardiac tissue engineering and regeneration is the establishment of functional perfusion and structure to achieve timely angiogenesis and effective vascularization, which are essential to the survival of thick implants and the integration of repaired tissue with host heart. In this paper, we review four major approaches to promoting angiogenesis and vascularization in cardiac tissue engineering and regeneration: delivery of pro-angiogenic factors/molecules, direct cell implantation/cell sheet grafting, fabrication of prevascularized cardiac constructs, and the use of bioreactors to promote angiogenesis and vascularization. We further provide a detailed review and discussion on the early perfusion design in nature-derived biomaterials, synthetic biodegradable polymers, tissue-derived acellular scaffolds/whole hearts, and hydrogel derived from extracellular matrix. A better understanding of the current approaches and their advantages, limitations, and hurdles could be useful for developing better materials for future clinical applications. PMID:27480586

Establishing Early Functional Perfusion and Structure in Tissue Engineered Cardiac Constructs.

PubMed

Wang, Bo; Patnaik, Sourav S; Brazile, Bryn; Butler, J Ryan; Claude, Andrew; Zhang, Ge; Guan, Jianjun; Hong, Yi; Liao, Jun

2015-01-01

Myocardial infarction (MI) causes massive heart muscle death and remains a leading cause of death in the world. Cardiac tissue engineering aims to replace the infarcted tissues with functional engineered heart muscles or revitalize the infarcted heart by delivering cells, bioactive factors, and/or biomaterials. One major challenge of cardiac tissue engineering and regeneration is the establishment of functional perfusion and structure to achieve timely angiogenesis and effective vascularization, which are essential to the survival of thick implants and the integration of repaired tissue with host heart. In this paper, we review four major approaches to promoting angiogenesis and vascularization in cardiac tissue engineering and regeneration: delivery of pro-angiogenic factors/molecules, direct cell implantation/cell sheet grafting, fabrication of prevascularized cardiac constructs, and the use of bioreactors to promote angiogenesis and vascularization. We further provide a detailed review and discussion on the early perfusion design in nature-derived biomaterials, synthetic biodegradable polymers, tissue-derived acellular scaffolds/whole hearts, and hydrogel derived from extracellular matrix. A better understanding of the current approaches and their advantages, limitations, and hurdles could be useful for developing better materials for future clinical applications.

Biomarkers for cardiac cachexia: reality or utopia.

PubMed

Martins, Telma; Vitorino, Rui; Amado, Francisco; Duarte, José Alberto; Ferreira, Rita

2014-09-25

Cardiac cachexia is a serious complication of chronic heart failure, characterized by significant weight loss and body wasting. Chronic heart failure-related muscle wasting results from a chronic imbalance in the activation of anabolic or catabolic pathways, caused by a series of immunological, metabolic, and neurohormonal processes. In spite of the high morbidity and mortality associated to this condition, there is no universally accepted definition or specific biomarkers for cardiac cachexia, which makes its diagnosis and treatment difficult. Several hormonal, inflammatory and oxidative stress molecules have been proposed as serological markers of prognosis in cardiac cachexia but with doubtful success. As individual biomarkers may have limited sensitivity and specificity, multimarker strategies involving mediators of the biological processes modulated by cardiac cachexia will strongly contribute for the diagnosis and management of the disease, as well as for the establishment of new therapeutic targets. An integrated analysis of the biomarkers proposed so far for cardiac cachexia is made in the present review, highlighting the biological processes to which they are related. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human β-cardiac myosin.

PubMed

Spudich, James A; Aksel, Tural; Bartholomew, Sadie R; Nag, Suman; Kawana, Masataka; Yu, Elizabeth Choe; Sarkar, Saswata S; Sung, Jongmin; Sommese, Ruth F; Sutton, Shirley; Cho, Carol; Adhikari, Arjun S; Taylor, Rebecca; Liu, Chao; Trivedi, Darshan; Ruppel, Kathleen M

2016-01-01

Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the fundamental force-generating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles. © 2016. Published by The Company of Biologists Ltd.

Nanowired three-dimensional cardiac patches

NASA Astrophysics Data System (ADS)

Dvir, Tal; Timko, Brian P.; Brigham, Mark D.; Naik, Shreesh R.; Karajanagi, Sandeep S.; Levy, Oren; Jin, Hongwei; Parker, Kevin K.; Langer, Robert; Kohane, Daniel S.

2011-11-01

Engineered cardiac patches for treating damaged heart tissues after a heart attack are normally produced by seeding heart cells within three-dimensional porous biomaterial scaffolds. These biomaterials, which are usually made of either biological polymers such as alginate or synthetic polymers such as poly(lactic acid) (PLA), help cells organize into functioning tissues, but poor conductivity of these materials limits the ability of the patch to contract strongly as a unit. Here, we show that incorporating gold nanowires within alginate scaffolds can bridge the electrically resistant pore walls of alginate and improve electrical communication between adjacent cardiac cells. Tissues grown on these composite matrices were thicker and better aligned than those grown on pristine alginate and when electrically stimulated, the cells in these tissues contracted synchronously. Furthermore, higher levels of the proteins involved in muscle contraction and electrical coupling are detected in the composite matrices. It is expected that the integration of conducting nanowires within three-dimensional scaffolds may improve the therapeutic value of current cardiac patches.

Cardiac consequences to skeletal muscle-centric therapeutics for Duchenne muscular dystrophy.

PubMed

Townsend, DeWayne; Yasuda, Soichiro; Chamberlain, Jeffrey; Metzger, Joseph M

2009-02-01

Duchenne muscular dystrophy (DMD) is a fatal disease of muscle deterioration. Duchenne muscular dystrophy affects all striated muscles in the body, including the heart. Recent advances in palliative care, largely directed at improving respiratory function, have extended life but paradoxically further unmasked emergent heart disease in DMD patients. New experimental strategies have shown promise in restoring dystrophin in the skeletal muscles of dystrophin- deficient animals. These strategies often have little or no capacity for restitution of dystrophin in the hearts of these animals. This article draws on both clinical data and recent experimental data to posit that effective skeletal muscle restricted therapies for DMD will paradoxically heighten cardiomyopathy and heart failure in these patients.

Sex-based differences in plasma chemistry and cardiac marker test results in Siamese fighting fowl.

PubMed

Sribhen, Choosri; Choothesa, Apassara; Songserm, Thaveesak; Issariyodom, Supaporn; Sribhen, Kosit

2006-09-01

Variations in the results of plasma chemistry analysis as a function of sex have rarely been demonstrated in avian species. The aim of the present study was to investigate sex-related differences in values for routine biochemical variables, including conventional muscle enzymes, and novel cardiac markers in female and male Siamese fighting fowl. Plasma chemistry analytes and cardiac marker proteins (creatine kinase-MB and cardiac troponin T) were measured in 70 Siamese fighting fowl using automated chemistry and immunoassay analyzers. Data were compared by 2-tailed t tests between sexes, and Spearman rank correlation between conventional and novel cardiac markers. Male fowl had significantly higher uric acid concentration and gamma-glutamyltransferase activity; whereas, female fowl had significantly higher total cholesterol, triglycerides, and calcium concentrations, and alkaline phosphatase activity. As compared with female fowl, the fighting cocks also had significantly higher plasma concentrations of creatine kinase-MB and cardiac troponin T. Significant correlations between cardiac troponin T, but not creatine kinase-MB, and the activities of conventional muscle enzymes (creatine kinase, aspartate aminotransferase and lactate dehydrogenase) were observed in male but not in female fowl. These results indicate that sex-specific differences exist for several biochemical parameters and cardiac marker proteins in fighting fowl, and that such differences should be considered in interpreting laboratory test results.

Anti-striated muscle antibody activity produced by Trypanosoma cruzi.

PubMed

Acosta, A M; Sadigursky, M; Santos-Buch, C A

1983-03-01

We have previously shown that Trypanosoma cruzi shares antigenic determinants with preparations of the calcium-sequestering adenosine triphosphatase of sarcoplasmic reticulum. The cross-reacting antigen (SRA) is also apparently present on the sarcolemma of cardiac myofibers. Using highly specific reference antisera to either the small membranes of T. cruzi or to a tryptic fragment of striated muscle SRA, it was shown that SRA is present in the striated muscle of animals representative of the evolutionary scale ranging from nonhuman primate to fish. The small membranes of nine different T. cruzi strains isolated from widely divergent areas of the American continents also reacted with the reference antisera. This indicates that SRA is present in these T. cruzi strains and may be prevalent among all T. cruzi strains. The shared T. cruzi-striated muscle antigen, SRA, may be a heteroantigen present in all T. cruzi strains and in the striated muscle of all classes of animals. Immunization of rabbits (three of five) or chickens (five pairs of five pairs) with striated muscle membrane preparations of different classes of animals, particularly those of nonhuman primate, chicken, and turtle, gave rise to IgG anti-allogeneic striated muscle antibody activity. Immunization of rabbits (four of nine) and chickens (five pairs of six pairs) with the small membranes of different T. cruzi strains also produced IgG anti-allogeneic striated muscle. These data indicate that T. cruzi shares cross-immunogenicity with striated muscle SRA. Since SRA is apparently present on the sarcolemma of cardiac myofibers, it may be implicated in the immunopathogenesis of Chagas' disease.

Diastolic scattered light fluctuation, resting force and twitch force in mammalian cardiac muscle

PubMed Central

Lakatta, E. G.; Lappé, D. L.

1981-01-01

1. When coherent light was passed through isolated isometric cardiac muscles during the diastolic or resting period, intensity fluctuations were observed in the scattered field. The frequency of these intensity fluctuations (f½) varied with many experimental interventions known to enhance Ca2+ flux into the cell. 2. In rat muscles stimulated at low frequencies (0.1 ± 2.0 min-1) stepwise increases (0.4-10 mm) of [Ca2+] in the bathing fluid ([Ca2+]e), or addition of ouabain (10-6-6 × 10-4 m) to the perfusate caused stepwise increases in f½. These were paralleled by increments in resting force (RF) such that the changes in f½ and RF were highly correlated. Substitution of K+ for Na+ in the perfusate resulted in parallel transients in RF and f½. 3. In contrast to the rat, most cat muscles stimulated at low frequencies in the steady state exhibited neither diastolic intensity fluctuations nor Ca2+-dependent changes in RF in [Ca2+]e of 10 mm or less; when [Ca2+]e was increased to 12-32 mm, however, steady-state Ca2+-dependent f½ and RF were observed. In a given [Ca2+]e reduction of [Na+]e increased f½. In the transient state following cessation of regular stimulation at more rapid rates (12-96 min-1) intensity fluctuations were present in all [Ca2+]e and decayed with time (seconds to minutes); the f½ and time course of the decay of the fluctuations were determined by the rate of prior stimulation and [Ca2+]e. 4. Maximum potentiation of twitch force in response to the above inotropic interventions was associated with an optimal level of f½ which was similar in both species; when higher levels of f½ were produced by more intense inotropic intervention, twitch force declined. Over the range of inotropic intervention up to and including that at which maximum twitch potentiation occurred, the increase in diastolic f½ predicted the extent of twitch potentiation with a high degree of accuracy (r > 0.97) both in the transient and steady states. 5. In contrast to the

Genetic dissection of cardiac growth control pathways

NASA Technical Reports Server (NTRS)

MacLellan, W. R.; Schneider, M. D.

2000-01-01

Cardiac muscle cells exhibit two related but distinct modes of growth that are highly regulated during development and disease. Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle irreversibly soon after birth, following which the predominant form of growth shifts from hyperplastic to hypertrophic. Much research has focused on identifying the candidate mitogens, hypertrophic agonists, and signaling pathways that mediate these processes in isolated cells. What drives the proliferative growth of embryonic myocardium in vivo and the mechanisms by which adult cardiac myocytes hypertrophy in vivo are less clear. Efforts to answer these questions have benefited from rapid progress made in techniques to manipulate the murine genome. Complementary technologies for gain- and loss-of-function now permit a mutational analysis of these growth control pathways in vivo in the intact heart. These studies have confirmed the importance of suspected pathways, have implicated unexpected pathways as well, and have led to new paradigms for the control of cardiac growth.

Design of a muscle cell-specific expression vector utilising human vascular smooth muscle alpha-actin regulatory elements.

PubMed

Keogh, M C; Chen, D; Schmitt, J F; Dennehy, U; Kakkar, V V; Lemoine, N R

1999-04-01

The facility to direct tissue-specific expression of therapeutic gene constructs is desirable for many gene therapy applications. We describe the creation of a muscle-selective expression vector which supports transcription in vascular smooth muscle, cardiac muscle and skeletal muscle, while it is essentially silent in other cell types such as endothelial cells, hepatocytes and fibroblasts. Specific transcriptional regulatory elements have been identified in the human vascular smooth muscle cell (VSMC) alpha-actin gene, and used to create an expression vector which directs the expression of genes in cis to muscle cells. The vector contains an enhancer element we have identified in the 5' flanking region of the human VSMC alpha-actin gene involved in mediating VSMC expression. Heterologous pairing experiments have shown that the enhancer does not interact with the basal transcription complex recruited at the minimal SV40 early promoter. Such a vector has direct application in the modulation of VSMC proliferation associated with intimal hyperplasia/restenosis.

Exome Sequencing Identified a Splice Site Mutation in FHL1 that Causes Uruguay Syndrome, an X-Linked Disorder With Skeletal Muscle Hypertrophy and Premature Cardiac Death.

PubMed

Xue, Yuan; Schoser, Benedikt; Rao, Aliz R; Quadrelli, Roberto; Vaglio, Alicia; Rupp, Verena; Beichler, Christine; Nelson, Stanley F; Schapacher-Tilp, Gudrun; Windpassinger, Christian; Wilcox, William R

2016-04-01

Previously, we reported a rare X-linked disorder, Uruguay syndrome in a single family. The main features are pugilistic facies, skeletal deformities, and muscular hypertrophy despite a lack of exercise and cardiac ventricular hypertrophy leading to premature death. An ≈19 Mb critical region on X chromosome was identified through identity-by-descent analysis of 3 affected males. Exome sequencing was conducted on one affected male to identify the disease-causing gene and variant. A splice site variant (c.502-2A>G) in the FHL1 gene was highly suspicious among other candidate genes and variants. FHL1A is the predominant isoform of FHL1 in cardiac and skeletal muscle. Sequencing cDNA showed the splice site variant led to skipping of exons 6 of the FHL1A isoform, equivalent to the FHL1C isoform. Targeted analysis showed that this splice site variant cosegregated with disease in the family. Western blot and immunohistochemical analysis of muscle from the proband showed a significant decrease in protein expression of FHL1A. Real-time polymerase chain reaction analysis of different isoforms of FHL1 demonstrated that the FHL1C is markedly increased. Mutations in the FHL1 gene have been reported in disorders with skeletal and cardiac myopathy but none has the skeletal or facial phenotype seen in patients with Uruguay syndrome. Our data suggest that a novel FHL1 splice site variant results in the absence of FHL1A and the abundance of FHL1C, which may contribute to the complex and severe phenotype. Mutation screening of the FHL1 gene should be considered for patients with uncharacterized myopathies and cardiomyopathies. © 2016 American Heart Association, Inc.

Does the intercept of the heat-stress relation provide an accurate estimate of cardiac activation heat?

PubMed

Pham, Toan; Tran, Kenneth; Mellor, Kimberley M; Hickey, Anthony; Power, Amelia; Ward, Marie-Louise; Taberner, Andrew; Han, June-Chiew; Loiselle, Denis

2017-07-15

The heat of activation of cardiac muscle reflects the metabolic cost of restoring ionic homeostasis following a contraction. The accuracy of its measurement depends critically on the abolition of crossbridge cycling. We abolished crossbridge activity in isolated rat ventricular trabeculae by use of blebbistatin, an agent that selectively inhibits myosin II ATPase. We found cardiac activation heat to be muscle length independent and to account for 15-20% of total heat production at body temperature. We conclude that it can be accurately estimated at minimal muscle length. Activation heat arises from two sources during the contraction of striated muscle. It reflects the metabolic expenditure associated with Ca 2+ pumping by the sarcoplasmic reticular Ca 2+ -ATPase and Ca 2+ translocation by the Na + /Ca 2+ exchanger coupled to the Na + ,K + -ATPase. In cardiac preparations, investigators are constrained in estimating its magnitude by reducing muscle length to the point where macroscopic twitch force vanishes. But this experimental protocol has been criticised since, at zero force, the observed heat may be contaminated by residual crossbridge cycling activity. To eliminate this concern, the putative thermal contribution from crossbridge cycling activity must be abolished, at least at minimal muscle length. We achieved this using blebbistatin, a selective inhibitor of myosin II ATPase. Using a microcalorimeter, we measured the force production and heat output, as functions of muscle length, of isolated rat trabeculae from both ventricles contracting isometrically at 5 Hz and at 37°C. In the presence of blebbistatin (15 μmol l -1 ), active force was zero but heat output remained constant, at all muscle lengths. Activation heat measured in the presence of blebbistatin was not different from that estimated from the intercept of the heat-stress relation in its absence. We thus reached two conclusions. First, activation heat is independent of muscle length. Second

Neuropeptide tyrosine (NPY)--a major cardiac neuropeptide.

PubMed

Gu, J; Polak, J M; Adrian, T E; Allen, J M; Tatemoto, K; Bloom, S R

1983-05-07

A newly discovered bioactive peptide, neuropeptide tyrosine (NPY), has been found in the human cardiac nervous system. Dense concentrations of NPY-immunoreactive nerve fibres were found in association with nodal tissue (atrioventricular node 22.1 +/- 3.7 pmol/g). NPY nerve fibres were seen in close contact with cardiac muscle fibres and were also found around the coronary vessels (19.6 +/- 6.2 pmol/g). Analysis of the peptide by high-performance liquid chromatography demonstrated that it was present in a single molecular form, closely similar or identical to that of the isolated bioactive peptide. Cardiac function in man has long been known to be influenced by cholinergic and adrenergic nerves. There now appears to be a further component of the nervous system in the human heart, involving peptidergic nerves containing NPY.

Investigation following resuscitated cardiac arrest.

PubMed

Skinner, Jonathan R

2013-01-01

Roughly two thirds of resuscitated cardiac arrests in children and youth are due to inherited heart diseases. The most commonly implicated are the cardiac ion channelopathies long QT syndrome, CPVT (catecholaminergic polymorphic ventricular tachycardia) and Brugada syndrome. Diagnosis is pivotal to further management of the child if he/she survives, and also to other family members who may be at risk. Thorough investigation of the cardiac arrest survivor is essential to either identify or exclude inherited heart disease. If standard cardiac investigation does not reveal a diagnosis, pharmacological provocation tests are needed to unmask electrocardiographic signs of disease, even if, due to severe brain injury, it is planned ultimately to allow a natural death. Examples are the ajmaline/flecainide challenge for Brugada syndrome and epinephrine for CPVT. A supportive, informative and sympathetic approach to the family is essential. An arrhythmia specialist and a cardiac genetic service should be involved early, with storage of DNA and cardiac/genetic investigation of the family. This review proposes a diagnostic algorithm-based approach to the investigation of this increasingly common clinical scenario.

X-ray diffraction evidence for myosin-troponin connections and tropomyosin movement during stretch activation of insect flight muscle

PubMed Central

Perz-Edwards, Robert J.; Irving, Thomas C.; Baumann, Bruce A. J.; Gore, David; Hutchinson, Daniel C.; Kržič, Uroš; Porter, Rebecca L.; Ward, Andrew B.; Reedy, Michael K.

2011-01-01

Stretch activation is important in the mechanical properties of vertebrate cardiac muscle and essential to the flight muscles of most insects. Despite decades of investigation, the underlying molecular mechanism of stretch activation is unknown. We investigated the role of recently observed connections between myosin and troponin, called “troponin bridges,” by analyzing real-time X-ray diffraction “movies” from sinusoidally stretch-activated Lethocerus muscles. Observed changes in X-ray reflections arising from myosin heads, actin filaments, troponin, and tropomyosin were consistent with the hypothesis that troponin bridges are the key agent of mechanical signal transduction. The time-resolved sequence of molecular changes suggests a mechanism for stretch activation, in which troponin bridges mechanically tug tropomyosin aside to relieve tropomyosin’s steric blocking of myosin–actin binding. This enables subsequent force production, with cross-bridge targeting further enhanced by stretch-induced lattice compression and thick-filament twisting. Similar linkages may operate in other muscle systems, such as mammalian cardiac muscle, where stretch activation is thought to aid in cardiac ejection. PMID:21148419

Muscle as a “Mediator“ of Systemic Metabolism

PubMed Central

Baskin, Kedryn K.; Winders, Benjamin R.; Olson, Eric N.

2015-01-01

Skeletal and cardiac muscles play key roles in the regulation of systemic energy homeostasis and display remarkable plasticity in their metabolic responses to caloric availability and physical activity. In this Perspective we discuss recent studies highlighting transcriptional mechanisms that govern systemic metabolism by striated muscles. We focus on the participation of the Mediator complex in this process, and suggest that tissue-specific regulation of Mediator subunits impacts metabolic homeostasis. PMID:25651178

Artificial aortic valve dysfunction due to pannus and thrombus – different methods of cardiac surgical management

PubMed Central

Marcinkiewicz, Anna; Kośmider, Anna; Walczak, Andrzej; Zwoliński, Radosław; Jaszewski, Ryszard

2015-01-01

Introduction Approximately 60 000 prosthetic valves are implanted annually in the USA. The risk of prosthesis dysfunction ranges from 0.1% to 4% per year. Prosthesis valve dysfunction is usually caused by a thrombus obstructing the prosthetic discs. However, 10% of prosthetic valves are dysfunctional due to pannus formation, and 12% of prostheses are damaged by both fibrinous and thrombotic components. The authors present two patients with dysfunctional aortic prostheses who were referred for cardiac surgery. Different surgical solutions were used in the treatment of each case. Case study 1 The first patient was a 71-year-old woman whose medical history included arterial hypertension, stable coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and hypercholesterolemia; she had previously undergone left-sided mastectomy and radiotherapy. The patient was admitted to the Cardiac Surgery Department due to aortic prosthesis dysfunction. Transthoracic echocardiography revealed complete obstruction of one disc and a severe reduction in the mobility of the second. The mean transvalvular gradient was very high. During the operation, pannus covering the discs’ surface was found. A biological aortic prosthesis was reimplanted without complications. Case study 2 The second patient was an 87-year-old woman with arterial hypertension, persistent atrial fibrillation, and COPD, whose past medical history included gastric ulcer disease and ischemic stroke. As in the case of the first patient, she was admitted due to valvular prosthesis dysfunction. Preoperative transthoracic echocardiography revealed an obstruction of the posterior prosthetic disc and significant aortic regurgitation. Transesophageal echocardiography and fluoroscopy confirmed the prosthetic dysfunction. During the operation, a thrombus growing around a minor pannus was found. The thrombus and pannus were removed, and normal functionality of the prosthetic valve was restored

The Popeye domain containing 2 (popdc2) gene in zebrafish is required for heart and skeletal muscle development

PubMed Central

Kirchmaier, Bettina C.; Poon, Kar Lai; Schwerte, Thorsten; Huisken, Jan; Winkler, Christoph; Jungblut, Benno; Stainier, Didier Y.; Brand, Thomas

2013-01-01

The Popeye domain containing (Popdc) genes encode a family of transmembrane proteins with an evolutionary conserved Popeye domain. These genes are abundantly expressed in striated muscle tissue, however their function is not well understood. In this study we have investigated the role of the popdc2 gene in zebrafish. Popdc2 transcripts were detected in the embryonic myocardium and transiently in the craniofacial and tail musculature. Morpholino oligonucleotide-mediated knockdown of popdc2 resulted in aberrant development of skeletal muscle and heart. Muscle segments in the trunk were irregularly shaped and craniofacial muscles were severely reduced or even missing. In the heart, pericardial edema was prevalent in the morphants and heart chambers were elongated and looping was abnormal. These pathologies in muscle and heart were alleviated after reducing the morpholino concentration. However the heart still was abnormal displaying cardiac arrhythmia at later stages of development. Optical recordings of cardiac contractility revealed irregular ventricular contractions with a 2:1, or 3:1 atrial/ventricular conduction ratio, which caused a significant reduction in heart frequency. Recordings of calcium transients with high spatiotemporal resolution using a transgenic calcium indicator line (Tg(cmlc2:gCaMP)s878) and SPIM microscopy confirmed the presence of a severe arrhythmia phenotype. Our results identify popdc2 as a gene important for striated muscle differentiation and cardiac morphogenesis. In addition it is required for the development of the cardiac conduction system. PMID:22290329

Optimal iodine staining of cardiac tissue for X-ray computed tomography.

PubMed

Butters, Timothy D; Castro, Simon J; Lowe, Tristan; Zhang, Yanmin; Lei, Ming; Withers, Philip J; Zhang, Henggui

2014-01-01

X-ray computed tomography (XCT) has been shown to be an effective imaging technique for a variety of materials. Due to the relatively low differential attenuation of X-rays in biological tissue, a high density contrast agent is often required to obtain optimal contrast. The contrast agent, iodine potassium iodide ([Formula: see text]), has been used in several biological studies to augment the use of XCT scanning. Recently I2KI was used in XCT scans of animal hearts to study cardiac structure and to generate 3D anatomical computer models. However, to date there has been no thorough study into the optimal use of I2KI as a contrast agent in cardiac muscle with respect to the staining times required, which has been shown to impact significantly upon the quality of results. In this study we address this issue by systematically scanning samples at various stages of the staining process. To achieve this, mouse hearts were stained for up to 58 hours and scanned at regular intervals of 6-7 hours throughout this process. Optimal staining was found to depend upon the thickness of the tissue; a simple empirical exponential relationship was derived to allow calculation of the required staining time for cardiac samples of an arbitrary size.

The effect of moderate-intensity exercise on the expression of HO-1 mRNA and activity of HO in cardiac and vascular smooth muscle of spontaneously hypertensive rats.

PubMed

Ren, Cailing; Qi, Jie; Li, Wanwei; Zhang, Jun

2016-04-01

The objective of this study was to observe the effects of moderate-intensity training on the activity of heme oxygenase (HO) and expression of HO-1 mRNA in the aorta and the cardiac muscle of spontaneously hypertensive rats (SHRs). After 9 weeks of swimming exercise, the activity of HO and expression of HO-1 mRNA in the SHRs were measured. The resting blood pressure in the exercise group was increased by 1.7% (P > 0.05), whereas it was significantly elevated by 10.3% (P < 0.01) in the SHR rats. Compared with animals in the control and sedentary groups, the expression level of HO-1 mRNA of aorta and cardiac muscle in the exercise group was significantly enhanced (P < 0.01). The HO activity and the content of plasma carbon monoxide (CO) in the sedentary group were dramatically decreased (P < 0.05 and P < 0.01, respectively) compared with the control group. HO activity and content of plasma CO in the exercise group were significantly higher compared with those in the sedentary group (P < 0.05 and P < 0.01, respectively). The HO/CO metabolic pathway might be involved in the regulation of blood pressure of the SHR models.

A technique for studying cardiac myosin dynamics using optical tweezers

NASA Astrophysics Data System (ADS)

Paolino, Michael; Migirditch, Sam; Nesmelov, Yuri; Hester, Brooke; Appalachian State Biophysics; Optical Sciences Facility Team

A primary protein involved in human muscle contraction is myosin, which exists in α- and β- isoforms. Myosin exerts forces on actin filaments when ATP is present, driving muscle contraction. A significant decrease in the population of cardiac α-myosin has been linked to heart failure. It is proposed that slow β-myosin in a failing heart could, through introduction of a drug, be made to mimic the action of α-myosin, thereby improving cardiac muscle performance. In working towards testing this hypothesis, the focus of this work is to develop a technique to measure forces exerted by myosin on actin using optical tweezers. An actin-myosin arrangement is constructed between two optically trapped polystyrene microspheres. The displacement of a microsphere is monitored when ATP is introduced, and the force responsible is measured. With this achieved, we can then modify the actin-myosin arrangement, for example with varying amounts of α- and β- myosin and test the effects on forces exerted. In this work, assemblies of actin and myosin molecules and preliminary force measurements are discussed. North Carolina Space Grant.

Localization of dichlorofluorescin in cardiac myocytes: implications for assessment of oxidative stress

PubMed Central

SWIFT, LUTHER M.; SARVAZYAN, NARINE

2011-01-01

Localization and staining features of the oxidant-sensitive fluorescent probe 2 7 - dichlorofluorescin (DCFH) were evaluated in isolated cardiac muscle cells. Cardiomyocytes rapidly accumulated the probe and retained steady levels of DCFH and its highly fluorescent oxidized product dichlorofluorescein (DCF) in probe-free medium for 1.5 h. DCF was associated with mitochondria and was released by the proton ionophore carbonyl cyanide m-chlorophenylhydrazone but not by saponin, which permeabilizes the plasma membrane. A mitochondrial distribution of DCF was also suggested by experiments with the mitochondrial marker MitoTracker Red, in which quenching was observed between DCF and MitoTracker Red in live cells. Isolated cardiac mitochondria rapidly accumulated DCF, and high micromolar concentrations of the probe inhibited ADP-stimulated respiration rate. The study provides an information base essential for the interpretation and design of experiments with DCF as a marker of oxidative stress in cardiac muscle and reveals preferential localization of the probe in mitochondria. PMID:10710368

Overexpression of connexin 43 using a retroviral vector improves electrical coupling of skeletal myoblasts with cardiac myocytes in vitro

PubMed Central

Tolmachov, Oleg; Ma, Yu-Ling; Themis, Michael; Patel, Pravina; Spohr, Hilmar; MacLeod, Kenneth T; Ullrich, Nina D; Kienast, Yvonne; Coutelle, Charles; Peters, Nicholas S

2006-01-01

Background Organ transplantation is presently often the only available option to repair a damaged heart. As heart donors are scarce, engineering of cardiac grafts from autologous skeletal myoblasts is a promising novel therapeutic strategy. The functionality of skeletal muscle cells in the heart milieu is, however, limited because of their inability to integrate electrically and mechanically into the myocardium. Therefore, in pursuit of improved cardiac integration of skeletal muscle grafts we sought to modify primary skeletal myoblasts by overexpression of the main gap-junctional protein connexin 43 and to study electrical coupling of connexin 43 overexpressing myoblasts to cardiac myocytes in vitro. Methods To create an efficient means for overexpression of connexin 43 in skeletal myoblasts we constructed a bicistronic retroviral vector MLV-CX43-EGFP expressing the human connexin 43 cDNA and the marker EGFP gene. This vector was employed to transduce primary rat skeletal myoblasts in optimised conditions involving a concomitant use of the retrovirus immobilising protein RetroNectin® and the polycation transduction enhancer Transfectam®. The EGFP-positive transduced cells were then enriched by flow cytometry. Results More than four-fold overexpression of connexin 43 in the transduced skeletal myoblasts, compared with non-transduced cells, was shown by Western blotting. Functionality of the overexpressed connexin 43 was demonstrated by microinjection of a fluorescent dye showing enhanced gap-junctional intercellular transfer in connexin 43 transduced myoblasts compared with transfer in non-transduced myoblasts. Rat cardiac myocytes were cultured in multielectrode array culture dishes together with connexin 43/EGFP transduced skeletal myoblasts, control non-transduced skeletal myoblasts or alone. Extracellular field action potential activation rates in the co-cultures of connexin 43 transduced skeletal myoblasts with cardiac myocytes were significantly higher than

Overexpression of connexin 43 using a retroviral vector improves electrical coupling of skeletal myoblasts with cardiac myocytes in vitro.

PubMed

Tolmachov, Oleg; Ma, Yu-Ling; Themis, Michael; Patel, Pravina; Spohr, Hilmar; Macleod, Kenneth T; Ullrich, Nina D; Kienast, Yvonne; Coutelle, Charles; Peters, Nicholas S

2006-06-06

Organ transplantation is presently often the only available option to repair a damaged heart. As heart donors are scarce, engineering of cardiac grafts from autologous skeletal myoblasts is a promising novel therapeutic strategy. The functionality of skeletal muscle cells in the heart milieu is, however, limited because of their inability to integrate electrically and mechanically into the myocardium. Therefore, in pursuit of improved cardiac integration of skeletal muscle grafts we sought to modify primary skeletal myoblasts by overexpression of the main gap-junctional protein connexin 43 and to study electrical coupling of connexin 43 overexpressing myoblasts to cardiac myocytes in vitro. To create an efficient means for overexpression of connexin 43 in skeletal myoblasts we constructed a bicistronic retroviral vector MLV-CX43-EGFP expressing the human connexin 43 cDNA and the marker EGFP gene. This vector was employed to transduce primary rat skeletal myoblasts in optimised conditions involving a concomitant use of the retrovirus immobilising protein RetroNectin and the polycation transduction enhancer Transfectam. The EGFP-positive transduced cells were then enriched by flow cytometry. More than four-fold overexpression of connexin 43 in the transduced skeletal myoblasts, compared with non-transduced cells, was shown by Western blotting. Functionality of the overexpressed connexin 43 was demonstrated by microinjection of a fluorescent dye showing enhanced gap-junctional intercellular transfer in connexin 43 transduced myoblasts compared with transfer in non-transduced myoblasts. Rat cardiac myocytes were cultured in multielectrode array culture dishes together with connexin 43/EGFP transduced skeletal myoblasts, control non-transduced skeletal myoblasts or alone. Extracellular field action potential activation rates in the co-cultures of connexin 43 transduced skeletal myoblasts with cardiac myocytes were significantly higher than in the co-cultures of non

Inactivation of Smad5 in Endothelial Cells and Smooth Muscle Cells Demonstrates that Smad5 Is Required for Cardiac Homeostasis

PubMed Central

Umans, Lieve; Cox, Luk; Tjwa, Marc; Bito, Virginie; Vermeire, Liesbeth; Laperre, Kjell; Sipido, Karin; Moons, Lieve; Huylebroeck, Danny; Zwijsen, An

2007-01-01

Smads are intracellular signaling proteins that transduce signals elicited by members of the transforming growth factor (TGF)-β superfamily. Smad5 and Smad1 are highly homologous, and they mediate primarily bone morphogenetic protein (Bmp) signals. We used the Cre-loxP system and Sm22-Cre and Tie-1-Cre mice to study the function of Smad5 in the developing blood vessel wall. Analysis of embryos demonstrated that deletion of Smad5 in endothelial or smooth muscle cells resulted in a normal organization of embryonic and extra-embryonic vasculature. Angiogenic assays performed in adult mice revealed that mutant mice display a comparable angiogenic and vascular remodeling response to control mice. In Sm22-Cre;Smad5fl/− mice, Smad5 is also deleted in cardiomyocytes. Echocardiographic analysis on those 9-month-old female mice demonstrated larger left ventricle internal diameters and decreased fractional shortening compared with control littermates without signs of cardiac hypertrophy. The decreased cardiac contractility was associated with a decreased performance in a treadmill experiment. In isolated cardiomyocytes, fractional shortening was significantly reduced compared with control cells. These data demonstrate that restricted deletion of Smad5 in the blood vessel wall results in viable mice. However, loss of Smad5 in cardiomyocytes leads to a mild heart defect. PMID:17456754

Inactivation of Smad5 in endothelial cells and smooth muscle cells demonstrates that Smad5 is required for cardiac homeostasis.

PubMed

Umans, Lieve; Cox, Luk; Tjwa, Marc; Bito, Virginie; Vermeire, Liesbeth; Laperre, Kjell; Sipido, Karin; Moons, Lieve; Huylebroeck, Danny; Zwijsen, An

2007-05-01

Smads are intracellular signaling proteins that transduce signals elicited by members of the transforming growth factor (TGF)-beta superfamily. Smad5 and Smad1 are highly homologous, and they mediate primarily bone morphogenetic protein (Bmp) signals. We used the Cre-loxP system and Sm22-Cre and Tie-1-Cre mice to study the function of Smad5 in the developing blood vessel wall. Analysis of embryos demonstrated that deletion of Smad5 in endothelial or smooth muscle cells resulted in a normal organization of embryonic and extra-embryonic vasculature. Angiogenic assays performed in adult mice revealed that mutant mice display a comparable angiogenic and vascular remodeling response to control mice. In Sm22-Cre; Smad5(fl/-) mice, Smad5 is also deleted in cardiomyocytes. Echocardiographic analysis on those 9-month-old female mice demonstrated larger left ventricle internal diameters and decreased fractional shortening compared with control littermates without signs of cardiac hypertrophy. The decreased cardiac contractility was associated with a decreased performance in a treadmill experiment. In isolated cardiomyocytes, fractional shortening was significantly reduced compared with control cells. These data demonstrate that restricted deletion of Smad5 in the blood vessel wall results in viable mice. However, loss of Smad5 in cardiomyocytes leads to a mild heart defect.

Cardiac torsion and electromagnetic fields: the cardiac bioinformation hypothesis.

PubMed

Burleson, Katharine O; Schwartz, Gary E

2005-01-01

Although in physiology the heart is often referred to as a simple piston pump, there are in fact two additional features that are integral to cardiac physiology and function. First, the heart as it contracts in systole, also rotates and produces torsion due to the structure of the myocardium. Second, the heart produces a significant electromagnetic field with each contraction due to the coordinated depolarization of myocytes producing a current flow. Unlike the electrocardiogram, the magnetic field is not limited to volume conduction and extends outside the body. The therapeutic potential for interaction of this cardioelectromagnetic field both within and outside the body is largely unexplored. It is our hypothesis that the heart functions as a generator of bioinformation that is central to normative functioning of body. The source of this bioinformation is based on: (1) vortex blood flow in the left ventricle; (2) a cardiac electromagnetic field and both; (3) heart sounds; and (4) pulse pressure which produce frequency and amplitude information. Thus, there is a multidimensional role for the heart in physiology and biopsychosocial dynamics. Recognition of these cardiac properties may result in significant implications for new therapies for cardiovascular disease based on increasing cardiac energy efficiency (coherence) and bioinformation from the cardioelectromagnetic field. Research studies to test this hypothesis are suggested.

Electrophysiological effects of haloperidol on isolated rabbit Purkinje fibers and guinea pigs papillary muscles under normal and simulated ischemia.

PubMed

Yan, Dong; Cheng, Lu-feng; Song, Hong-Yan; Turdi, Subat; Kerram, Parhat

2007-08-01

Overdoses of haloperidol are associated with major ventricular arrhythmias, cardiac conduction block, and sudden death. The aim of this experiment was to study the effect of haloperidol on the action potentials in cardiac Purkinje fibers and papillary muscles under normal and simulated ischemia conditions in rabbits and guinea pigs. Using the standard intracellular microelectrode technique, we examined the effects of haloperidol on the action potential parameters [action potential amplitude (APA), phase 0 maximum upstroke velocity (V(max)), action potential amplitude at 90% of repolarization (APD(90)), and effective refractory period (ERP)] in rabbit cardiac Purkinje fibers and guinea pig cardiac papillary cells, in which both tissues were under simulated ischemic conditions. Under ischemic conditions, different concentrations of haloperidol depressed APA and prolonged APD(90) in a concentration-dependent manner in rabbit Purkinje fibers. Haloperidol (3 micromol/L) significantly depressed APA and prolonged APD(90), and from 1 micromol/L, haloperidol showed significant depression on V(max); ERP was not significantly affected. In guinea pig cardiac papillary muscles, the thresholds of significant reduction in APA, V(max), EPR, and APD(90) were 10, 0.3, 1, and 1 mumol/L, respectively, for haloperidol. Compared with cardiac conductive tissues, papillary muscles were more sensitive to ischemic conditions. Under ischemia, haloperidol prolonged ERP and APD(90) in a concentration-dependent manner and precipitated the decrease in V(max) induced by ischemia. The shortening of ERP and APD(90) in papillary muscle action potentials may be inhibited by haloperidol.

Cardiac damage in athlete's heart: When the "supernormal" heart fails!

PubMed

Carbone, Andreina; D'Andrea, Antonello; Riegler, Lucia; Scarafile, Raffaella; Pezzullo, Enrica; Martone, Francesca; America, Raffaella; Liccardo, Biagio; Galderisi, Maurizio; Bossone, Eduardo; Calabrò, Raffaele

2017-06-26

Intense exercise may cause heart remodeling to compensate increases in blood pressure or volume by increasing muscle mass. Cardiac changes do not involve only the left ventricle, but all heart chambers. Physiological cardiac modeling in athletes is associated with normal or enhanced cardiac function, but recent studies have documented decrements in left ventricular function during intense exercise and the release of cardiac markers of necrosis in athlete's blood of uncertain significance. Furthermore, cardiac remodeling may predispose athletes to heart disease and result in electrical remodeling, responsible for arrhythmias. Athlete's heart is a physiological condition and does not require a specific treatment. In some conditions, it is important to differentiate the physiological adaptations from pathological conditions, such as hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle, and non-compaction myocardium, for the greater risk of sudden cardiac death of these conditions. Moreover, some drugs and performance-enhancing drugs can cause structural alterations and arrhythmias, therefore, their use should be excluded.

Targeted Temperature Management After Pediatric Cardiac Arrest Due To Drowning: Outcomes and Complications.

PubMed

Moler, Frank W; Hutchison, Jamie S; Nadkarni, Vinay M; Silverstein, Faye S; Meert, Kathleen L; Holubkov, Richard; Page, Kent; Slomine, Beth S; Christensen, James R; Dean, J Michael

2016-08-01

Performance Category outcomes (≤ 3). In comatose survivors of out-of-hospital pediatric cardiac arrest due to drowning, hypothermia did not result in a statistically significant benefit in survival with good functional outcome or mortality at 1 year, as compared with normothermia. High risk of culture-proven bacterial infection was observed in both groups.

Recent advances on the role of long non-coding RNA H19 in regulating mammalian muscle growth and development.

PubMed

Qin, Chen Yu; Cai, He; Qing, Han Rui; Li, Li; Zhang, Hong Ping

2017-12-20

As one of the first identified long non-coding RNAs (lncRNAs), H19 plays a wide range of roles in vivo, including not only as a tumor suppressor and oncogene involved in disease process, but also as a regulator of growth and development of multiple tissues in mammalian embryos. The function of H19 in muscles (both skeletal and cardiac muscle) draws widespread attention due to the following two reasons. On one hand, H19 promotes myogenic differentiation and myogenesis of skeletal muscle satellite cells (SMSCs) via regulating Igf2 in cis. On the other hand, H19 also modulates the target genes in trans, including sponging let-7, miR-106 or miR-29 to mediate myocyte glucose uptake, cardiomyocyte proliferation and tendon repair, as well as promote embryonic development and muscle regeneration through binding to MBD1 as a chromatin modifier. In this review, we summarize the role of H19 in mammalian muscles, which will provide a reference for further research to unveil the molecular mechanism of muscle growth and development.

Effects of hypothyroidism on the skeletal muscle blood flow response to contractions.

PubMed

Bausch, L; McAllister, R M

2003-04-01

Hypothyroidism is associated with impaired blood flow to skeletal muscle under whole body exercise conditions. It is unclear whether poor cardiac and/or vascular function account for blunted muscle blood flow. Our experiment isolated a small group of hindlimb muscles and simulated exercise via tetanic contractions. We hypothesized that muscle blood flow would be attenuated in hypothyroid rats (HYPO) compared with euthyroid rats (EUT). Rats were made hypothyroid by mixing propylthiouracil in their drinking water (2.35 x 10-3 mol/l). Treatment efficacy was evidenced by lower serum T3 concentrations and resting heart rates in HYPO (both P<0.05). In the experimental preparation, isometric contractions of the lower right hindlimb muscles at a rate of 30 tetani/min were induced via sciatic nerve stimulation. Regional blood flows were determined by the radiolabelled microsphere method at three time points: rest, 2 min of contractions and 10 min of contractions. Muscle blood flow generally increased from rest ( approximately 5-10 ml/min per 100 g) through contractions for both groups. Further, blood flow during contractions did not differ between groups for any muscle (eg. red section of gastrocnemius muscle; EUT, 59.9 +/- 14.1; HYPO, 61.1 +/- 15.0; NS between groups). These findings indicate that hypothyroidism does not significantly impair skeletal muscle blood flow when only a small muscle mass is contracting. Our findings suggest that impaired blood flow under whole body exercise is accounted for by inadequate cardiac function rather than abnormal vascular function.

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity (Review).

PubMed

Belloum, Yassine; Rannou-Bekono, Françoise; Favier, François B

2017-05-01

Cachexia is a wasting syndrome observed in many patients suffering from several chronic diseases including cancer. In addition to the progressive loss of skeletal muscle mass, cancer cachexia results in cardiac function impairment. During the severe stage of the disease, patients as well as animals bearing cancer cells display cardiac atrophy. Cardiac energy metabolism is also impeded with disruption of mitochondrial homeostasis and reduced oxidative capacity, although the available data remain equivocal. The release of inflammatory cytokines by tumor is a key mechanism in the initiation of heart failure. Oxidative stress, which results from the combination of chemotherapy, inadequate antioxidant consumption and chronic inflammation, will further foster heart failure. Protein catabolism is due to the concomitant activation of proteolytic systems and inhibition of protein synthesis, both processes being triggered by the deactivation of the Akt/mammalian target of rapamycin pathway. The reduction in oxidative capacity involves AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1α dysregulation. The nuclear factor-κB transcription factor plays a prominent role in the coordination of these alterations. Physical exercise appears as an interesting non-pharmaceutical way to counteract cancer cachexia-induced-heart failure. Indeed, aerobic training has anti-inflammatory effects, increases anti-oxidant defenses, prevents atrophy and promotes oxidative metabolism. The present review points out the importance of better understanding the concurrent structural and metabolic changes within the myocardium during cancer and the protective effects of exercise against cardiac cachexia.

Emerging Cardiac Imaging Modalities for the Early Detection of Cardiotoxicity Due to Anticancer Therapies.

PubMed

López-Fernández, Teresa; Thavendiranathan, Paaladinesh

2017-06-01

The undeniable advances in the field of oncology have finally led to a decrease in overall cancer-related mortality. However, this population of long-term cancer survivors is now facing a shift toward a substantial increase in cardiovascular morbidity and mortality. Because the development of overt cardiotoxicity can be associated with poor outcomes, preclinical identification of cardiac toxicity is important. This will promote early instauration of treatments to prevent overt heart dysfunction and allow oncologists to continue cancer therapy in an uninterrupted manner. Surveillance strategies for the early detection of cardiac injury include cardiac imaging and biomarkers during treatment. In this review, we outline existing cardiac imaging modalities to detect myocardial changes in patients undergoing cancer treatment and in survivors, and their strengths and limitations. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

[Cardiac Anaesthesia: Anaesthesiological Management].

PubMed

Renner, Jochen; Bein, Berthold; Broch, Ole

2018-05-01

The anaesthesiological management of patients scheduled for cardiac surgery has been refined distinctively over the last decade due to different reasons. The continuing growth of the elderly patient population and the increasing number of combined cardiac surgery procedures in octogenarians on the one hand are one aspect. The rapid development of minimally invasive cardiac surgery and the enhancements in mechanical, artificial heart assist devices on the other hand can be seen as additional decisive factors. All of these innovations in the field of cardiac surgery implicate further enhancements regarding the anaesthesiological management. This review article addresses the following subareas of cardiac anaesthesia: significance of pharmacological myocardial protection, anaesthetic management during cardiopulmonary bypass, importance of "Enhanced Recovery After Cardiac Surgery"-protocols as well as innovations in the field of minimally invasive cardiac surgery like transcatheter aortic valve implantation. Georg Thieme Verlag KG Stuttgart · New York.

The papillary muscles as shock absorbers of the mitral valve complex. An experimental study.

PubMed

Joudinaud, Thomas M; Kegel, Corrine L; Flecher, Erwan M; Weber, Patricia A; Lansac, Emmanuel; Hvass, Ulrich; Duran, Carlos M G

2007-07-01

Although it is known that the papillary muscles ensure the continuity between the left ventricle (LV) and the mitral apparatus, their precise mechanism needs further study. We hypothesize that the papillary muscles function as shock absorbers to maintain a constant distance between their tips and the mitral annulus during the entire cardiac cycle. Sonomicrometry crystals were implanted in five sheep in the mitral annulus at the trigones (T1 and T2), mid anterior annulus (AA) mid posterior annulus (PA), base of the posterior lateral scallops (P1 and P2), tips of papillary muscles (M1 and M2), and LV apex. LV and aortic pressures were simultaneously recorded and used to define the different phases of the cardiac cycle. No significant distance changes were found during the cardiac cycle between each papillary muscle tip and their corresponding mitral hemi-annulus: M1-T1, (3.5+/-2%); M1-P1 (5+/-2%); M1-PA (5+/-3%); M2-T2 (2.7+/-2%); M2-P2 (6.1+/-3%); and M2-AA (4.2+/-3%); (p>0.05, ANOVA). Significant changes were observed in distances between each papillary muscle tip and the contralateral hemi-mitral annulus: M1-T2 (1.7+/-3%); M1-P2 (23+/-6%); M1-AA (6+/-3%); M2-T1 (8+/-3%); M2-P1 (10.5+/-6%); and M2-PA (12.6+/-8%); (p<0.05 ANOVA). The distance changes between LV apex and each papillary muscle tip were significantly different: apex-M1 (12.9+/-1%) and apex-M2 (10.5+/-1%) and different from the averaged distance change between the LV apex and each annulus crystal (8.3+/-1%) with p<0.05. The papillary muscles seem to be independent mechanisms designed to work as shock absorbers to maintain the basic mitral valve geometry constant during the cardiac cycle.

Long-term effects of brief hypoxia due to cardiac arrest: Hippocampal reductions and memory deficits.

PubMed

Stamenova, Vess; Nicola, Raneen; Aharon-Peretz, Judith; Goldsher, Dorith; Kapeliovich, Michael; Gilboa, Asaf

2018-05-01

To examine the effects of brief hypoxia (<7 min) due to cardiac arrest on the integrity of the brain and performance on memory and executive functions tasks. Patients after out-of-hospital cardiac arrest (CA) (n = 9), who were deemed neurologically intact on discharge, were compared to matched patients with myocardial infarction (MI) (n = 9). A battery of clinical and experimental memory and executive functions neuropsychological tests were administered and MRI scans for all patients were collected. Measures of subcortical and cortical volumes and cortical thickness were obtained using FreeSurfer. Manual segmentations of the hippocampus were also performed. APACHE-II scores were calculated based on metrics collected at admission to ICCU for all patients. Significant differences between the two groups were observed on several verbal memory tests. Both hippocampi were significantly reduced (p < 0.05) in the CA patients, relative to MI patients. Hippocampal subfields segmentation showed significantly reduced presubiculum volumes bilaterally. CA patients had on average 10% reduction in volumes bilaterally across hippocampal subfields. No cortical thickness differences survived correction. Significant correlations were observed in the CA group only between the hippocampal volumes and performance on verbal memory tasks, including recollection. Hippocampal volumes and several memory measures (but not other cognitive domains) were strongly correlated with APACHE-II scores on admission in the CA group, but not in the MI group CONCLUSIONS: Chronic patients with cardiac arrest who were discharged from hospital in "good neurological condition" showed an average of 10% reduction in hippocampal volume bilaterally and significant verbal memory deficits relative to matched controls with myocardial infarction, suggesting even brief hypoxic periods suffice to lead to specific hippocampal damage. Copyright © 2018 Elsevier B.V. All rights reserved.

Skeletal Muscle, but not Cardiovascular Function, Is Altered in a Mouse Model of Autosomal Recessive Hypophosphatemic Rickets.

PubMed

Wacker, Michael J; Touchberry, Chad D; Silswal, Neerupma; Brotto, Leticia; Elmore, Chris J; Bonewald, Lynda F; Andresen, Jon; Brotto, Marco

2016-01-01

Autosomal recessive hypophosphatemic rickets (ARHR) is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well-characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand in order to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL-fast-twitch muscle), soleus (SOL-slow-twitch muscle), heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum) which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2α or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In summary, these

Skeletal Muscle, but not Cardiovascular Function, Is Altered in a Mouse Model of Autosomal Recessive Hypophosphatemic Rickets

PubMed Central

Wacker, Michael J.; Touchberry, Chad D.; Silswal, Neerupma; Brotto, Leticia; Elmore, Chris J.; Bonewald, Lynda F.; Andresen, Jon; Brotto, Marco

2016-01-01

Autosomal recessive hypophosphatemic rickets (ARHR) is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well-characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand in order to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL-fast-twitch muscle), soleus (SOL–slow-twitch muscle), heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum) which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2α or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In summary

Inpatient cardiac rehabilitation programs' exercise therapy for patients undergoing cardiac surgery: National Korean Questionnaire Survey.

PubMed

Seo, Yong Gon; Jang, Mi Ja; Park, Won Hah; Hong, Kyung Pyo; Sung, Jidong

2017-02-01

Inpatient cardiac rehabilitation (ICR) has been commonly conducted after cardiac surgery in many countries, and has been reported a lots of results. However, until now, there is inadequacy of data on the status of ICR in Korea. This study described the current status of exercise therapy in ICR that is performed after cardiac surgery in Korean hospitals. Questionnaires modified by previous studies were sent to the departments of thoracic surgery of 10 hospitals in Korea. Nine replies (response rate 90%) were received. Eight nurses and one physiotherapist completed the questionnaire. Most of the education on wards after cardiac surgery was conducted by nurses. On postoperative day 1, four sites performed sitting on the edge of bed, sit to stand, up to chair, and walking in the ward. Only one site performed that exercise on postoperative day 2. One activity (stairs up and down) was performed on different days at only two sites. Patients received education preoperatively and predischarge for preventing complications and reducing muscle weakness through physical inactivity. The results of the study demonstrate that there are small variations in the general care provided by nurses after cardiac surgery. Based on the results of this research, we recommended that exercise therapy programs have to conduct by exercise specialists like exercise physiologists or physiotherapists for patients in hospitalization period.

The concerted movement of the switch region of Troponin I in cardiac muscle thin filaments as tracked by conventional and pulsed (DEER) EPR.

PubMed

Potluri, Phani R; Chamoun, Jean; Cooke, James A; Badr, Myriam; Guse, Joanna A; Rayes, Roni; Cordina, Nicole M; McCamey, Dane; Fajer, Piotr G; Brown, Louise J

2017-12-01

The absence of a crystal structure of the calcium free state of the cardiac isoform of the troponin complex has hindered our understanding of how the simple binding of Ca 2+ triggers conformational changes in troponin which are then propagated to enable muscle contraction. Here we have used continuous wave (CW) and Double Electron-Electron Resonance (DEER) pulsed EPR spectroscopy to measure distances between TnI and TnC to track the movement of the functionally important regulatory 'switch' region of cardiac Tn. Spin labels were placed on the switch region of Troponin I and distances measured to Troponin C. Under conditions of high Ca 2+ , the interspin distances for one set (TnI151/TnC84) were 'short' (9-10Å) with narrow distance distribution widths (3-8Å) indicating the close interaction of the switch region with the N-lobe of TnC. Additional spin populations representative of longer interspin distances were detected by DEER. These longer distance populations, which were ∼16-19Å longer than the short distance populations, possessed notably broader distance distribution widths (14-29Å). Upon Ca 2+ removal, the interspin population shifted toward the longer distances, indicating the release of the switch region from TnC and an overall increase in disorder for this region. Together, our results suggest that under conditions of low Ca 2+ , the close proximity of the TnI switch region to TnC in the cardiac isoform is necessary for promoting the interaction between the regulatory switch helix with the N-lobe of cardiac Troponin C, which, unlike the skeletal isoform, is largely in a closed conformation. Copyright © 2017 Elsevier Inc. All rights reserved.

Functional nonequality of the cardiac and skeletal ryanodine receptors.

PubMed

Nakai, J; Ogura, T; Protasi, F; Franzini-Armstrong, C; Allen, P D; Beam, K G

1997-02-04

Dihydropyridine receptors (DHPRs), which are voltage-gated Ca2+ channels, and ryanodine receptors (RyRs), which are intracellular Ca2+ release channels, are expressed in diverse cell types, including skeletal and cardiac muscle. In skeletal muscle, there appears to be reciprocal signaling between the skeletal isoforms of both the DHPR and the RyR (RyR-1), such that Ca2+ release activity of RyR-1 is controlled by the DHPR and Ca2+ channel activity of the DHPR is controlled by RyR-1. Dyspedic skeletal muscle cells, which do not express RyR-1, lack excitation-contraction coupling and have an approximately 30-fold reduction in L-type Ca2+ current density. Here we have examined the ability of the predominant cardiac and brain RyR isoform, RyR-2, to substitute for RyR-1 in interacting with the skeletal DHPR. When RyR-2 is expressed in dyspedic muscle cells, it gives rise to spontaneous intracellular Ca2+ oscillations and supports Ca2+ entry-induced Ca2+ release. However, unlike RyR-1, the expressed RyR-2 does not increase the Ca2+ channel activity of the DHPR, nor is the gating of RyR-2 controlled by the skeletal DHPR. Thus, the ability to participate in skeletal-type reciprocal signaling appears to be a unique feature of RyR-1.

Quantitative cardiac SPECT reconstruction with reduced image degradation due to patient anatomy

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

Tsui, B.M.W.; Zhao, X.D.; Gregoriou, G.K.

1994-12-01

Patient anatomy has complicated effects on cardiac SPECT images. The authors investigated reconstruction methods which substantially reduced these effects for improved image quality. A 3D mathematical cardiac-torso (MCAT) phantom which models the anatomical structures in the thorax region were used in the study. The phantom was modified to simulate variations in patient anatomy including regions of natural thinning along the myocardium, body size, diaphragmatic shape, gender, and size and shape of breasts for female patients. Distributions of attenuation coefficients and Tl-201 uptake in different organs in a normal patient were also simulated. Emission projection data were generated from the phantomsmore » including effects of attenuation and detector response. The authors have observed the attenuation-induced artifacts caused by patient anatomy in the conventional FBP reconstructed images. Accurate attenuation compensation using iterative reconstruction algorithms and attenuation maps substantially reduced the image artifacts and improved quantitative accuracy. They conclude that reconstruction methods which accurately compensate for non-uniform attenuation can substantially reduce image degradation caused by variations in patient anatomy in cardiac SPECT.« less

A-type potassium currents in smooth muscle.

PubMed

Amberg, Gregory C; Koh, Sang Don; Imaizumi, Yuji; Ohya, Susumu; Sanders, Kenton M

2003-03-01

A-type currents are voltage-gated, calcium-independent potassium (Kv) currents that undergo rapid activation and inactivation. Commonly associated with neuronal and cardiac cell-types, A-type currents have also been identified and characterized in vascular, genitourinary, and gastrointestinal smooth muscle cells. This review examines the molecular identity, biophysical properties, pharmacology, regulation, and physiological function of smooth muscle A-type currents. In general, this review is intended to facilitate the comparison of A-type currents present in different smooth muscles by providing a comprehensive report of the literature to date. This approach should also aid in the identification of areas of research requiring further attention.

Image reconstruction in higher dimensions: myocardial perfusion imaging of tracer dynamics with cardiac motion due to deformation and respiration

DOE PAGES

Shrestha, Uttam M.; Seo, Youngho; Botvinick, Elias H.; ...

2015-10-09

Myocardial perfusion imaging (MPI) using slow rotating large field of view cameras requires spatiotemporal reconstruction of dynamically acquired data to capture the time variation of the radiotracer concentration. In vivo, MPI contains additional degrees of freedom involving unavoidable motion of the heart due to quasiperiodic beating and the effects of respiration, which can severely degrade the quality of the images. This work develops a technique for a single photon emission computed tomography (SPECT) that reconstructs the distribution of the radiotracer concentration in the myocardium using a tensor product of different sets of basis functions that approximately describe the spatiotemporal variationmore » of the radiotracer concentration and the motion of the heart. In this study the temporal B-spline basis functions are chosen to reflect the dynamics of the radiotracer, while the intrinsic deformation and the extrinsic motion of the heart are described by a product of a discrete set of Gaussian basis functions. Reconstruction results are presented showing the dynamics of the tracer in the myocardium as it deforms due to cardiac beating, and is displaced due to respiratory motion. We find these results are compared with the conventional 4D-spatiotemporal reconstruction method that models only the temporal changes of the tracer activity. The higher dimensional reconstruction method proposed here improves bias, yet the signal-to-noise ratio (SNR) decreases slightly due to redistribution of the counts over the cardiac-respiratory gates. Finally, there is a trade-off between the number of gates and the number of projections per gate to achieve high contrast images.« less

Image reconstruction in higher dimensions: myocardial perfusion imaging of tracer dynamics with cardiac motion due to deformation and respiration

NASA Astrophysics Data System (ADS)

Shrestha, Uttam M.; Seo, Youngho; Botvinick, Elias H.; Gullberg, Grant T.

2015-11-01

Myocardial perfusion imaging (MPI) using slow rotating large field of view cameras requires spatiotemporal reconstruction of dynamically acquired data to capture the time variation of the radiotracer concentration. In vivo, MPI contains additional degrees of freedom involving unavoidable motion of the heart due to quasiperiodic beating and the effects of respiration, which can severely degrade the quality of the images. This work develops a technique for a single photon emission computed tomography (SPECT) that reconstructs the distribution of the radiotracer concentration in the myocardium using a tensor product of different sets of basis functions that approximately describe the spatiotemporal variation of the radiotracer concentration and the motion of the heart. In this study the temporal B-spline basis functions are chosen to reflect the dynamics of the radiotracer, while the intrinsic deformation and the extrinsic motion of the heart are described by a product of a discrete set of Gaussian basis functions. Reconstruction results are presented showing the dynamics of the tracer in the myocardium as it deforms due to cardiac beating, and is displaced due to respiratory motion. These results are compared with the conventional 4D-spatiotemporal reconstruction method that models only the temporal changes of the tracer activity. The higher dimensional reconstruction method proposed here improves bias, yet the signal-to-noise ratio (SNR) decreases slightly due to redistribution of the counts over the cardiac-respiratory gates. Additionally, there is a trade-off between the number of gates and the number of projections per gate to achieve high contrast images.

Image reconstruction in higher dimensions: myocardial perfusion imaging of tracer dynamics with cardiac motion due to deformation and respiration

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

Shrestha, Uttam M.; Seo, Youngho; Botvinick, Elias H.

Myocardial perfusion imaging (MPI) using slow rotating large field of view cameras requires spatiotemporal reconstruction of dynamically acquired data to capture the time variation of the radiotracer concentration. In vivo, MPI contains additional degrees of freedom involving unavoidable motion of the heart due to quasiperiodic beating and the effects of respiration, which can severely degrade the quality of the images. This work develops a technique for a single photon emission computed tomography (SPECT) that reconstructs the distribution of the radiotracer concentration in the myocardium using a tensor product of different sets of basis functions that approximately describe the spatiotemporal variationmore » of the radiotracer concentration and the motion of the heart. In this study the temporal B-spline basis functions are chosen to reflect the dynamics of the radiotracer, while the intrinsic deformation and the extrinsic motion of the heart are described by a product of a discrete set of Gaussian basis functions. Reconstruction results are presented showing the dynamics of the tracer in the myocardium as it deforms due to cardiac beating, and is displaced due to respiratory motion. We find these results are compared with the conventional 4D-spatiotemporal reconstruction method that models only the temporal changes of the tracer activity. The higher dimensional reconstruction method proposed here improves bias, yet the signal-to-noise ratio (SNR) decreases slightly due to redistribution of the counts over the cardiac-respiratory gates. Finally, there is a trade-off between the number of gates and the number of projections per gate to achieve high contrast images.« less

Image reconstruction in higher dimensions: myocardial perfusion imaging of tracer dynamics with cardiac motion due to deformation and respiration.

PubMed

Shrestha, Uttam M; Seo, Youngho; Botvinick, Elias H; Gullberg, Grant T

2015-11-07

Myocardial perfusion imaging (MPI) using slow rotating large field of view cameras requires spatiotemporal reconstruction of dynamically acquired data to capture the time variation of the radiotracer concentration. In vivo, MPI contains additional degrees of freedom involving unavoidable motion of the heart due to quasiperiodic beating and the effects of respiration, which can severely degrade the quality of the images. This work develops a technique for a single photon emission computed tomography (SPECT) that reconstructs the distribution of the radiotracer concentration in the myocardium using a tensor product of different sets of basis functions that approximately describe the spatiotemporal variation of the radiotracer concentration and the motion of the heart. In this study the temporal B-spline basis functions are chosen to reflect the dynamics of the radiotracer, while the intrinsic deformation and the extrinsic motion of the heart are described by a product of a discrete set of Gaussian basis functions. Reconstruction results are presented showing the dynamics of the tracer in the myocardium as it deforms due to cardiac beating, and is displaced due to respiratory motion. These results are compared with the conventional 4D-spatiotemporal reconstruction method that models only the temporal changes of the tracer activity. The higher dimensional reconstruction method proposed here improves bias, yet the signal-to-noise ratio (SNR) decreases slightly due to redistribution of the counts over the cardiac-respiratory gates. Additionally, there is a trade-off between the number of gates and the number of projections per gate to achieve high contrast images.

Influence of aging on the activity of mice Sca-1+CD31- cardiac stem cells.

PubMed

Wu, Qiong; Zhan, Jinxi; Pu, Shiming; Qin, Liu; Li, Yun; Zhou, Zuping

2017-01-03

Therapeutic application of cardiac resident stem/progenitor cells (CSC/CPCs) is limited due to decline of their regenerative potential with donor age. A variety of studies have shown that the cardiac aging was the problem of the stem cells, but little is known about the impact of age on the subgroups CSC/CPCs, the relationship between subgroups CSC/CPCs ageing and age-related dysfunction. Here, we studied Sca-1+CD31- subgroups of CSCs from younger(2~3months) and older(22~24months) age mice, biological differentiation was realized using specific mediums for 14 days to induce cardiomyocyte, smooth muscle cells or endothelial cells and immunostain analysis of differentiated cell resulting were done. Proliferation and cell cycle were measured by flow cytometry assay, then used microarray to dissect variability from younger and older mice. Although the number of CSCs was higher in older mice, the advanced age significantly reduced the differentiation ability into cardiac cell lineages and the proliferation ability. Transcriptional changes in Sca-1+CD31- subgroups of CSCs during aging are related to Vitamin B6 metabolism, circadian rhythm, Tyrosine metabolism, Complement and coagulation cascades. Taking together these results indicate that Cardiac resident stem/progenitor cells have significant differences in their proliferative, pluripotency and gene profiles and those differences are age depending.

Electrostimulation of muscles as a method for the treatment and prophylaxis of hemodynamic disturbances during prolonged hypokinesia

NASA Technical Reports Server (NTRS)

Dukhin, Y. O.; Zhukovskyy, L. Y.

1980-01-01

Hemodynamic and periopheral circulation indexes were recorded before, at the end of, and 5 days after 10 days of electrostimulation for 45 min daily, at rest and after a physical loading test. It was found that stroke and minute volume, cardiac output, and regional circulation improved and heart rate and peripheral resistance decreased. The functional state of the cardiac muscle and vascular tone are improved by electrostimulation of selected groups of skeletal muscles.

General anesthesia in cardiac surgery: a review of drugs and practices.

PubMed

Alwardt, Cory M; Redford, Daniel; Larson, Douglas F

2005-06-01

General anesthesia is defined as complete anesthesia affecting the entire body with loss of consciousness, analgesia, amnesia, and muscle relaxation. There is a wide spectrum of agents able to partially or completely induce general anesthesia. Presently, there is not a single universally accepted technique for anesthetic management during cardiac surgery. Instead, the drugs and combinations of drugs used are derived from the pathophysiologic state of the patient and individual preference and experience of the anesthesiologist. According to the definition of general anesthesia, current practices consist of four main components: hypnosis, analgesia, amnesia, and muscle relaxation. Although many of the agents highlighted in this review are capable of producing more than one of these effects, it is logical that drugs producing these effects are given in combination to achieve the most beneficial effect. This review features a discussion of currently used anesthetic drugs and clinical practices of general anesthesia during cardiac surgery. The information in this particular review is derived from textbooks, current literature, and personal experience, and is designed as a general overview of anesthesia during cardiac surgery.

Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

NASA Astrophysics Data System (ADS)

Gulick, Tod; Chung, Mina K.; Pieper, Stephen J.; Lange, Louis G.; Schreiner, George F.

1989-09-01

Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.

Clonal analysis reveals a common origin between nonsomite-derived neck muscles and heart myocardium

PubMed Central

Lescroart, Fabienne; Hamou, Wissam; Francou, Alexandre; Théveniau-Ruissy, Magali; Kelly, Robert G.; Buckingham, Margaret

2015-01-01

Neck muscles constitute a transition zone between somite-derived skeletal muscles of the trunk and limbs, and muscles of the head, which derive from cranial mesoderm. The trapezius and sternocleidomastoid neck muscles are formed from progenitor cells that have expressed markers of cranial pharyngeal mesoderm, whereas other muscles in the neck arise from Pax3-expressing cells in the somites. Mef2c-AHF-Cre genetic tracing experiments and Tbx1 mutant analysis show that nonsomitic neck muscles share a gene regulatory network with cardiac progenitor cells in pharyngeal mesoderm of the second heart field (SHF) and branchial arch-derived head muscles. Retrospective clonal analysis shows that this group of neck muscles includes laryngeal muscles and a component of the splenius muscle, of mixed somitic and nonsomitic origin. We demonstrate that the trapezius muscle group is clonally related to myocardium at the venous pole of the heart, which derives from the posterior SHF. The left clonal sublineage includes myocardium of the pulmonary trunk at the arterial pole of the heart. Although muscles derived from the first and second branchial arches also share a clonal relationship with different SHF-derived parts of the heart, neck muscles are clonally distinct from these muscles and define a third clonal population of common skeletal and cardiac muscle progenitor cells within cardiopharyngeal mesoderm. By linking neck muscle and heart development, our findings highlight the importance of cardiopharyngeal mesoderm in the evolution of the vertebrate heart and neck and in the pathophysiology of human congenital disease. PMID:25605943

Clonal analysis reveals a common origin between nonsomite-derived neck muscles and heart myocardium.

PubMed

Lescroart, Fabienne; Hamou, Wissam; Francou, Alexandre; Théveniau-Ruissy, Magali; Kelly, Robert G; Buckingham, Margaret

2015-02-03

Neck muscles constitute a transition zone between somite-derived skeletal muscles of the trunk and limbs, and muscles of the head, which derive from cranial mesoderm. The trapezius and sternocleidomastoid neck muscles are formed from progenitor cells that have expressed markers of cranial pharyngeal mesoderm, whereas other muscles in the neck arise from Pax3-expressing cells in the somites. Mef2c-AHF-Cre genetic tracing experiments and Tbx1 mutant analysis show that nonsomitic neck muscles share a gene regulatory network with cardiac progenitor cells in pharyngeal mesoderm of the second heart field (SHF) and branchial arch-derived head muscles. Retrospective clonal analysis shows that this group of neck muscles includes laryngeal muscles and a component of the splenius muscle, of mixed somitic and nonsomitic origin. We demonstrate that the trapezius muscle group is clonally related to myocardium at the venous pole of the heart, which derives from the posterior SHF. The left clonal sublineage includes myocardium of the pulmonary trunk at the arterial pole of the heart. Although muscles derived from the first and second branchial arches also share a clonal relationship with different SHF-derived parts of the heart, neck muscles are clonally distinct from these muscles and define a third clonal population of common skeletal and cardiac muscle progenitor cells within cardiopharyngeal mesoderm. By linking neck muscle and heart development, our findings highlight the importance of cardiopharyngeal mesoderm in the evolution of the vertebrate heart and neck and in the pathophysiology of human congenital disease.

Angiotensin II promotes differentiation of mouse c-kit-positive cardiac stem cells into pacemaker-like cells

PubMed Central

XUE, CHENG; ZHANG, JUN; LV, ZHAN; LIU, HUI; HUANG, CONGXIN; YANG, JING; WANG, TEN

2015-01-01

Cardiac stem cells (CSCs) can differentiate into cardiac muscle-like cells; however, it remains unknown whether CSCs may possess the ability to differentiate into pacemaker cells. The aim of the present study was to determine whether angiotensin II (Ang II) could promote the specialization of CSCs into pacemaker-like cells. Mouse CSCs were treated with Ang II from day 3–5, after cell sorting. The differentiation potential of the cells was then analyzed by morphological analysis, flow cytometry, reverse transcription-polymerase chain reaction, immunohistochemistry and patch clamp analysis. Treatment with Ang II resulted in an increased number of cardiac muscle-like cells (32.7±4.8% vs. 21.5±4.8%; P<0.05), and inhibition of smooth muscle-like cells (6.2±7.3% vs. 20.5±5.1%; P<0.05). Following treatment with Ang II, increased levels of the cardiac progenitor-specific markers GATA4 and Nkx2.5 were observed in the cells. Furthermore, the transcript levels of pacemaker function-related genes, including hyperpolarization-activated cyclic nucleotide-gated (HCN)2, HCN4, T-box (Tbx)2 and Tbx3, were significantly upregulated. Immunofluorescence analysis confirmed the increased number of pacemaker-like cells. The pacemaker current (If) was recorded in the cells derived from CSCs, treated with Ang II. In conclusion, treatment of CSCs with Ang II during the differentiation process modified cardiac-specific gene expression and resulted in the enhanced formation of pacemaker-like cells. PMID:25572000

Pay attention to cardiac remodeling in cancer cachexia.

PubMed

Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

2016-07-01

Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival.

The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation

PubMed Central

Whitnall, Megan; Rahmanto, Yohan Suryo; Sutak, Robert; Xu, Xiangcong; Becker, Erika M.; Mikhael, Marc R.; Ponka, Prem; Richardson, Des R.

2008-01-01

There is no effective treatment for the cardiomyopathy of the most common autosomal recessive ataxia, Friedreich's ataxia (FA). The identification of potentially toxic mitochondrial (MIT) iron (Fe) deposits in FA suggests that Fe plays a role in its pathogenesis. This study used the muscle creatine kinase conditional frataxin (Fxn) knockout (mutant) mouse model that reproduces the classical traits associated with cardiomyopathy in FA. We examined the mechanisms responsible for the increased cardiac MIT Fe loading in mutants. Moreover, we explored the effect of Fe chelation on the pathogenesis of the cardiomyopathy. Our investigation showed that increased MIT Fe in the myocardium of mutants was due to marked transferrin Fe uptake, which was the result of enhanced transferrin receptor 1 expression. In contrast to the mitochondrion, cytosolic ferritin expression and the proportion of cytosolic Fe were decreased in mutant mice, indicating cytosolic Fe deprivation and markedly increased MIT Fe targeting. These studies demonstrated that loss of Fxn alters cardiac Fe metabolism due to pronounced changes in Fe trafficking away from the cytosol to the mitochondrion. Further work showed that combining the MIT-permeable ligand pyridoxal isonicotinoyl hydrazone with the hydrophilic chelator desferrioxamine prevented cardiac Fe loading and limited cardiac hypertrophy in mutants but did not lead to overt cardiac Fe depletion or toxicity. Fe chelation did not prevent decreased succinate dehydrogenase expression in the mutants or loss of cardiac function. In summary, we show that loss of Fxn markedly alters cellular Fe trafficking and that Fe chelation limits myocardial hypertrophy in the mutant. PMID:18621680

FET-biosensor for cardiac troponin biomarker

NASA Astrophysics Data System (ADS)

Arshad, Mohd Khairuddin Md; Faris Mohamad Fathil, Mohamad; Hashim, Uda

2017-11-01

Acute myocardial infarction or myocardial infarction (MI) is a major health problem, due to diminished flow of blood to the heart, leads to higher rates of mortality and morbidity. The most specific markers for cardiac injury are cardiac troponin I (cTnI) and cardiac troponin T (cTnT) which have been considered as `gold standard'. Due to higher specificity, determination of the level of cardiac troponins became a predominant indicator for MI. Currently, field-effect transistor (FET)-based biosensors have been main interest to be implemented in portable sensors with the ultimate application in point-of-care testing (POCT). In this paper, we review on the FET-based biosensor based on its principle of operation, integration with nanomaterial, surface functionalization as well as immobilization, and the introduction of additional gate (for ambipolar conduction) on the device architecture for the detection of cardiac troponin I (cTnI) biomarker.

Recurrent aborted sudden cardiac death with seizures and rhabdomyolysis due to bulimia-induced hypokalemia: report of one case.

PubMed

Finsterer, Josef; Stöllberger, Claudia

2014-06-01

Recurrent vomiting due to bulimia associated with abuse of furosemide and laxatives causing severe hypokalemia may result in recurrent aborted sudden cardiac death (SCD) and seizures. We report a 25-year-old female with a history of bulimia associated with abuse of furosemide and laxatives since the age of 15 years, migraine since puberty, renal abscesses at age 20 y, and rhabdomyolysis of unknown cause at age 24 y. She experienced aborted SCD due to severe hypokalemia with symptomatic seizures at 21 and 25 years of age. Bulimia patients additionally taking laxatives or furosemide are at particular risk of SCD and rhabdomyolysis and require periodic determination of electrolytes, potassium substitution, and adequate psychiatric therapy and surveillance.

Enhanced Skeletal Muscle Expression of EcSOD Mitigates Streptozotocin-Induced Diabetic Cardiomyopathy by Reducing Oxidative Stress and Aberrant Cell Signaling

PubMed Central

Call, Jarrod A.; Chain, Kristopher H.; Martin, Kyle S.; Lira, Vitor A.; Okutsu, Mitsuharu; Zhang, Mei; Yan, Zhen

2015-01-01

Background Exercise training enhances extracellular superoxide dismutase (EcSOD) expression in skeletal muscle and elicits positive health outcomes in individuals with diabetes. The goal of this study was to determine if enhanced skeletal muscle expression of EcSOD is sufficient to mitigate streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM). Methods and Results Exercise training promotes EcSOD expression in skeletal muscle and provides protection against DCM; however, it is not known if enhanced EcSOD expression in skeletal muscle plays a functional role in this protection. Here, we show that skeletal muscle-specific EcSOD transgenic mice (TG) are protected from cardiac hypertrophy, fibrosis and dysfunction under the condition of type-1 diabetes induced by STZ injection. We also show that both exercise training and muscle-specific transgenic expression of EcSOD result in elevated EcSOD protein in the blood and heart without increased transcription in the heart, suggesting enhanced expression of EcSOD from skeletal muscle redistributes to the heart. Importantly, cardiac tissue in TG mice displayed significantly reduced oxidative stress, aberrant cell signaling and inflammatory cytokine expression compared with wild type mice under the same diabetic condition. Conclusions Enhanced expression of EcSOD in skeletal muscle is sufficient to mitigate STZ-induced DCM through attenuation of oxidative stress, aberrant cell signaling and inflammation, suggesting a cross-organ mechanism by which exercise training improves cardiac function in diabetes. PMID:25504759

Assessment of cardiac function using myocardial perfusion imaging technique on SPECT with 99mTc sestamibi

NASA Astrophysics Data System (ADS)

Gani, M. R. A.; Nazir, F.; Pawiro, S. A.; Soejoko, D. S.

2016-03-01

Suspicion on coronary heart disease can be confirmed by observing the function of left ventricle cardiac muscle with Myocardial Perfusion Imaging techniques. The function perfusion itself is indicated by the uptake of radiopharmaceutical tracer. The 31 patients were studied undergoing the MPI examination on Gatot Soebroto Hospital using 99mTc-sestamibi radiopharmaceutical with stress and rest conditions. Stress was stimulated by physical exercise or pharmacological agent. After two hours, the patient did rest condition on the same day. The difference of uptake percentage between stress and rest conditions will be used to determine the malfunction of perfusion due to ischemic or infarct. Degradation of cardiac function was determined based on the image-based assessment of five segments of left ventricle cardiac. As a result, 8 (25.8%) patients had normal myocardial perfusion and 11 (35.5%) patients suspected for having partial ischemia. Total ischemia occurred to 8 (25.8%) patients with reversible and irreversible ischemia and the remaining 4 (12.9%) patients for partial infarct with characteristic the percentage of perfusion ≤50%. It is concluded that MPI technique of image-based assessment on uptake percentage difference between stress and rest conditions can be employed to predict abnormal perfusion as complementary information to diagnose the cardiac function.

Cardiac-Biology-In-Space

NASA Image and Video Library

2017-08-21

Astronauts experience structural changes to their heart during long-duration spaceflight, but the biological basis of that is not clearly understood. Jonathon Baio, a doctoral student at Loma Linda University’s School of Medicine, details an investigation of cardiovascular stem cells that hopes to better understand their role in cardiac biology and tissue regeneration, which could advance ways to maintain cardiac health of astronauts during extended missions as well inform future treatments to reverse heart muscle loss upon return to Earth, and may help the medical community combat cardiovascular disease, one of the world’s leading causes of death. For more on space station science, please visit: Twitter: https://twitter.com/ISS_Research or @ISS_research Website: https://www.nasa.gov/mission_pages/station/research/index.html _______________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/

Cardiac Ochronosis

PubMed Central

Erek, Ersin; Casselman, Filip P.A.; Vanermen, Hugo

2004-01-01

We report the case of 67-year-old woman who underwent aortic valve replacement and mitral valve repair due to ochronotic valvular disease (alkaptonuria), which was diagnosed incidentally during cardiac surgery. PMID:15745303

CARFMAP: A Curated Pathway Map of Cardiac Fibroblasts.

PubMed

Nim, Hieu T; Furtado, Milena B; Costa, Mauro W; Kitano, Hiroaki; Rosenthal, Nadia A; Boyd, Sarah E

2015-01-01

The adult mammalian heart contains multiple cell types that work in unison under tightly regulated conditions to maintain homeostasis. Cardiac fibroblasts are a significant and unique population of non-muscle cells in the heart that have recently gained substantial interest in the cardiac biology community. To better understand this renaissance cell, it is essential to systematically survey what has been known in the literature about the cellular and molecular processes involved. We have built CARFMAP (http://visionet.erc.monash.edu.au/CARFMAP), an interactive cardiac fibroblast pathway map derived from the biomedical literature using a software-assisted manual data collection approach. CARFMAP is an information-rich interactive tool that enables cardiac biologists to explore the large body of literature in various creative ways. There is surprisingly little overlap between the cardiac fibroblast pathway map, a foreskin fibroblast pathway map, and a whole mouse organism signalling pathway map from the REACTOME database. Among the use cases of CARFMAP is a common task in our cardiac biology laboratory of identifying new genes that are (1) relevant to cardiac literature, and (2) differentially regulated in high-throughput assays. From the expression profiles of mouse cardiac and tail fibroblasts, we employed CARFMAP to characterise cardiac fibroblast pathways. Using CARFMAP in conjunction with transcriptomic data, we generated a stringent list of six genes that would not have been singled out using bioinformatics analyses alone. Experimental validation showed that five genes (Mmp3, Il6, Edn1, Pdgfc and Fgf10) are differentially regulated in the cardiac fibroblast. CARFMAP is a powerful tool for systems analyses of cardiac fibroblasts, facilitating systems-level cardiovascular research.

MCAT elements and the TEF-1 family of transcription factors in muscle development and disease.

PubMed

Yoshida, Tadashi

2008-01-01

MCAT elements are located in the promoter-enhancer regions of cardiac, smooth, and skeletal muscle-specific genes including cardiac troponin T, beta-myosin heavy chain, smooth muscle alpha-actin, and skeletal alpha-actin, and play a key role in the regulation of these genes during muscle development and disease. The binding factors of MCAT elements are members of the transcriptional enhancer factor-1 (TEF-1) family. However, it has not been fully understood how these transcription factors confer cell-specific expression in muscle, because their expression patterns are relatively broad. Results of recent studies revealed multiple mechanisms whereby TEF-1 family members control MCAT element-dependent muscle-specific gene expression, including posttranslational modifications of TEF-1 family members, the presence of muscle-selective TEF-1 cofactors, and cell-selective control of TEF-1 accessibility to MCAT elements. In addition, of particular interest, recent studies regarding MCAT element-dependent transcription of the myocardin gene and the smooth muscle alpha-actin gene in muscle provide evidence for the transcriptional diversity among distinct cell types and subtypes. This article summarizes the role of MCAT elements and the TEF-1 family of transcription factors in muscle development and disease, and reviews recent progress in our understanding of the transcriptional regulatory mechanisms involved in MCAT element-dependent muscle-specific gene expression.

MicroRNA-133 mediates cardiac diseases: Mechanisms and clinical implications

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

Liu, Yi; Liang, Yan; Zhang, Jin-fang

MicroRNAs (miRNAs) belong to the family of small non-coding RNAs that mediate gene expression by post-transcriptional regulation. Increasing evidence have demonstrated that miR-133 is enriched in muscle tissues and myogenic cells, and its aberrant expression could induce the occurrence and development of cardiac disorders, such as cardiac hypertrophy, heart failure, etc. In this review, we summarized the regulatory roles of miR-133 in cardiac disorders and the underlying mechanisms, which suggest that miR-133 may be a potential diagnostic and therapeutic tool for cardiac disorders. - Highlights: • miR-218 is frequently downregulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis.more » • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways.« less

MicroRNA-327 regulates cardiac hypertrophy and fibrosis induced by pressure overload.

PubMed

Ji, Yue; Qiu, Ming; Shen, Yejiao; Gao, Li; Wang, Yaqing; Sun, Wei; Li, Xinli; Lu, Yan; Kong, Xiangqing

2018-04-01

MicroRNA (miRNA/miR) dysregulation has been reported to be fundamental in the development and progression of cardiac hypertrophy and fibrosis. In the present study, miR-327 levels in fibroblasts were increased in response to cardiac hypertrophy induced by transverse aortic constriction with prominent cardiac fibrosis, particularly when compared with the levels in unstressed cardiomyocytes. In neonatal rat cardiac fibroblasts, induced expression of miR-327 upregulated fibrosis-associated gene expression and activated angiotensin II-induced differentiation into myofibroblasts, as assessed via α-smooth muscle actin staining. By contrast, miR-327 knockdown mitigated angiotensin II-induced differentiation. Cardiac fibroblast proliferation was not affected under either condition. In a mouse model subjected to transverse aortic constriction, miR-327 knockdown through tail-vein injection reduced the development of cardiac fibrosis and ventricular dysfunction. miR-327 was demonstrated to target integrin β3 and diminish the activation of cardiac fibroblasts. Thus, the present study supports the use of miR-327 as a therapeutic target in the reduction of cardiac fibrosis.

Cardiac rehabilitation improves coronary endothelial function in patients with heart failure due to dilated cardiomyopathy: A positron emission tomography study.

PubMed

Legallois, Damien; Belin, Annette; Nesterov, Sergey V; Milliez, Paul; Parienti, J-J; Knuuti, Juhani; Abbas, Ahmed; Tirel, Olivier; Agostini, Denis; Manrique, Alain

2016-01-01

Endothelial dysfunction is common in patients with heart failure and is associated with poor clinical outcome. Cardiac rehabilitation is able to enhance peripheral endothelial function but its impact on coronary vasomotion remains unknown. We aimed to evaluate the effect of cardiac rehabilitation on coronary vasomotion in patients with heart failure. We prospectively enrolled 29 clinically stable heart failure patients from non-ischaemic dilated cardiomyopathy and without coronary risk factors. Myocardial blood flow was quantified using (15)-O water positron emission tomography at rest and during a cold pressor test, before and after 12 weeks of cardiac rehabilitation and optimization of medical therapy. Rest myocardial blood flow was significantly improved after the completion of rehabilitation compared to baseline (1.31 ± 0.38 mL/min/g vs. 1.16 ± 0.41 mL/min/g, p = 0.04). The endothelium-related change in myocardial blood flow from rest to cold pressor test and the percentage of myocardial blood flow increase during the cold pressor test were both significantly improved after cardiac rehabilitation (respectively from -0.03 ± 0.22 mL/min/g to 0.19 ± 0.22 mL/min/g, p < 0.001 and from 101.5 ± 16.5% to 118.3 ± 24.4%, p < 0.001). Left ventricular ejection fraction, plasma levels of brain natriuretic peptide, maximal oxygen consumption and the Minnesota Living with Heart Failure Questionnaire score were also significantly improved. The improvement was not related to uptitration of medical therapy. Coronary endothelial function is altered in patients with heart failure due to non-ischaemic dilated cardiomyopathy. In these patients, cardiac rehabilitation significantly improves coronary vasomotion. © The European Society of Cardiology 2014.

Mechanical Properties of Respiratory Muscles

PubMed Central

Sieck, Gary C.; Ferreira, Leonardo F.; Reid, Michael B.; Mantilla, Carlos B.

2014-01-01

Striated respiratory muscles are necessary for lung ventilation and to maintain the patency of the upper airway. The basic structural and functional properties of respiratory muscles are similar to those of other striated muscles (both skeletal and cardiac). The sarcomere is the fundamental organizational unit of striated muscles and sarcomeric proteins underlie the passive and active mechanical properties of muscle fibers. In this respect, the functional categorization of different fiber types provides a conceptual framework to understand the physiological properties of respiratory muscles. Within the sarcomere, the interaction between the thick and thin filaments at the level of cross-bridges provides the elementary unit of force generation and contraction. Key to an understanding of the unique functional differences across muscle fiber types are differences in cross-bridge recruitment and cycling that relate to the expression of different myosin heavy chain isoforms in the thick filament. The active mechanical properties of muscle fibers are characterized by the relationship between myoplasmic Ca2+ and cross-bridge recruitment, force generation and sarcomere length (also cross-bridge recruitment), external load and shortening velocity (cross-bridge cycling rate), and cross-bridge cycling rate and ATP consumption. Passive mechanical properties are also important reflecting viscoelastic elements within sarcomeres as well as the extracellular matrix. Conditions that affect respiratory muscle performance may have a range of underlying pathophysiological causes, but their manifestations will depend on their impact on these basic elemental structures. PMID:24265238

M-cadherin and its sisters in development of striated muscle.

PubMed

Kaufmann, U; Martin, B; Link, D; Witt, K; Zeitler, R; Reinhard, S; Starzinski-Powitz, A

1999-04-01

Cadherins are calcium-dependent, transmembrane intercellular adhesion proteins with morphoregulatory functions in the development and maintenance of tissues. In the development of striated muscle, the expression and function of mainly M-, N-, and R-cadherin has been studied so far. While these three cadherins are expressed in skeletal muscle cells, of these only N-cadherin is expressed in cardiac muscle. In this review, M-, N-, and R-cadherin are discussed as important players in the terminal differentiation and possibly also in the commitment of skeletal muscle cells. Furthermore, reports are described which evaluate the essential role of N-cadherin in the formation of heart tissue.

Double muscling in cattle due to mutations in the myostatin gene

PubMed Central

McPherron, Alexandra C.; Lee, Se-Jin

1997-01-01

Myostatin (GDF-8) is a member of the transforming growth factor β superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals. PMID:9356471

Isometric exercise: cardiovascular responses in normal and cardiac populations.

PubMed

Hanson, P; Nagle, F

1987-05-01

Isometric exercise produces a characteristic pressor increase in blood pressure which may be important in maintaining perfusion of muscle during sustained contraction. This response is mediated by combined central and peripheral afferent input to medullary cardiovascular centers. In normal individuals the increase in blood pressure is mediated by a rise in cardiac output with little or no change in systemic vascular resistance. However, the pressor response is also maintained during pharmacologic blockade or surgical denervation by increasing systemic vascular resistance. Left ventricular function is normally maintained or improves in normal subjects and cardiac patients with mild impairment of left ventricular contractility. Patients with poor left ventricular function may show deterioration during isometric exercise, although this pattern of response is difficult to predict from resting studies. Recent studies have shown that patients with uncomplicated myocardial infarction can perform submaximum isometric exercise such as carrying weights in the range of 30 to 50 lb without difficulty or adverse responses. In addition, many patients who show ischemic ST depression or angina during dynamic exercise may have a reduced ischemic response during isometric or combined isometric and dynamic exercise. Isometric exercises are frequently encountered in activities of daily living and many occupational tasks. Cardiac patients should be gradually exposed to submaximum isometric training in supervised cardiac rehabilitation programs. Specific job tasks that require isometric or combined isometric and dynamic activities may be evaluated by work simulation studies. This approach to cardiac rehabilitation may facilitate patients who wish to return to a job requiring frequent isometric muscle contraction. Finally, there is a need for additional research on the long-term effects of isometric exercise training on left ventricular hypertrophy and performance. The vigorous training

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.

Upper-body progressive resistance training improves strength and household physical activity performance in women attending cardiac rehabilitation.

PubMed

Coke, Lola A; Staffileno, Beth A; Braun, Lynne T; Gulanick, Meg

2008-01-01

The purpose of this study was to examine the impact of moderate-intensity, progressive, upper-body resistance training (RT) on muscle strength and perceived performance of household physical activities (HPA) among women in cardiac rehabilitation. The 10-week, pretest-posttest, experiment randomized women to either usual care (UC) aerobic exercise or RT. Muscle strength for 5 upper-body RT exercises (chest press, shoulder press, biceps curl, lateral row, and triceps extension) was measured using the 1-Repetition Maximum Assessment. The RT group progressively increased weight lifted using 40%, 50%, and 60% of obtained 1-Repetition Maximum Assessment at 3-week intervals. Perceived performance of HPA was measured with the Kimble Household Activities Scale. The RT group (n = 16, mean age 64 +/- 11) significantly increased muscle strength in all 5 exercises in comparison with the UC group (n = 14, mean age 65 +/- 10) (chest press, 18% vs 11%; shoulder press, 24% vs 14%; biceps curl, 21% vs 12%; lateral row, 32% vs 9%; and triceps extension, 28% vs 20%, respectively). By study end, Household Activities Scale scores significantly increased (F = 13.878, P = .001) in the RT group (8.75 +/- 3.19 vs 11.25 +/- 2.14), whereas scores in the UC group decreased (8.60 +/- 3.11 vs 6.86 +/- 4.13). Progressive upper-body RT in women shows promise as an effective tool to increase muscle strength and improve the ability to perform HPA after a cardiac event. Beginning RT early after a cardiac event in a monitored cardiac rehabilitation environment can maximize the strengthening benefit.

Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.

PubMed

Hinze, Florian; Dieterich, Christoph; Radke, Michael H; Granzier, Henk; Gotthardt, Michael

2016-12-01

Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction. Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction.

Loss of Notch3 Signaling in Vascular Smooth Muscle Cells Promotes Severe Heart Failure Upon Hypertension.

PubMed

Ragot, Hélène; Monfort, Astrid; Baudet, Mathilde; Azibani, Fériel; Fazal, Loubina; Merval, Régine; Polidano, Evelyne; Cohen-Solal, Alain; Delcayre, Claude; Vodovar, Nicolas; Chatziantoniou, Christos; Samuel, Jane-Lise

2016-08-01

Hypertension, which is a risk factor of heart failure, provokes adaptive changes at the vasculature and cardiac levels. Notch3 signaling plays an important role in resistance arteries by controlling the maturation of vascular smooth muscle cells. Notch3 deletion is protective in pulmonary hypertension while deleterious in arterial hypertension. Although this latter phenotype was attributed to renal and cardiac alterations, the underlying mechanisms remained unknown. To investigate the role of Notch3 signaling in the cardiac adaptation to hypertension, we used mice with either constitutive Notch3 or smooth muscle cell-specific conditional RBPJκ knockout. At baseline, both genotypes exhibited a cardiac arteriolar rarefaction associated with oxidative stress. In response to angiotensin II-induced hypertension, the heart of Notch3 knockout and SM-RBPJκ knockout mice did not adapt to pressure overload and developed heart failure, which could lead to an early and fatal acute decompensation of heart failure. This cardiac maladaptation was characterized by an absence of media hypertrophy of the media arteries, the transition of smooth muscle cells toward a synthetic phenotype, and an alteration of angiogenic pathways. A subset of mice exhibited an early fatal acute decompensated heart failure, in which the same alterations were observed, although in a more rapid timeframe. Altogether, these observations indicate that Notch3 plays a major role in coronary adaptation to pressure overload. These data also show that the hypertrophy of coronary arterial media on pressure overload is mandatory to initially maintain a normal cardiac function and is regulated by the Notch3/RBPJκ pathway. © 2016 American Heart Association, Inc.

Task Failure during Exercise to Exhaustion in Normoxia and Hypoxia Is Due to Reduced Muscle Activation Caused by Central Mechanisms While Muscle Metaboreflex Does Not Limit Performance

PubMed Central

Torres-Peralta, Rafael; Morales-Alamo, David; González-Izal, Miriam; Losa-Reyna, José; Pérez-Suárez, Ismael; Izquierdo, Mikel; Calbet, José A. L.

2016-01-01

To determine whether task failure during incremental exercise to exhaustion (IE) is principally due to reduced neural drive and increased metaboreflex activation eleven men (22 ± 2 years) performed a 10 s control isokinetic sprint (IS; 80 rpm) after a short warm-up. This was immediately followed by an IE in normoxia (Nx, PIO2:143 mmHg) and hypoxia (Hyp, PIO2:73 mmHg) in random order, separated by a 120 min resting period. At exhaustion, the circulation of both legs was occluded instantaneously (300 mmHg) during 10 or 60 s to impede recovery and increase metaboreflex activation. This was immediately followed by an IS with open circulation. Electromyographic recordings were obtained from the vastus medialis and lateralis. Muscle biopsies and blood gases were obtained in separate experiments. During the last 10 s of the IE, pulmonary ventilation, VO2, power output and muscle activation were lower in hypoxia than in normoxia, while pedaling rate was similar. Compared to the control sprint, performance (IS-Wpeak) was reduced to a greater extent after the IE-Nx (11% lower P < 0.05) than IE-Hyp. The root mean square (EMGRMS) was reduced by 38 and 27% during IS performed after IE-Nx and IE-Hyp, respectively (Nx vs. Hyp: P < 0.05). Post-ischemia IS-EMGRMS values were higher than during the last 10 s of IE. Sprint exercise mean (IS-MPF) and median (IS-MdPF) power frequencies, and burst duration, were more reduced after IE-Nx than IE-Hyp (P < 0.05). Despite increased muscle lactate accumulation, acidification, and metaboreflex activation from 10 to 60 s of ischemia, IS-Wmean (+23%) and burst duration (+10%) increased, while IS-EMGRMS decreased (−24%, P < 0.05), with IS-MPF and IS-MdPF remaining unchanged. In conclusion, close to task failure, muscle activation is lower in hypoxia than in normoxia. Task failure is predominantly caused by central mechanisms, which recover to great extent within 1 min even when the legs remain ischemic. There is dissociation between the

Liquiritigenin attenuates cardiac injury induced by high fructose-feeding through fibrosis and inflammation suppression.

PubMed

Xie, Xiong-Wei

2017-02-01

Diabetes combined with cardiomyopathy is considered as an essential complication, showing diastolic persistently and causing cardiac injury, which is linked to fibrosis progression and inflammation response. Fibrosis and inflammation response are two markers for cardiomyopathy. Liquiritigenin is a flavanone, isolated from Radix glycyrrhiza, which exhibits various biological properties, including anti-cancer and anti-inflammatory activities. Here, in our study, the protective effects and anti-inflammatory activity of liquiritigenin were explored in mice and cardiac muscle cells treated by fructose to reveal the possible mechanism by which liquiritigenin attenuates cardiac injury. The mice were separated into five groups. The diabetic model of mouse was established with 30% high fructose feeding. Liquiritigenin dramatically reduced the lipid accumulation induced by high fructose diet. Compared to mice only treated with high fructose, mice in the presence of liquiritigenin after fructose feeding developed less cardiac fibrosis with lower levels of alpha smooth muscle-actin (α-SMA), Collagen type I, Collagen type II, TGF-β1 and Procol1a1. Additionally, liquiritigenin markedly down-regulated inflammatory cytokines secretion and phosphorylated NF-κB via inhibiting IKKα/IκBα signaling pathway. Our results indicate that liquiritigenin has a protective role in high fructose feeding-triggered cardiac injury through fibrosis and inflammation response suppression by inactivating NF-κB signaling pathway. Thus, liquiritigenin may be a potential candidate for diabetes-associated cardiac injury. Copyright © 2016. Published by Elsevier Masson SAS.

Muscle Activation During Peripheral Nerve Field Stimulation Occurs Due to Recruitment of Efferent Nerve Fibers, Not Direct Muscle Activation.

PubMed

Frahm, Ken Steffen; Hennings, Kristian; Vera-Portocarrero, Louis; Wacnik, Paul W; Mørch, Carsten Dahl

2016-08-01

Peripheral nerve field stimulation (PNFS) is a potential treatment for chronic low-back pain. Pain relief using PNFS is dependent on activation of non-nociceptive Aβ-fibers. However, PNFS may also activate muscles, causing twitches and discomfort. In this study, we developed a mathematical model, to investigate the activation of sensory and motor nerves, as well as direct muscle fiber activation. The extracellular field was estimated using a finite element model based on the geometry of CT scanned lumbar vertebrae. The electrode was modeled as being implanted to a depth of 10-15 mm. Three implant directions were modeled; horizontally, vertically, and diagonally. Both single electrode and "between-lead" stimulation between contralateral electrodes were modeled. The extracellular field was combined with models of sensory Aβ-nerves, motor neurons and muscle fibers to estimate their activation thresholds. The model showed that sensory Aβ fibers could be activated with thresholds down to 0.563 V, and the lowest threshold for motor nerve activation was 7.19 V using between-lead stimulation with the cathode located closest to the nerves. All thresholds for direct muscle activation were above 500 V. The results suggest that direct muscle activation does not occur during PNFS, and concomitant motor and sensory nerve fiber activation are only likely to occur when using between-lead configuration. Thus, it may be relevant to investigate the location of the innervation zone of the low-back muscles prior to electrode implantation to avoid muscle activation. © 2016 International Neuromodulation Society.

An elderly-onset limb girdle muscular dystrophy type 1B (LGMD1B) with pseudo-hypertrophy of paraspinal muscles.

PubMed

Furuta, Mitsuru; Sumi-Akamaru, Hisae; Takahashi, Masanori P; Hayashi, Yukiko K; Nishino, Ichizo; Mochizuki, Hideki

2016-09-01

Mutations in LMNA, encoding A-type lamins, lead to diverse disorders, collectively called "laminopathies," which affect the striated muscle, cardiac muscle, adipose tissue, skin, peripheral nerve, and premature aging. We describe a patient with limb-girdle muscular dystrophy type 1B (LGMD1B) carrying a heterozygous p.Arg377His mutation in LMNA, in whom skeletal muscle symptom onset was at the age of 65 years. Her weakness started at the erector spinae muscles, which showed marked pseudo-hypertrophy even at the age of 72 years. Her first episode of syncope was at 44 years; however, aberrant cardiac conduction was not revealed until 60 years. The p.Arg377His mutation has been previously reported in several familial LMNA-associated myopathies, most of which showed muscle weakness before the 6th decade. This is the first report of pseudo-hypertrophy of paravertebral muscles in LMNA-associated myopathies. The pseudo-hypertrophy of paravertebral muscles and the elderly-onset of muscle weakness make this case unique and reportable. Copyright © 2016 Elsevier B.V. All rights reserved.

Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0.

PubMed

Kollberg, Gittan; Tulinius, Már; Gilljam, Thomas; Ostman-Smith, Ingegerd; Forsander, Gun; Jotorp, Peter; Oldfors, Anders; Holme, Elisabeth

2007-10-11

Storage of glycogen is essential for glucose homeostasis and for energy supply during bursts of activity and sustained muscle work. We describe three siblings with profound muscle and heart glycogen deficiency caused by a homozygous stop mutation (R462-->ter) in the muscle glycogen synthase gene. The oldest brother died from sudden cardiac arrest at the age of 10.5 years. Two years later, an 11-year-old brother showed muscle fatigability, hypertrophic cardiomyopathy, and an abnormal heart rate and blood pressure while exercising; a 2-year-old sister had no symptoms. In muscle-biopsy specimens obtained from the two younger siblings, there was lack of glycogen, predominance of oxidative fibers, and mitochondrial proliferation. Glucose tolerance was normal. Copyright 2007 Massachusetts Medical Society.

Cardiac damage in athlete’s heart: When the “supernormal” heart fails!

PubMed Central

Carbone, Andreina; D’Andrea, Antonello; Riegler, Lucia; Scarafile, Raffaella; Pezzullo, Enrica; Martone, Francesca; America, Raffaella; Liccardo, Biagio; Galderisi, Maurizio; Bossone, Eduardo; Calabrò, Raffaele

2017-01-01

Intense exercise may cause heart remodeling to compensate increases in blood pressure or volume by increasing muscle mass. Cardiac changes do not involve only the left ventricle, but all heart chambers. Physiological cardiac modeling in athletes is associated with normal or enhanced cardiac function, but recent studies have documented decrements in left ventricular function during intense exercise and the release of cardiac markers of necrosis in athlete’s blood of uncertain significance. Furthermore, cardiac remodeling may predispose athletes to heart disease and result in electrical remodeling, responsible for arrhythmias. Athlete’s heart is a physiological condition and does not require a specific treatment. In some conditions, it is important to differentiate the physiological adaptations from pathological conditions, such as hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle, and non-compaction myocardium, for the greater risk of sudden cardiac death of these conditions. Moreover, some drugs and performance-enhancing drugs can cause structural alterations and arrhythmias, therefore, their use should be excluded. PMID:28706583

ALDH2 restores exhaustive exercise-induced mitochondrial dysfunction in skeletal muscle

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

Zhang, Qiuping; Zheng, Jianheng; Qiu, Jun

Background: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is highly expressed in heart and skeletal muscles, and is the major enzyme that metabolizes acetaldehyde and toxic aldehydes. The cardioprotective effects of ALDH2 during cardiac ischemia/reperfusion injury have been recognized. However, less is known about the function of ALDH2 in skeletal muscle. This study was designed to evaluate the effect of ALDH2 on exhaustive exercise-induced skeletal muscle injury. Methods: We created transgenic mice expressing ALDH2 in skeletal muscles. Male wild-type C57/BL6 (WT) and ALDH2 transgenic mice (ALDH2-Tg), 8-weeks old, were challenged with exhaustive exercise for 1 week to induce skeletal muscle injury. Animalsmore » were sacrificed 24 h post-exercise and muscle tissue was excised. Results: ALDH2-Tg mice displayed significantly increased treadmill exercise capacity compared to WT mice. Exhaustive exercise caused an increase in mRNA levels of the muscle atrophy markers, Atrogin-1 and MuRF1, and reduced mitochondrial biogenesis and fusion in WT skeletal muscles; these effects were attenuated in ALDH2-Tg mice. Exhaustive exercise also enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of Beclin1 and Bnip3; the effects of which were mitigated by ALDH2 overexpression. In addition, ALDH2-Tg reversed the increase of an oxidative stress biomarker (4-hydroxynonenal) and decreased levels of mitochondrial antioxidant proteins, including manganese superoxide dismutase and NAD(P)H:quinone oxidoreductase 1, in skeletal muscle induced by exhaustive exercise. Conclusion: ALDH2 may reverse skeletal muscle mitochondrial dysfunction due to exhaustive exercise by regulating mitochondria dynamic remodeling and enhancing the quality of mitochondria. - Highlights: • Skeletal muscle ALDH2 expression and activity declines during exhaustive exercise. • ALDH2 overexpression enhances physical performance and restores

[Cardiac resynchronization therapy for heart failure - from experimental pacing to evidence-based therapy].

PubMed

Götze, S; Butter, C; Fleck, E

2006-01-01

Within the last decade, cardiac resynchronization therapy (CRT) has become an evidence-based cornerstone for a subset of patients with chronic heart failure. For those, who suffer from ischemic or non-ischemic cardiomyopathies at NYHA III or IV, have sinus rhythm, a left bundle branch block and a left ventricular ejection fraction below 35%, CRT has evolved as an important treatment option with promising results. Numerous studies have shown that in these patients pacemaker-mediated correction of intra- and interventicular conduction disturbances can improve not only clinical symptoms, exercise tolerance and the frequency of hospitalizations, but even more important the overall mortality. These clinical results are due to several functional aspects. In the failing heart characteristic intra- and interventricular alterations in electrical conduction result in mechanical asynchrony that leads to an abnormal contraction of the left ventricle with delayed activation of the lateral wall, a paradoxical septal movement, a reduced diastolic filling and a mitral regurgitation due to dyssynchrony of papillary muscle activation. It is conceivable that these functional changes have fatal consequences for the failing heart. AV-optimized left- or biventricular stimulation by modern pacemakers can correct the pathological dyssynchrony, thereby improving cardiac function and clinical outcome in these patients. Although tremendous progress in cardiac resynchronization therapy has been made during the last decade, a couple of questions still need to be resolved. Critical issues are the identification of patients, who will predictably benefit from CRT, the value of CRT-pacemakers versus CRT-ICDs, and the usefullness of CRT in patients with atrial fibrillation.

Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.

PubMed

Kennedy, Hannah; Haack, Tobias B; Hartill, Verity; Mataković, Lavinija; Baumgartner, E Regula; Potter, Howard; Mackay, Richard; Alston, Charlotte L; O'Sullivan, Siobhan; McFarland, Robert; Connolly, Grainne; Gannon, Caroline; King, Richard; Mead, Scott; Crozier, Ian; Chan, Wandy; Florkowski, Chris M; Sage, Martin; Höfken, Thomas; Alhaddad, Bader; Kremer, Laura S; Kopajtich, Robert; Feichtinger, René G; Sperl, Wolfgang; Rodenburg, Richard J; Minet, Jean Claude; Dobbie, Angus; Strom, Tim M; Meitinger, Thomas; George, Peter M; Johnson, Colin A; Taylor, Robert W; Prokisch, Holger; Doudney, Kit; Mayr, Johannes A

2016-09-01

We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.