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Sample records for skeletal muscle amino

  1. Amino acids in healthy aging skeletal muscle.

    PubMed

    Riddle, Emily S; Stipanuk, Martha H; Thalacker-Mercer, Anna E

    2016-01-01

    Life expectancy in the U.S. and globally continues to increase. Despite increased life expectancy quality of life is not enhanced, and older adults often experience chronic age-related disease and functional disability, including frailty. Additionally, changes in body composition such as the involuntary loss of skeletal muscle mass (i.e. sarcopenia) and subsequent increases in adipose tissue can augment disease and disability in this population. Furthermore, increased oxidative stress and decreased antioxidant concentrations may also lead to metabolic dysfunction in older adults. Specific amino acids, including leucine, cysteine and its derivative taurine, and arginine can play various roles in healthy aging, especially in regards to skeletal muscle health. Leucine and arginine play important roles in muscle protein synthesis and cell growth while cysteine and arginine play important roles in quenching oxidative stress. Evidence suggests that supplemental doses of each of these amino acids may improve the aging phenotype. However, additional research is required to establish the doses required to achieve positive outcomes in humans. PMID:26709665

  2. Induction of amino acid transporters expression by endurance exercise in rat skeletal muscle

    SciTech Connect

    Murakami, Taro Yoshinaga, Mariko

    2013-10-04

    Highlights: •Regulation of amino acid transporter expression in working muscle remains unclear. •Expression of amino acid transporters for leucine were induced by a bout of exercise. •Requirement of leucine in muscle cells might regulate expression of its transporters. •This information is beneficial for understanding the muscle remodeling by exercise. -- Abstract: We here investigated whether an acute bout of endurance exercise would induce the expression of amino acid transporters that regulate leucine transport across plasma and lysosomal membranes in rat skeletal muscle. Rats ran on a motor-driven treadmill at a speed of 28 m/min for 90 min. Immediately after the exercise, we observed that expression of mRNAs encoding L-type amino acid transporter 1 (LAT1) and CD98 was induced in the gastrocnemius, soleus, and extensor digitorum longus (EDL) muscles. Sodium-coupled neutral amino acid transporter 2 (SNAT2) mRNA was also induced by the exercise in those three muscles. Expression of proton-assisted amino acid transporter 1 (PAT1) mRNA was slightly but not significantly induced by a single bout of exercise in soleus and EDL muscles. Exercise-induced mRNA expression of these amino acid transporters appeared to be attenuated by repeated bouts of the exercise. These results suggested that the expression of amino acid transporters for leucine may be induced in response to an increase in the requirement for this amino acid in the cells of working skeletal muscles.

  3. Exercise and amino acid anabolic cell signaling and the regulation of skeletal muscle mass.

    PubMed

    Pasiakos, Stefan M

    2012-07-01

    A series of complex intracellular networks influence the regulation of skeletal muscle protein turnover. In recent years, studies have examined how cellular regulators of muscle protein turnover modulate metabolic mechanisms contributing to the loss, gain, or conservation of skeletal muscle mass. Exercise and amino acids both stimulate anabolic signaling potentially through several intracellular pathways including the mammalian target of rapamycin complex 1 and the mitogen activated protein kinase cell signaling cascades. As novel molecular regulators of muscle integrity continue to be explored, a contemporary analysis of the literature is required to understand the metabolic mechanisms by which contractile forces and amino acids affect cellular process that contribute to long-term adaptations and preservation of muscle mass. This article reviews the literature related to how exercise and amino acid availability affect cellular regulators of skeletal muscle mass, especially highlighting recent investigations that have identified mechanisms by which contractile forces and amino acids modulate muscle health. Furthermore, this review will explore integrated exercise and nutrition strategies that promote the maintenance of muscle health by optimizing exercise, and amino acid-induced cell signaling in aging adults susceptible to muscle loss. PMID:22852061

  4. Skeletal muscle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  5. Regulation of protein degradation pathways by amino acids and insulin in skeletal muscle of neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The rapid gain in lean mass in neonates requires greater rates of protein synthesis than degradation. We previously delineated the molecular mechanisms by which insulin and amino acids, especially leucine, modulate skeletal muscle protein synthesis and how this changes with development. In the curre...

  6. PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle.

    PubMed

    Hatazawa, Yukino; Tadaishi, Miki; Nagaike, Yuta; Morita, Akihito; Ogawa, Yoshihiro; Ezaki, Osamu; Takai-Igarashi, Takako; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Kamei, Yasutomi; Miura, Shinji

    2014-01-01

    Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism. PMID:24638054

  7. Taurine: the appeal of a safe amino acid for skeletal muscle disorders.

    PubMed

    De Luca, Annamaria; Pierno, Sabata; Camerino, Diana Conte

    2015-01-01

    Taurine is a natural amino acid present as free form in many mammalian tissues and in particular in skeletal muscle. Taurine exerts many physiological functions, including membrane stabilization, osmoregulation and cytoprotective effects, antioxidant and anti-inflammatory actions as well as modulation of intracellular calcium concentration and ion channel function. In addition taurine may control muscle metabolism and gene expression, through yet unclear mechanisms. This review summarizes the effects of taurine on specific muscle targets and pathways as well as its therapeutic potential to restore skeletal muscle function and performance in various pathological conditions. Evidences support the link between alteration of intracellular taurine level in skeletal muscle and different pathophysiological conditions, such as disuse-induced muscle atrophy, muscular dystrophy and/or senescence, reinforcing the interest towards its exogenous supplementation. In addition, taurine treatment can be beneficial to reduce sarcolemmal hyper-excitability in myotonia-related syndromes. Although further studies are necessary to fill the gaps between animals and humans, the benefit of the amino acid appears to be due to its multiple actions on cellular functions while toxicity seems relatively low. Human clinical trials using taurine in various pathologies such as diabetes, cardiovascular and neurological disorders have been performed and may represent a guide-line for designing specific studies in patients of neuromuscular diseases. PMID:26208967

  8. REGULATION OF CARDIAC AND SKELETAL MUSCLE PROTEIN SYNTHESIS BY INDIVIDUAL BRANCHED-CHAIN AMINO ACIDS IN NEONATAL PIGS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle grows at a very rapid rate in the neonatal pig, due in part to an enhanced sensitivity of protein synthesis to the postprandial rise in amino acids. An increase in leucine alone stimulates protein synthesis in skeletal muscle of the neonatal pig; however, the effect of isoleucine and...

  9. Effect of exercise and obesity on skeletal muscle amino acid uptake

    SciTech Connect

    Friedman, J.E.

    1988-01-01

    To determine if amino acid uptake by muscle of the obese Zucker rat is impaired, epitrochlearis (EPI) and soleus strip (SOL) muscles from 32 pairs of female lean (Fa/-) and obese (fa/fa) Zucker rats were incubated using ({sup 14}C){alpha}-aminoisobutyric acid (AIB). Because contractile activity also influences amino acid uptake, the effect of acute endurance exercise on amino acid uptake by skeletal muscle from lean and obese rats was also studied. Muscle wet and dry weights were similar in lean and obese rats. However, both muscle protein content and concentration from obese rats were significantly reduced. In preliminary studies, pinning EPI at resting length during incubation significantly increased AIB uptake and reduced muscle water accumulation. AIB uptake was similar in stripped and intact SOL. Lean and obese rats were studied at rest or following a 1 hr treadmill run at 8% grade Muscles were pinned, and preincubated for 30 min at 37{degree}C in Krebs Ringer bicarbonate buffer (KRB) containing 5mM glucose under 95:5 O{sub 2}/CO{sub 2}, followed by 30, 60, 120, or 180 min of incubation in KRB with 0.5 mM AIB, ({sup 14}C)-AIB to measure amino acid, and ({sup 3}H)-inulin to determine extracellular water.

  10. Effect of insulin on system A amino acid transport in human skeletal muscle.

    PubMed Central

    Bonadonna, R C; Saccomani, M P; Cobelli, C; DeFronzo, R A

    1993-01-01

    Transmembrane transport of neutral amino acids in skeletal muscle is mediated by at least four different systems (system A, ASC, L, and Nm), and may be an important target for insulin's effects on amino acid and protein metabolism. We have measured net amino acid exchanges and fractional rates of inward (k(in), min-1) and outward (kout, min-1) transmembrane transport of 2-methylaminoisobutyric acid (MeAIB, a nonmetabolizable amino acid analogue, specific for system A amino acid transport) in forearm deep tissues (skeletal muscle), by combining the forearm perfusion technique and a novel dual tracer ([1-H3]-D-mannitol and 2-[1-14C]-methylaminoisobutyric acid) approach for measuring in vivo the activity of system A amino acid transport. Seven healthy lean subjects were studied. After a baseline period, insulin was infused into the brachial artery to achieve local physiologic hyperinsulinemia (76 +/- 8 microU/ml vs 6.4 +/- 1.6 microU/ml in the basal period, P < 0.01) without affecting systemic hormone and substrate concentrations. Insulin switched forearm amino acid exchange from a net output (-2,630 +/- 1,100 nmol/min per kig of forearm tissue) to a net uptake (1,610 +/- 600 nmol/min per kg, P < 0.01 vs baseline). Phenylalanine and tyrosine balances simultaneously shifted from a net output (-146 +/- 47 and -173 +/- 34 nmol/min per kg, respectively) to a zero balance (16.3 +/- 51 for phenylalanine and 15.5 +/- 14.3 nmol/min per kg for tyrosine, P < 0.01 vs baseline for both), showing that protein synthesis and breakdown were in equilibrium during hyperinsulinemia. Net negative balances of alanine, methionine, glycine, threonine and asparagine (typical substrates for system A amino acid transport) also were decreased by insulin, whereas serine (another substrate for system A transport) shifted from a zero balance to net uptake. Insulin increased k(in) of MeAIB from a basal value of 11.8.10(-2) +/- 1.7.10(-2).min-1 to 13.7.10(-2) +/- 2.2.10(-2).min-1 (P < 0.02 vs the postabsorptive value), whereas kout was unchanged. We conclude that physiologic hyperinsulinemia stimulates the activity of system A amino acid transport in human skeletal muscle, and that this effect may play a role in determining the overall concomitant response of muscle amino acid/protein metabolism to insulin. PMID:8432860

  11. The role of amino acids in skeletal muscle adaptation to exercise.

    PubMed

    Aguirre, Nick; van Loon, Luc J C; Baar, Keith

    2013-01-01

    The synthesis of new protein is necessary for both strength and endurance adaptations. While the proteins that are made might differ, myofibrillar proteins following resistance exercise and mitochondrial proteins and metabolic enzymes following endurance exercise, the basic premise of shifting to a positive protein balance after training is thought to be the same. What is less clear is the contribution of nutrition to the adaptive process. Following resistance exercise, proteins rich in the amino acid leucine increase the activation of mTOR, the rate of muscle protein synthesis (MPS), and the rate of muscle mass and strength gains. However, an effect of protein consumption during acute post-exercise recovery on mitochondrial protein synthesis has yet to be demonstrated. Protein ingestion following endurance exercise does facilitate an increase in skeletal MPS, supporting muscle repair, growth and remodeling. However, whether this results in improved performance has yet to be demonstrated. The current literature suggests that a strength athlete will experience an increased sensitivity to protein feeding for at least 24 h after exercise, but immediate consumption of 0.25 g/kg bodyweight of rapidly absorbed protein will enhance MPS rates and drive the skeletal muscle hypertrophic response. At rest, ∼0.25 g/kg bodyweight of dietary protein should be consumed every 4-5 h and another 0.25-0.5 g/kg bodyweight prior to sleep to facilitate the postprandial muscle protein synthetic response. In this way, consuming dietary protein can complement intense exercise training and facilitate the skeletal muscle adaptive response. PMID:23899757

  12. [Effect of branched-chain amino acids mixture on repair of atrophied rats' skeletal muscles].

    PubMed

    Turtikova, O V; Lysenko, E A; Nemirovskaja, T L; Shenkman, B S

    2014-01-01

    Loss of muscle mass (atrophy) is a regular consequence of gravitational unloading. In hypogravity, muscle atrophy ensues from depression of protein synthesis and increase of its degradation. Both of these processes underlie also atrophy caused by muscle immobilization, cancer cachexia, cardiomyopathy and age-related sarcopenia. At the same time, atrophy of skeletal muscles due to chronic alcohol intoxication is the outcome of protein synthesis depression primarily. The study was part of a program aimed to develop a technique for atrophied muscle recovery by activation of anabolic signal pathways. A similar approach is applied to correct hypogravity-induced atrophy; however, analysis of effectiveness of this approach to the treatment of alcoholic muscle atrophy will be more "pure", as proteolytic processes in intoxicated animals are on the level typical of the intact ones. The issue in hand was whether injection of branched-chain amino acids (BCAA) would facilitate repair of m. gastrocnemius medialis in rats in the period of 30 days after 16-week alcoholic intoxication. BCAA was shown to enhance regain size by fast muscular fibers, full recovery of phosphorylated p90RSK concentrations without consequential effects on general proliferative processes and myonuclear number in rat's m. gastrocnemius medialis. PMID:25928985

  13. Regulation of protein degradation pathways by amino acids and insulin in skeletal muscle of neonatal pigs

    PubMed Central

    2014-01-01

    Background The rapid gain in lean mass in neonates requires greater rates of protein synthesis than degradation. We previously delineated the molecular mechanisms by which insulin and amino acids, especially leucine, modulate skeletal muscle protein synthesis and how this changes with development. In the current study, we identified mechanisms involved in protein degradation regulation. In experiment 1, 6- and 26-d-old pigs were studied during 1) euinsulinemic-euglycemic-euaminoacidemic, 2) euinsulinemic-euglycemic-hyperaminoacidemic, and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps for 2 h. In experiment 2, 5-d-old pigs were studied during 1) euinsulinemic-euglycemic-euaminoacidemic-euleucinemic, 2) euinsulinemic-euglycemic-hypoaminoacidemic-hyperleucinemic, and 3) euinsulinemic-euglycemic-euaminoacidemic-hyperleucinemic clamps for 24 h. We determined in muscle indices of ubiquitin-proteasome, i.e., atrogin-1 (MAFbx) and muscle RING-finger protein-1 (MuRF1) and autophagy-lysosome systems, i.e., unc51-like kinase 1 (UKL1), microtubule-associated protein light chain 3 (LC3), and lysosomal-associated membrane protein 2 (Lamp-2). For comparison, we measured ribosomal protein S6 (rpS6) and eukaryotic initiation factor 4E (eIF4E) activation, components of translation initiation. Results Abundance of atrogin-1, but not MuRF1, was greater in 26- than 6-d-old pigs and was not affected by insulin, amino acids, or leucine. Abundance of ULK1 and LC3 was higher in younger pigs and not affected by treatment. The LC3-II/LC3-I ratio was reduced and ULK1 phosphorylation increased by insulin, amino acids, and leucine. These responses were more profound in younger pigs. Abundance of Lamp-2 was not affected by treatment or development. Abundance of eIF4E, but not rpS6, was higher in 6- than 26-d-old-pigs but unaffected by treatment. Phosphorylation of eIF4E was not affected by treatment, however, insulin, amino acids, and leucine stimulated rpS6 phosphorylation, and the responses decreased with development. Conclusions The rapid growth of neonatal muscle is in part due to the positive balance between the activation of protein synthesis and degradation signaling. Insulin, amino acids, and, particularly, leucine, act as signals to modulate muscle protein synthesis and degradation in neonates. PMID:24438646

  14. Stimulation of skeletal muscle protein synthesis in neonatal pigs by long-term infusion of leucine is amino acid dependent

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Infusing leucine for 1 hr increases skeletal muscle protein synthesis in neonatal pigs, but this is not sustained for 2 h unless the leucine-induced fall in amino acids is prevented. We aimed to determine whether continuous leucine infusion can stimulate protein synthesis for a prolonged period whe...

  15. Influence of ageing and essential amino acids on quantitative patterns of troponin T alternative splicing in human skeletal muscle

    PubMed Central

    Berg, Arthur; Drummond, Micah J.; Rasmussen, Blake B.; Kimball, Scot R.

    2015-01-01

    Ageing is associated with a loss of skeletal muscle performance, a condition referred to as sarcopenia. In part, the age-related reduction in performance is due to a selective loss in muscle fiber mass, but mass-independent effects have also been demonstrated. An important mass-independent determinant of muscle performance is the pattern of expression of isoforms of proteins that participate in muscle contraction, e.g. the troponins. In the present study we tested the hypothesis that ageing impairs alternative splicing of the pre-mRNA encoding fast troponin T (Tnnt3) in human vastus lateralis muscle. Furthermore, we hypothesized that resistance exercise alone or in combination with consumption of essential amino acids will attenuate age-associated effects on Tnnt3 alternative splicing. Our results indicate that ageing negatively affects the pattern of Tnnt3 pre-mRNA alternative splicing in a manner that correlates quantitatively with age-associated reductions in muscle performance. Interestingly, whereas vastus lateralis Tnnt3 alternative splicing was unaffected by a bout of resistance exercise 24 hour prior to muscle biopsy, ingestion of a mixture of essential amino acids after resistance exercise resulted in a significant shift in the pattern of Tnnt3 spliceform expression in both age groups to one predicted to promote greater muscle performance. We conclude that essential amino acid supplementation after resistance exercise may provide a means to reduce impairments in skeletal muscle quality during ageing in humans. PMID:26201856

  16. Does Branched-Chain Amino Acids Supplementation Modulate Skeletal Muscle Remodeling through Inflammation Modulation? Possible Mechanisms of Action

    PubMed Central

    Nicastro, Humberto; da Luz, Claudia Ribeiro; Chaves, Daniela Fojo Seixas; Bechara, Luiz Roberto Grassmann; Voltarelli, Vanessa Azevedo; Rogero, Marcelo Macedo; Lancha, Antonio Herbert

    2012-01-01

    Skeletal muscle protein turnover is modulated by intracellular signaling pathways involved in protein synthesis, degradation, and inflammation. The proinflammatory status of muscle cells, observed in pathological conditions such as cancer, aging, and sepsis, can directly modulate protein translation initiation and muscle proteolysis, contributing to negative protein turnover. In this context, branched-chain amino acids (BCAAs), especially leucine, have been described as a strong nutritional stimulus able to enhance protein translation initiation and attenuate proteolysis. Furthermore, under inflammatory conditions, BCAA can be transaminated to glutamate in order to increase glutamine synthesis, which is a substrate highly consumed by inflammatory cells such as macrophages. The present paper describes the role of inflammation on muscle remodeling and the possible metabolic and cellular effects of BCAA supplementation in the modulation of inflammatory status of skeletal muscle and the consequences on protein synthesis and degradation. PMID:22536489

  17. Regulation of mTOR by amino acids and resistance exercise in skeletal muscle.

    PubMed

    Deldicque, L; Theisen, D; Francaux, M

    2005-05-01

    Resistance exercise disturbs skeletal muscle homeostasis leading to activation of catabolic and anabolic processes within the muscle cell. A current challenge of exercise biology is to describe the molecular mechanisms of regulation by which contractile activity stimulates net protein breakdown during exercise and net protein synthesis during recovery. Muscle growth is optimized by combining exercise and appropriate nutritional strategies, such as amino acid (AA) and carbohydrate ingestion. The effects are integrated at the level of one central regulatory protein, mTOR (mammalian target of rapamycin). mTOR is a complex protein integrating signals of the energetic status of the cell and environmental stimuli to control protein synthesis, protein breakdown and therefore cell growth. mTOR is known to be activated by insulin, and the mechanisms involved are well documented. The ways by which exercise and AA lead to mTOR activation remain partially unclear. Exercise and AA use different signalling pathways upstream of mTOR. Exercise seems to recruit partially the same pathway as insulin, whereas AA could act more directly on mTOR. During resistance exercise, the activity of mTOR could be acutely blunted by AMP-activated protein kinase (AMPK), thus inhibiting protein synthesis and enhancing AA availability for energy metabolism. During recovery, the inhibition of mTOR by AMPK is suppressed, and its activation is maximized by the presence of AA. There appears to be a requirement for a minimal concentration of plasma insulin to stimulate muscle protein synthesis in response to resistance exercise and AA ingestion. PMID:15702344

  18. Aging differentially affects human skeletal muscle amino acid transporter expression when essential amino acids are ingested after exercise

    PubMed Central

    Dickinson, Jared M.; Drummond, Micah J.; Coben, Jennifer R.; Volpi, Elena; Rasmussen, Blake B.

    2012-01-01

    Background & Aims Amino acid transporters have been proposed as regulators of protein synthesis. The primary aim of this study was to determine whether amino acid transporter expression is increased in human muscle following resistance exercise (RE) coupled with essential amino acid (EAA) ingestion, and whether a differential response occurs with aging. Secondly, we aimed to compare this response to a previous study examining RE alone. Methods Young (n=7, 30±2yr) and older men (n=6, 70±2yr) ingested EAA 1h after RE. Muscle biopsies were obtained at rest and 3 and 6h postexercise to examine amino acid transporter mRNA and protein expression. Results In both age groups, RE+EAA increased mRNA of L-type amino acid transporter 1 (LAT1)/solute linked carrier (SLC)7A5, sodium-coupled neutral amino acid transporter 2 (SNAT2)/SLC38A2, and cationic amino acid transporter 1/SLC7A1 (p<0.05). SNAT2 protein increased in young at 3 and 6h (p<0.05), whereas old maintained higher LAT1 protein (p<0.05). Compared to RE alone, RE+EAA enhanced amino acid transporter expression only in young (p<0.05). Conclusions RE increases muscle amino acid transporter expression in young and older adults, however, postexercise EAA ingestion enhances amino acid transporter expression only in young indicating that aging may influence the function of specific amino acid transporters. PMID:22889597

  19. Amino acid sequence of rabbit fast-twitch skeletal muscle calsequestrin deduced from cDNA and peptide sequencing.

    PubMed Central

    Fliegel, L; Ohnishi, M; Carpenter, M R; Khanna, V K; Reithmeier, R A; MacLennan, D H

    1987-01-01

    Partial amino acid sequence analysis of rabbit fast-twitch skeletal muscle calsequestrin permitted the construction of synthetic oligonucleotides that were used as both primers and probes for the synthesis and isolation of cDNAs encoding calsequestrin from neonatal rabbit skeletal muscle libraries. The cDNA sequence encodes a processed protein of 367 residues with a Mr of 42,435 and a 28-residue amino-terminal signal sequence. The deduced amino acid sequence agreed closely with the portions of the mature protein that were sequenced using standard protein sequencing. The neonatal protein, however, contains an acidic carboxyl-terminal extension not present in the adult protein, suggesting that the cDNA sequence may have arisen from an alternatively spliced neonatal transcript. A single transcript of 1.9-2.0 kilobases was seen in neonatal skeletal muscle mRNA. A glycosylation site and two potential phosphorylation sites were detected. Although the protein contains about two acidic residues for each Ca2+ bound, there is no repeating distribution of acidic residues and no evidence of EF hand structures. Hydropathy plots show no transmembrane sequences, and structural analyses suggest that less than half of the protein is likely to be highly structured. This sequence defines the characteristics of a class of high-capacity, moderate-affinity, Ca2+ binding proteins. Images PMID:3469659

  20. Enhanced skeletal muscle protein synthesis rates in pigs treated with somatotropin requires fed amino acids levels

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic somatotropin (pST) treatment in pigs increases skeletal muscle protein synthesis and circulating insulin, a known promoter of protein synthesis. Previously, we showed that the pST-mediated rise in insulin alone could not account for the pST-induced increase in protein synthesis. This study...

  1. Effect of protein/essential amino acids and resistance training on skeletal muscle hypertrophy: A case for whey protein

    PubMed Central

    2010-01-01

    Regardless of age or gender, resistance training or provision of adequate amounts of dietary protein (PRO) or essential amino acids (EAA) can increase muscle protein synthesis (MPS) in healthy adults. Combined PRO or EAA ingestion proximal to resistance training, however, can augment the post-exercise MPS response and has been shown to elicit a greater anabolic effect than exercise plus carbohydrate. Unfortunately, chronic/adaptive response data comparing the effects of different protein sources is limited. A growing body of evidence does, however, suggest that dairy PRO, and whey in particular may: 1) stimulate the greatest rise in MPS, 2) result in greater muscle cross-sectional area when combined with chronic resistance training, and 3) at least in younger individuals, enhance exercise recovery. Therefore, this review will focus on whey protein supplementation and its effects on skeletal muscle mass when combined with heavy resistance training. PMID:20565767

  2. Effects of eccentric exercise on branched-chain amino acid profiles in rat serum and skeletal muscle.

    PubMed

    Qun, Z; Xinkai, Y; Jing, W

    2014-04-01

    Supplementation of branched-chain amino acid (BCAA) is often used to attenuate exercise-induced skeletal muscle damage and promote adaptation, but no definitive conclusion on the benefits of BCAA on muscle recovery after injurious exercise can be drawn. Exploration of the systematic BCAA alteration in muscular injury-repair stage per se without any BCAA supplement should provide some useful information in favour of BCAA application in muscle regeneration after injury. One bout of 90-min downhill-running exercise was performed to cause rat skeletal muscle injury. After exercise, myofibrillar BCAA concentrations showed minor changes compared with exercise before, while serum concentrations of BCAA were lower after exercise. Especially, serum leucine, isoleucine and total BCAA concentrations 2 weeks post-run were significantly lower than normal values of exercise before (p = 0.008, p = 0.041, p = 0.015). The data demonstrate that a single eccentric exercise can significantly decrease the serum BCAA concentrations, which mean high utilization of BCAA for myogenesis after injurious exercise. PMID:23451863

  3. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle.

    PubMed Central

    Biolo, G; Declan Fleming, R Y; Wolfe, R R

    1995-01-01

    We have investigated the mechanisms of the anabolic effect of insulin on muscle protein metabolism in healthy volunteers, using stable isotopic tracers of amino acids. Calculations of muscle protein synthesis, breakdown, and amino acid transport were based on data obtained with the leg arteriovenous catheterization and muscle biopsy. Insulin was infused (0.15 mU/min per 100 ml leg) into the femoral artery to increase femoral venous insulin concentration (from 10 +/- 2 to 77 +/- 9 microU/ml) with minimal systemic perturbations. Tissue concentrations of free essential amino acids decreased (P < 0.05) after insulin. The fractional synthesis rate of muscle protein (precursor-product approach) increased (P < 0.01) after insulin from 0.0401 +/- 0.0072 to 0.0677 +/- 0.0101%/h. Consistent with this observation, rates of utilization for protein synthesis of intracellular phenylalanine and lysine (arteriovenous balance approach) also increased from 40 +/- 8 to 59 +/- 8 (P < 0.05) and from 219 +/- 21 to 298 +/- 37 (P < 0.08) nmol/min per 100 ml leg, respectively. Release from protein breakdown of phenylalanine, leucine, and lysine was not significantly modified by insulin. Local hyperinsulinemia increased (P < 0.05) the rates of inward transport of leucine, lysine, and alanine, from 164 +/- 22 to 200 +/- 25, from 126 +/- 11 to 221 +/- 30, and from 403 +/- 64 to 595 +/- 106 nmol/min per 100 ml leg, respectively. Transport of phenylalanine did not change significantly. We conclude that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport. Images PMID:7860765

  4. Skeletal muscle relaxants.

    PubMed

    See, Sharon; Ginzburg, Regina

    2008-02-01

    Health care providers prescribe skeletal muscle relaxants for a variety of indications. However, the comparative efficacy of these drugs is not well known. Skeletal muscle relaxants consist of both antispasticity and antispasmodic agents, a distinction prescribers often overlook. The antispasticity agents-baclofen, tizanidine, dantrolene, and diazepam-aid in improving muscle hypertonicity and involuntary jerks. Antispasmodic agents, such as cyclobenzaprine, are primarily used to treat musculoskeletal conditions. Much of the evidence from clinical trials regarding skeletal muscle relaxants is limited because of poor methodologic design, insensitive assessment methods, and small numbers of patients. Although trial results seem to support the use of these agents for their respective indications, efficacy data from comparator trials did not particularly favor one skeletal muscle relaxant over another. Therefore, the choice of a skeletal muscle relaxant should be based on its adverse-effect profile, tolerability, and cost. PMID:18225966

  5. Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin and amino acids act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs, and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to tr...

  6. Soy-dairy protein blend and whey protein ingestion after resistance exercise increases amino acid transport and transporter expression in human skeletal muscle

    PubMed Central

    Reidy, P. T.; Walker, D. K.; Dickinson, J. M.; Gundermann, D. M.; Drummond, M. J.; Timmerman, K. L.; Cope, M. B.; Mukherjea, R.; Jennings, K.; Volpi, E.

    2014-01-01

    Increasing amino acid availability (via infusion or ingestion) at rest or postexercise enhances amino acid transport into human skeletal muscle. It is unknown whether alterations in amino acid availability, from ingesting different dietary proteins, can enhance amino acid transport rates and amino acid transporter (AAT) mRNA expression. We hypothesized that the prolonged hyperaminoacidemia from ingesting a blend of proteins with different digestion rates postexercise would enhance amino acid transport into muscle and AAT expression compared with the ingestion of a rapidly digested protein. In a double-blind, randomized clinical trial, we studied 16 young adults at rest and after acute resistance exercise coupled with postexercise (1 h) ingestion of either a (soy-dairy) protein blend or whey protein. Phenylalanine net balance and transport rate into skeletal muscle were measured using stable isotopic methods in combination with femoral arteriovenous blood sampling and muscle biopsies obtained at rest and 3 and 5 h postexercise. Phenylalanine transport into muscle and mRNA expression of select AATs [system L amino acid transporter 1/solute-linked carrier (SLC) 7A5, CD98/SLC3A2, system A amino acid transporter 2/SLC38A2, proton-assisted amino acid transporter 1/SLC36A1, cationic amino acid transporter 1/SLC7A1] increased to a similar extent in both groups (P < 0.05). However, the ingestion of the protein blend resulted in a prolonged and positive net phenylalanine balance during postexercise recovery compared with whey protein (P < 0.05). Postexercise myofibrillar protein synthesis increased similarly between groups. We conclude that, while both protein sources enhanced postexercise AAT expression, transport into muscle, and myofibrillar protein synthesis, postexercise ingestion of a protein blend results in a slightly prolonged net amino acid balance across the leg compared with whey protein. PMID:24699854

  7. Branched-chain amino acid-containing dipeptides, identified from whey protein hydrolysates, stimulate glucose uptake rate in L6 myotubes and isolated skeletal muscles.

    PubMed

    Morifuji, Masashi; Koga, Jinichiro; Kawanaka, Kentaro; Higuchi, Mitsuru

    2009-02-01

    In earlier studies we showed that dietary whey protein increased skeletal muscle and liver glycogen content in exercise-trained rats. However, little is known about whether ingredients of whey protein stimulate skeletal muscle glycogen accumulation. The aim of this study was to identify bioactive peptides in whey protein hydrolysates (WPH) which stimulated glucose uptake and glycogen synthesis rate in skeletal muscles. Branched-chain amino acid (BCAA)-containing dipeptides in WPH were identified using LC/MS/MS. L6 myotubes and isolated epitrochlearis muscles were used for the glucose uptake assays. The myotubes and muscles were incubated with or without 1 mM dipeptides, LY294002 a phosphoinositide 3-kinase (PI3-kinase) inhibitor, or GF102903X an atypical protein kinase C (aPKC) inhibitor, followed by measurement of 2-deoxyglucose uptake. Isolated muscles were incubated for 3 h with or without 1 mM Ile-Leu to determine glycogen synthesis rate. The BCAA-containing dipeptides, Ile-Val, Leu-Val, Val-Leu, Ile-Ile, Leu-Ile, Ile-Leu, and Leu-Leu were detected in the WPH by LC/MS/MS. These dipeptides caused significant stimulation in glucose uptake rate in the L6 myotubes. Ile-Leu, the main component in WPH, also stimulated glucose uptake in isolated skeletal muscles. Stimulation of glucose uptake by Ile-Leu was completely inhibited by treatment with either LY294002, or GF109203X in both L6 cells and isolated muscles. Ile-Leu increased glycogen contents in isolated muscles. These results suggest that BCAA-containing bioactive dipeptides in WPH stimulate glucose uptake in skeletal muscles via the PI3-kinase and aPKC pathways, resulting in increased skeletal muscle glycogen contents. PMID:19352067

  8. Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle.

    PubMed Central

    Maggs, D G; Jacob, R; Rife, F; Lange, R; Leone, P; During, M J; Tamborlane, W V; Sherwin, R S

    1995-01-01

    To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P < 0.0001) in muscle (3710 microM) and adipose tissue (2760 microM) compared with plasma (87 microM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P < 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P < 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P < 0.001) and twofold increase in norepinephrine (P < 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism. Images PMID:7615807

  9. Structure of Skeletal Muscle

    MedlinePlus

    ... Home » Cancer Registration & Surveillance Modules » Anatomy & Physiology » Muscular System » Structure of Skeletal Muscle Cancer Registration & Surveillance Modules Anatomy & Physiology Intro to the Human Body Body Functions & Life Process Anatomical Terminology Review Quiz ...

  10. A multiple indicator, residue detection method for measurement of amino acid transport in skeletal muscle in vivo

    SciTech Connect

    Bading, J.R.; Ekman, L.G.; Roh, M.S.; Gelbard, A.; Brennan, M.F.

    1984-01-01

    The authors' aim is to develop a method, applicable to man, for quantitative study of amino acid transport in skeletal muscle using tracer amino acids labeled with N-13 or C-11. Fasted, barbiturate-anesthetized dogs were catheterized for femoral artery injection. A mixture of N-13 L-glutamate (Glu) and Tc-99m HSA in 0.5-1.0 ml of saline was bolus injected, and radiolabel kinetics recorded over superficial thigh muscle with a collimated detector. Data for recirculation correction were simultaneously recorded over the contralateral site. The extracellular agent EDTA, labeled with In-113m, was used in the same manner to study molecular kinetics in the interstitial fluid. Regional tissue masses were measured with transmission scans, and regional blood plasma volumes were determined from equilibrium plasma concentrations and quantitative scans of HSA. Plasma mean transit times were computed from HSA kinetics (height/area method) and used with the plasma volume and tissue mass data to determine regional plasma flow/tissue mass. Values ranged from 2 to 22 ml/min/100g. Extraction efficiencies E were determined graphically from the kinetic data. Measured capillary E's for both Glu and EDTA are directly related to the plasma mean transmit times. The data indicate the capillary wall to be the primary barrier to passage of glutamate into muscle cells; the interstitium-intracellular E is nearly unity. Capillary permeability-surface area products were computed (Renkin-Crone model) to be 4.6 +- 0.9 and 2.1 +- 0.5 ml/min/100g for Glu and EDTA respectively. This relatively simple method provides reproducible values of transport parameters which are consistent with published values.

  11. Branched chain amino acid uptake and muscle free amino acid concentrations predict postoperative muscle nitrogen balance.

    PubMed

    Johnson, D J; Jiang, Z M; Colpoys, M; Kapadia, C R; Smith, R J; Wilmore, D W

    1986-11-01

    Amino acid solutions rich in branched chain amino acids (BCAA) are commonly utilized both clinically and in experimental protocols in an attempt to reduce skeletal muscle and whole body protein catabolism. To investigate the effectiveness of BCAA infusion, amino acid formulas containing varying concentrations of BCAA were given during operation in this study to three groups of dogs undergoing a standard laparotomy and retroperitoneal dissection. A fourth group was given saline alone. With the use of previously described hindquarter flux techniques, individual and total amino acid nitrogen exchange rates were measured and utilized in estimating skeletal muscle protein catabolism. Intracellular free amino acid concentrations were measured in percutaneous muscle biopsy samples. Although there was no relationship with the rate of BCAA infusion, there was a significant correlation between the rate of BCAA uptake by muscle and diminished total nitrogen release from hindquarter skeletal muscle after operation. There was also a significant relationship between muscle nitrogen balance and the postoperative change in the muscle concentration of either total amino acids or the single amino acid glutamine. When combined in a single equation, BCAA uptake and the change in muscle free amino acid concentration predict skeletal muscle nitrogen release with an r = 0.86. Thus, the rate of BCAA uptake and the free glutamine or total amino acid concentration in muscle appear to be independent predictors of muscle nitrogen balance. The nitrogen-sparing effect of BCAA in skeletal muscle is unrelated to infusion concentration or rate of infusion. PMID:3767484

  12. [Muscle-skeletal pain].

    PubMed

    Vygonskaya, M V; Filatova, E G

    2016-01-01

    The paper is devoted to the most complicated aspects of low back pain. The differences between specific and nonspecific low back pain using the "red flags" system is highlighted. The authors consider the causes of pain chronification (the "yellow flags" system) and the necessity of using a biopsychosocial model. Main pathogenetic mechanisms of chronic muscle/skeletal pain are considered and the possible involvement of several mechanism in the pathogenesis of chronic pain as well as the use of complex therapy is discussed. The high efficacy and safety of ketorolac in treatment of nonspecific muscle/skeletal pain is demonstrated. PMID:27042717

  13. High Insulin Combined With Essential Amino Acids Stimulates Skeletal Muscle Mitochondrial Protein Synthesis While Decreasing Insulin Sensitivity in Healthy Humans

    PubMed Central

    Robinson, Matthew M.; Soop, Mattias; Sohn, Tae Seo; Morse, Dawn M.; Schimke, Jill M.; Klaus, Katherine A.

    2014-01-01

    Context: Insulin and essential amino acids (EAAs) regulate skeletal muscle protein synthesis, yet their independent effects on mitochondrial protein synthesis (MiPS) and oxidative function remain to be clearly defined. Objective: The purpose of this study was to determine the effects of high or low insulin with or without EAAs on MiPS. Design: Thirty participants were randomized to 3 groups of 10 each with each participant studied twice. Study groups comprised (1) low and high insulin, (2) low insulin with and without EAAs, and (3) high insulin with and without EAAs. Setting: The study was conducted in an in-patient clinical research unit. Participants: Eligible participants were 18 to 45 years old, had a body mass index of <25 kg/m2, and were free of diseases and medications that might impair mitochondrial function. Intervention: Low (∼6 μU/mL) and high (∼40 μU/mL) insulin levels were maintained by iv insulin infusion during a somatostatin clamp while maintaining euglycemia (4.7–5.2 mM) and replacing GH and glucagon. The EAA infusion was 5.4% NephrAmine. l-[ring-13C6]Phenylalanine was infused, and muscle needle biopsies were performed. Main Outcomes: Muscle MiPS, oxidative enzymes, and plasma amino acid metabolites were measured. Results: MiPS and oxidative enzyme activities did not differ between low and high insulin (MiPS: 0.07 ± 0.009 vs 0.07 ± 0.006%/h, P = .86) or between EAAs and saline during low insulin (MiPS: 0.05 ± 0.01 vs 0.07 ± 0.01, P = .5). During high insulin, EAAs in comparison with saline increased MiPS (0.1 ± 0.01 vs 0.06 ± 0.01, P < .05) and cytochrome c oxidase activity (P < .05) but not citrate synthase (P = .27). EAA infusion decreased (P < .05) the glucose infusion rates needed to maintain euglycemia during low (∼40%) and high insulin (∼24%). Conclusion: EAAs increased MiPS and oxidative enzyme activity only with high insulin concentrations. PMID:25222757

  14. Hydrolyzed protein supplementation improves protein content and peroxidation of skeletal muscle by adjusting the plasma amino acid spectrums in rats after exhaustive swimming exercise: a pilot study

    PubMed Central

    2014-01-01

    Background This study was designed to evaluate the effects of hydrolyzed protein supplementation upon skeletal muscle total protein and peroxidation in rats following exhaustive swimming exercise. Methods Twenty-four rats were randomized to 4 experimental groups (n = 6 per group): control group fed standard diet without exercise (SD), exercise (EX), exercise plus standard diet for 72 hours (EX + SD), and exercise plus standard diet supplemented with hydrolyzed protein (2 g/kg/d) for 72 hours (EX + HP). Immediately following exercise, the EX group was euthanized for collecting plasma and skeletal muscle samples. The EX + SD and EX + HP groups were fed their respective diets for 72 hour still plasma and skeletal muscle collection. Skeletal muscle samples were used to measure levels of total protein (TP), malondialdehyde (MDA), and protein carbonyl (PC). Plasma samples were used to analyze the amino acids spectrum. Results Compared with the EX + SD, EX + HP presented the significantly increased TP (P = 0.02) and decreased MDA and PC levels (P = 0.035). MDA was negatively correlated with the methionine levels. Moreover, EX + HP maintained higher levels of plasmaleucine, isoleucine, and methionine than EX + SD, which may be associated with the increased skeletal muscle TP levels observed (P < 0.05). Conclusions These results collectively suggest that hydrolyzed protein supplementation can improve skeletal muscle TP and ameliorate peroxidation damage in rats subjected to exhaustive exercise stress, which may be, at least in part, related with the maintenance of plasma leucine, isoleucine, and methionine levels. PMID:24565110

  15. LEUCINE STIMULATION OF SKELETAL MUSCLE PROTEIN SYNTHESIS DURING PROLONGED LEUCINE INFUSION IS DEPENDENT ON AMINO ACID AVAILABILITY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Leucine stimulates protein synthesis in cultured cells, mature rats and neonatal pigs. We have reported that leucine infusion increases protein synthesis in skeletal muscle of neonatal pigs during a 60-min infusion. When leucine infusion was prolonged for 120 min, however, protein synthesis was no...

  16. Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells.

    PubMed

    Atherton, Philip J; Smith, Ken; Etheridge, Timothy; Rankin, Debbie; Rennie, Michael J

    2010-05-01

    The essential amino acids (EAA) activate anabolic signalling through mechanisms, which are unclear in detail but include increased signalling through the mammalian target of rapamycin complex 1 (mTORC1). Of all the EAA, the branched chain amino acid (BCAA) leucine has been suggested as the most potent in stimulating protein synthesis, although there have been no studies investigating the effects of each EAA on anabolic signalling pathways. We therefore undertook a systematic analysis of the effect of each EAA on mTORC1 signalling in C2C12 myotubes whereby cells were serum (4 h) and amino acid (1 h) starved before stimulation with 2 mM of each amino acid. Immunoblotting was used to detect phosphorylated forms of protein kinase B (Akt)/mTORC1 signalling enzymes. The phosphorylation of Akt was unchanged by incubation with EAA. Phosphorylation of mTOR and 4E binding protein-1 (4EBP1) were increased 1.67 +/- 0.1-fold and 2.5 +/- 0.1-fold, respectively, in response to leucine stimulation but not in response to any other EAA. The phosphorylation of ribosomal s6 kinase (p70S6K1) was increased by stimulation with all EAA with the exceptions of isoleucine and valine. However, the increase with leucine was significantly greater, 5.9 +/- 0.3-fold compared to 1.6-2.0-fold for the non-BCAA EAA. This pattern of activation was identical in ribosomal protein s6 (RPS6) with the additional effect of leucine being 3.8 +/- 0.3-fold versus 1.5-2.0-fold. Phosphorylation of eukaryotic initiation/elongation factors eIF2alpha and eEF2 were unaffected by EAA. We conclude that leucine is unique amongst the amino acids in its capacity to stimulate both mTOR and 4EBP1 phosphorylation and to enhance p70S6K1 signalling. PMID:19882215

  17. Amino acid infusion fails to stimulate skeletal muscle protein synthesis up to one year post injury in children with severe burns

    PubMed Central

    Cotter, Matthew; Diaz, Eva C; Jennings, Kristofer; Herndon, David N; Børsheim, Elisabet

    2013-01-01

    Background Burn injury results in increased skeletal muscle protein turnover, where the magnitude of protein breakdown outweighs synthesis resulting in muscle wasting. The impact of increased amino acid (AA) provision on skeletal muscle fractional synthesis rate (FSR) in severely burned patients during their convalescence after discharge from hospital is not known. Subsequently, the purpose of this study was to determine skeletal muscle FSR in response to AA infusion in severely burned pediatric patients at discharge from hospital, and at six and twelve months post injury. Methods Stable isotope infusion studies were performed in the postprandial state and during intravenous AA infusion. Skeletal muscle biopsies were obtained and isotope enrichment determined in order to calculate skeletal muscle FSR. Patients were studied at discharge from hospital (n=11), and at six (n=15), and twelve months (n=14) post injury. Results The cohorts of patients studied at each time point post injury were not different with regards to age, body mass or burn size. AA infusion failed to stimulate FSR above basal values at discharge from hospital (0.27±0.04 vs. 0.26±0.06 %·hr−1), six months post injury (0.20±0.04 vs. 0.22±0.03 %·hr−1), and twelve months post injury (0.16±0.03 vs. 0.15±0.05 %·hr−1). Daily FSR was numerically lower at six months post burn (5.51±0.79 %·day−1) and significantly (P<0.05) lower at 12 months post burn (3.67±0.65 %·day−1) relative to discharge group (6.32±1.02 %·day−1). Discussion The findings of the current study suggest that the deleterious impact of burn injury on skeletal muscle AA metabolism persists for up to one year post injury. In light of these findings, nutritional and pharmacological strategies aimed at attenuating muscle protein breakdown post burn may be a more efficacious approach to maintaining muscle mass in severely burned patients. PMID:23694875

  18. Skeletal muscle glutathione after surgical trauma.

    PubMed Central

    Luo, J L; Hammarqvist, F; Andersson, K; Wernerman, J

    1996-01-01

    OBJECTIVE: The authors investigate the effect of surgical trauma on skeletal muscle concentrations of glutathione in patients undergoing selective abdominal surgery. SUMMARY BACKGROUND DATA: The posttraumatic state is accompanied by characteristic changes in the pattern of free amino acids and a decline of protein synthesis in human skeletal muscle. Glutathione has multiple metabolic functions that are involved in cellular homeostasis. It is unknown how surgical trauma affects the glutathione metabolism of skeletal muscle in surgical patients. METHODS: Eight patients undergoing elective abdominal surgery were investigated. Percutaneous muscle biopsies and blood samples were taken before operation and at 6, 24, and 48 hours after operation. The concentrations of glutathione were determined in muscle tissue, plasma, and whole blood, as well as the concentrations of the related amino acids in muscle and plasma. RESULTS: In skeletal muscle, the levels of both reduced and total glutathione decreased by 40% (p<0.01) at 24 hours and remained low at 48 hours after operation compared with the preoperative values. The glutathione concentration in plasma was 20% lower after operation compared with the concentration before operation (p<0.05). There were no changes at the whole blood levels of glutathione. Tissue glutamate and glutamine decreased significantly after operation (p<0.001), whereas intracellular cysteine and glycine remained unchanged. CONCLUSIONS: Skeletal muscle glutathione deficiency occurs after surgical trauma. This may lead to an increase in the susceptibility to intracellular oxidative injury. PMID:8633921

  19. Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability

    PubMed Central

    Fujita, Satoshi; Rasmussen, Blake B.; Cadenas, Jerson G.; Grady, James J.; Volpi, Elena

    2009-01-01

    Insulin promotes muscle anabolism, but it is still unclear whether it stimulates muscle protein synthesis in humans. We hypothesized that insulin can increase muscle protein synthesis only if it increases muscle amino acid availability. We measured muscle protein and amino acid metabolism using stable-isotope methodologies in 19 young healthy subjects at baseline and during insulin infusion in one leg at low (LD, 0.05), intermediate (ID, 0.15), or high (HD, 0.30 mU·min−1·100 ml−1) doses. Insulin was infused locally to induce muscle hyperinsulinemia within the physiological range while minimizing the systemic effects. Protein and amino acid kinetics across the leg were assessed using stable isotopes and muscle biopsies. The LD did not affect phenylalanine delivery to the muscle (−9 ± 18% change over baseline), muscle protein synthesis (16 ± 26%), breakdown, or net balance. The ID increased (P < 0.05) phenylalanine delivery (+63 ± 38%), muscle protein synthesis (+157 ± 54%), and net protein balance, with no change in breakdown. The HD did not change phenylalanine delivery (+12 ± 11%) or muscle protein synthesis (+9 ± 19%), and reduced muscle protein breakdown (−17 ± 15%), thus improving net muscle protein balance but to a lesser degree than the ID. Changes in muscle protein synthesis were strongly associated with changes in muscle blood flow and phenylalanine delivery and availability. In conclusion, physiological hyperinsulinemia promotes muscle protein synthesis as long as it concomitantly increases muscle blood flow, amino acid delivery and availability. PMID:16705054

  20. Expression of genes coding for selected amino acid transporters in small intestine, liver, and skeletal muscle of pigs fed excess branched-chain amino acids.

    PubMed

    Cervantes, M; Arce, N; García, H; Cota, M; Htoo, J K; Morales, A

    2015-01-01

    Excess Leu reduces the availability of Ile and Val in pigs likely by reducing absorption of the latter amino acids (AA). Twenty-four crossbred pigs were used to evaluate the effect of excess Leu alone or with surplus Ile and Val on the expression of cationic (b(0),(+)AT and CAT1) and neutral (B(0)AT1) AA transporters in the small intestine, liver, and skeletal muscle. Dietary treatments included: 1) basal diet; 2) basal plus 0.43% L-Leu (excess Leu); 3) basal plus 0.43% Leu, 0.20% L-Ile, and 0.25% L-Val (excess Leu, Ile, and Val). The basal diet contained 0.90% standardized ileal digestible Lys, as well as crystalline L-Lys, L-Thr, DL-Met, L-Trp, L-Leu, L-Ile, L-His, and L-Val. Diets 2 and 3 contained 52% more Leu and diet 3 contained 42% more Ile and Val compared with the basal diet. Excess Leu or excess Leu, Ile, and Val reduced b(0),(+)AT expression in the jejunum (P < 0.05) but had no effect in the ileum and liver. Excess Leu increased CAT1 expression in the ileum but reduced expression in the liver (P < 0.05). Excess Leu, Ile, and Val increased (P < 0.05) B(0)AT1 expression in the jejunum and tended to increase (P = 0.10) expression in the ileum. In general, b(0),(+)AT expression was higher but CAT1 expression was lower in the jejunum than in the ileum; B0AT1 was similarly expressed in the jejunum and ileum. Excess Leu or any branched-chain AA affects AA transporter expression, which may affect the absorption and availability of AA for animal growth. PMID:26345911

  1. The impact of leucine infusion on skeletal muscle amino acid and energy metabolism in severely traumatized patients.

    PubMed

    Lennmarken, C; Skullman, S; Wirén, M; Vinnars, E; Larsson, J

    1992-06-01

    The response to trauma is associated with increased energy requirements and net protein breakdown. The branched chain aminoacids, especially leucine, are considered to act by serving as a fuel for muscle tissue and by stimulating synthesis of proteins and controlling protein breakdown. Such results have been obtained mainly from in vitro studies. The present study was designed to evaluate the pharmacological effect of leucine infusion on muscle energy/amino acid metabolism in man after severe multiple trauma. 16 patients were studied and randomly allocated into 2 groups. Group 1 was given fat and 20% glucose while group 2 received 6 g N in form of leucine dissolved in 10% glucose solution and fat. The patients received 40 kcal/kg/24 h over an 8 day period after trauma. Biochemical analyses, muscle biopsies (energy substrates, electrolytes, amino acids), nitrogen balance and 3-methyl histidine excretion in urine were evaluated. Biochemical data revealed a significant increase (p < 0.05) of serum urea in group 2 day 4 and 8 after trauma. Muscle intracellular electrolytes (K(+), Mg(2+)) and energy substrates (ATP, phosphocreatine) showed a similar decrease in both groups. The intracellular muscle amino acids displayed a pattern known to be related to trauma without differences between the groups. The cumulative nitrogen balance 8 days after the injury was -93.5 g N +/- 10.1 (SEM) in group 1 and -73 g N +/- 7.5 in group 2. The 3-methylhistidine excretion was markedly increased similar in both groups. The present study demonstrated no significant pharmacological effect of leucine administration on muscle metabolism, nitrogen balance or 3-methylhistidine excretion in severely traumatized patients. Conventional balanced amino acid solutions are probably optimal to meet the patients actual requirements. PMID:16839989

  2. Mechanotransduction in skeletal muscle

    PubMed Central

    Burkholder, Thomas J.

    2007-01-01

    Mechanical signals are critical to the development and maintenance of skeletal muscle, but the mechanisms that convert these shape changes to biochemical signals is not known. When a deformation is imposed on a muscle, changes in cellular and molecular conformations link the mechanical forces with biochemical signals, and the close integration of mechanical signals with electrical, metabolic, and hormonal signaling may disguise the aspect of the response that is specific to the mechanical forces. The mechanically induced conformational change may directly activate downstream signaling and may trigger messenger systems to activate signaling indirectly. Major effectors of mechanotransduction include the ubiquitous mitogen activated protein kinase (MAP) and phosphatidylinositol-3’ kinase (PI-3K), which have well described receptor dependent cascades, but the chain of events leading from mechanical stimulation to biochemical cascade is not clear. This review will discuss the mechanics of biological deformation, loading of cellular and molecular structures, and some of the principal signaling mechanisms associated with mechanotransduction. PMID:17127292

  3. Skeletal muscle relaxant ingestion.

    PubMed

    Lebby, T I; Dugger, K; Lipscomb, J W; Leikin, J B

    1990-04-01

    We retrospectively analyzed 56 consecutive cases involving acute skeletal muscle relaxant exposure that were reported to the Poison Control Center over a 1-year period. The age range was 9 mo to 56 years (mean 18.9 +/- 13.1) with the site of exposure being the primary residence in 54 cases (96.4%). The reasons for inquiry to the Poison Center were reported to be intentional suicide in 26 cases (46.4%), accidental in 21 cases (37.5%), with intentional misuses in 5 cases (8.9%). No deaths were reported. Eighteen cases (32.1%) were reported with co-ingestants (average number of substances taken was 2.7 +/- 0.8). Of these cases 3 patients (16.7%) had major effects with life-threatening symptoms with 6 (33.3%) patients having no symptoms. Of the remaining 38 cases, 17 (44.7%) wer cyclobenzaprine, 6 (15.8%) were methocarbamol, 5 (13.2%) were carisoprodol, 5 (13.2%) were chlorzoxazone, 3 (7.89%) were Baclofen and the remainder were either life-threatening symptoms (2.6%), while 29 (74.3%) had no or minor effects with symptoms that subsided. We conclude that morbidity and mortality are low in pure skeletal muscle relaxant ingestion, however it may be increased in multiple ingestions. PMID:2327059

  4. Skeletal muscle-specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism.

    PubMed

    Miyake, Masato; Nomura, Akitoshi; Ogura, Atsushi; Takehana, Kenji; Kitahara, Yoshihiro; Takahara, Kazuna; Tsugawa, Kazue; Miyamoto, Chinobu; Miura, Naoko; Sato, Ryosuke; Kurahashi, Kiyoe; Harding, Heather P; Oyadomari, Miho; Ron, David; Oyadomari, Seiichi

    2016-02-01

    The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine.-Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle-specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism. PMID:26487695

  5. Skeletal muscle regeneration and impact of aging and nutrition.

    PubMed

    Domingues-Faria, Carla; Vasson, Marie-Paule; Goncalves-Mendes, Nicolas; Boirie, Yves; Walrand, Stephane

    2016-03-01

    After skeletal muscle injury a regeneration process takes place to repair muscle. Skeletal muscle recovery is a highly coordinated process involving cross-talk between immune and muscle cells. It is well known that the physiological activities of both immune cells and muscle stem cells decline with advancing age, thereby blunting the capacity of skeletal muscle to regenerate. The age-related reduction in muscle repair efficiency contributes to the development of sarcopenia, one of the most important factors of disability in elderly people. Preserving muscle regeneration capacity may slow the development of this syndrome. In this context, nutrition has drawn much attention: studies have demonstrated that nutrients such as amino acids, n-3 polyunsaturated fatty acids, polyphenols and vitamin D can improve skeletal muscle regeneration by targeting key functions of immune cells, muscle cells or both. Here we review the process of skeletal muscle regeneration with a special focus on the cross-talk between immune and muscle cells. We address the effect of aging on immune and skeletal muscle cells involved in muscle regeneration. Finally, the mechanisms of nutrient action on muscle regeneration are described, showing that quality of nutrition may help to preserve the capacity for skeletal muscle regeneration with age. PMID:26690801

  6. The effect of insulin on free amino acid pools and protein synthesis in rat skeletal muscle in vitro

    PubMed Central

    Hider, R. C.; Fern, E. B.; London, D. R.

    1971-01-01

    1. The effects of insulin in vitro on tissue pools and incorporation into protein of glycine and leucine in the extensor digitorum longus muscle of the rat are reported. 2. It was found that insulin decreased the lag period before the establishment of a linear rate of incorporation of radioactive glycine into protein. 3. The hormone increased the size of the free intracellular glycine pool. No such effect was found for leucine. The accumulation of radioactive glycine in the intracellular fluid compartment was increased. The content of radioactive leucine in the intracellular compartment was decreased. 4. Insulin decreased the specific radioactivity of both glycine and leucine in the extracellular fluid. 5. The hormone also decreased protein catabolism. 6. The effect on protein synthesis was not caused by an increase in the specific radioactivity of the extracellular pool but was possibly related to increased amino acid concentrations in this pool, which could in turn have affected the aggregation of ribosomes. PMID:5145892

  7. The impact of delivery profile of essential amino acids upon skeletal muscle protein synthesis in older men: clinical efficacy of pulse vs. bolus supply.

    PubMed

    Mitchell, W Kyle; Phillips, Bethan E; Williams, John P; Rankin, Debbie; Lund, Jonathan N; Wilkinson, Daniel J; Smith, Kenneth; Atherton, Philip J

    2015-09-01

    Essential amino acids (EAA) are responsible for skeletal muscle anabolic effects after nutrient intake. The pattern of appearance of EAA in blood, e.g., after intake of "slow" or "fast" protein sources or in response to grazing vs. bolus feeding patterns, may impact anabolism. However, the influence of this on muscle anabolism is poorly understood, particularly in older individuals. We determined the effects of divergent feeding profiles of EAA on blood flow, anabolic signaling, and muscle protein synthesis (MPS) in older men. Sixteen men (∼70 yr) consumed EAA either as a single dose (bolus, 15 g; n = 8) or as small repeated fractions (pulse, 4 × 3.75 g every 45 min; n = 8) during (13)C6 phenylalanine infusion. Repeated blood samples and muscle biopsies permitted measurement of fasting and postprandial plasma EAA, insulin, anabolic signaling, and MPS. Muscle blood flow was assessed by contrast-enhanced ultrasound (Sonovue). Bolus achieved rapid insulinemia (12.7 μiU/ml 25-min postfeed), essential aminoacidemia (∼3,000 μM, 45-65 min postfeed), and mTORC1 activity; pulse achieved attenuated insulin responses, gradual low-amplitude aminoacidemia (∼1,800 μM 80-195 min after feeding), and undetectable mTORC1 signaling. Despite this, equivalent anabolic responses were observed: fasting FSRs of 0.051 and 0.047%/h (bolus and pulse, respectively) increased to 0.084 and 0.073%/h, respectively. Moreover, pulse led to sustainment of MPS beyond 180 min, when bolus MPS had returned to basal rates. We detected no benefit of rapid aminoacidemia in this older population despite enhanced anabolic signaling and greater overall EAA exposure. Rather, apparent delayed onset of the "muscle-full" effect permitted identical MPS following low-amplitude-sustained EAA exposure. PMID:26152764

  8. Activation by Insulin and Amino Acids of Signaling Components Leading to Translation Initiation in Skeletal Muscle of Neonatal Pigs Is Developmentally Regulated

    PubMed Central

    Suryawan, Agus; Orellana, Renan A.; Nguyen, Hanh V.; Jeyapalan, Asumthia S.; Fleming, Jillian R.; Davis, Teresa A.

    2009-01-01

    Insulin (INS) and amino acids (AA) act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to translation initiation and how these responses change with development. Overnight fasted 6-day-old (n=4/group) and 26-day-old (n=6/group) pigs were studied during: 1) euinsulinemic-euglycemic-euaminoacidemic conditions (controls), 2) euinsulinemic-euglycemic-hyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, increased the phosphorylation of protein kinase B (PKB) and tuberous sclerosis 2 (TSC2). Both INS and AA increased protein synthesis and the phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1, and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and these responses were higher in 6-day-old compared to 26-day-old pigs. Both INS and AA decreased the binding of 4E-BP1 to eIF4E and increased eIF4E binding to eIF4G; these effects were greater in 6-day-old than in 26-day-old pigs. Neither INS nor AA altered the composition of mTORC1 (raptor, mTOR, and GβL) or mTORC2 (rictor, mTOR, and GβL) complexes. Furthermore, neither INS, AA, nor age had any effect on the abundance of Rheb and the phosphorylation of AMP-activated kinase (AMPK) and eukaryotic elongation factor 2 (eEF2). Our results suggest that the activation by insulin and amino acids of signaling components leading to translation initiation is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs. PMID:17878222

  9. Influences of carbohydrate plus amino acid supplementation on differing exercise intensity adaptations in older persons: skeletal muscle and endocrine responses.

    PubMed

    Onambélé-Pearson, Gladys Leopoldine; Breen, Leigh; Stewart, Claire E

    2010-06-01

    Losses in physiological function in healthy ageing occur partly as a consequence of reduced protein intake and partly as a consequence of less than 30-min/day of moderate to vigorous physical activity. The current study aimed to compare the effects of two different intensities of resistance training in healthy older adults, whose habitual dietary intake was supplemented with carbohydrate and amino acid preparations. We hypothesised that although intensive exercise with appropriate carbohydrate and amino acid supplementation would result in the most profound impact on in vivo markers of healthy physiologic and endocrine functions in previously sedentary older individuals, the effectiveness of the less intense exercise prescription with supplementation would also result in beneficial adaptations over and above findings of previous studies on low intensity exercise alone. Twenty-nine older adults (out of 32) completed the study after being randomly assigned to low (SUP_LowR, i.e., approximately 40% 1RM; n = 16) versus high resistance training (SUP_HighR, i.e., approximately 80% 1RM; n = 13) for 12 weeks. A carbohydrate supplement was ingested immediately before and during every exercise session and an amino acid cocktail was ingested post-exercise. Neither intervention significantly impacted upon body composition assessed using: Body mass index, waist/hip ratio and bioelectric impedance. Muscle strength increased similarly in the two groups with the SUP_HighR protocol showing 46 +/- 8%, 10.8 +/- 4.4% and 26.9 +/- 4.9% (P < 0.01) improvements in 1-RM strength, unilateral and bilateral knee extension torque, respectively, compared with 39 +/- 2%, 9.4 +/- 3.7% and 29.5 +/- 8.2% (P < 0.01) increments in the same measures in the SUP_LowR group. Lean muscle thickness however, showed a greater benefit of the SUP_LowR protocol (8.7 +/- 3.9% increase, P < 0.05) compared with the SUP_HighR protocol, which elicited no significant change. In terms of functional abilities, only the standing-from-lying (SFL) test exhibited an improvement in rate in the SUP_HighR group (-11.4%, P < 0.05). The SUP_LowR group, on the other hand, showed significant improvements in the get-up-and-go (-8.7 +/- 3.6%, P < 0.05), the SFL (-4.7% change, P = 0.05) and the 6-min walk (7.2 +/- 2.2% increase in distance covered, P < 0.01) tests. Following overnight fasting, serum levels of glucose changed significantly (-13 +/- 4.7% decrease, P < 0.01) in SUP_LowR. Serum levels of insulin (-25 +/- 5.3% decrease, P = 0.05), neuropeptide Y (-24 +/- 15.3% decrease, P = 0.02), and IGFBP-3 (-11 +/- 6.6% decrease, P = 0.03), changed significantly in SUP_HighR. Circulating levels of interleukin-6, tumour necrosis factor-alpha and insulin-like growth factor 1 did not alter significantly in either intervention group. These data suggest that whilst both interventions were beneficial in older persons, the end targets as well as metabolic and hormonal adaptations are different. The supplementation plus low exercise regimen tended to impact on muscle hypertrophy combined with increased habitual function. Supplementation plus high-intensity exercise regimen improved markers of strength, but not to a significantly greater extent than supplementation plus low intensity exercise. PMID:20431985

  10. Skeletal Muscle Hypertrophy after Aerobic Exercise Training

    PubMed Central

    Konopka, Adam R.; Harber, Matthew P.

    2014-01-01

    Current dogma suggests aerobic exercise training has minimal effect on skeletal muscle size. We and others have demonstrated that aerobic exercise acutely and chronically alters protein metabolism and induces skeletal muscle hypertrophy. These findings promote an antithesis to the status quo by providing novel perspective on skeletal muscle mass regulation and insight into exercise-countermeasures for populations prone to muscle loss. PMID:24508740

  11. Choosing a skeletal muscle relaxant.

    PubMed

    See, Sharon; Ginzburg, Regina

    2008-08-01

    Skeletal muscle relaxants are widely used in treating musculoskeletal conditions. However, evidence of their effectiveness consists mainly of studies with poor methodologic design. In addition, these drugs have not been proven to be superior to acetaminophen or nonsteroidal anti-inflammatory drugs for low back pain. Systematic reviews and meta-analyses support using skeletal muscle relaxants for short-term relief of acute low back pain when nonsteroidal anti-inflammatory drugs or acetaminophen are not effective or tolerated. Comparison studies have not shown one skeletal muscle relaxant to be superior to another. Cyclobenzaprine is the most heavily studied and has been shown to be effective for various musculoskeletal conditions. The sedative properties of tizanidine and cyclobenzaprine may benefit patients with insomnia caused by severe muscle spasms. Methocarbamol and metaxalone are less sedating, although effectiveness evidence is limited. Adverse effects, particularly dizziness and drowsiness, are consistently reported with all skeletal muscle relaxants. The potential adverse effects should be communicated clearly to the patient. Because of limited comparable effectiveness data, choice of agent should be based on side-effect profile, patient preference, abuse potential, and possible drug interactions. PMID:18711953

  12. Tropomyosins in skeletal muscle diseases.

    PubMed

    Kee, Anthony J; Hardeman, Edna C

    2008-01-01

    A number of congenital muscle diseases and disorders are caused by mutations in genes that encode the proteins present in or associated with the thin filaments of the muscle sarcomere. These genes include alpha-skeletal actin (ACTA1), beta-tropomyosin (TPM2), alpha-tropomyosin slow (TPM3), nebulin (NEB), troponin I fast (TNNI2), troponin T slow (TNNT1), troponin T fast (TNNT3) and cofilin (CFL2). Mutations in two of the four tropomyosin (Tm) genes, TPM2 and TPM3, result in at least three different skeletal muscle diseases and one disorder as distinguished by the presence of specific clinical features and/or structural abnormalities--nemaline myopathy (TPM2 and TPM3), distal arthrogryposis (TPM2), cap disease (TPM2) and congenital fiber type disproportion (TPM3). These diseases have overlapping clinical features and pathologies and there are cases of family members who have the same mutation, but different diseases (Table 1). The relatively recent discovery of nonmuscle or cytoskeletal Tms in skeletal muscle adds to this complexity since it is now possible that a disease-causing mutation could be in a striated isoform and a cytoskeletal isoform both present in muscle. PMID:19209820

  13. Signaling Pathways Related to Protein Synthesis and Amino Acid Concentration in Pig Skeletal Muscles Depend on the Dietary Protein Level, Genotype and Developmental Stages

    PubMed Central

    Liu, Yingying; Li, Fengna; Kong, Xiangfeng; Tan, Bie; Li, Yinghui; Duan, Yehui; Blachier, François; Hu, Chien-An A.; Yin, Yulong

    2015-01-01

    Muscle growth is regulated by the homeostatic balance of the biosynthesis and degradation of muscle proteins. To elucidate the molecular interactions among diet, pig genotype, and physiological stage, we examined the effect of dietary protein concentration, pig genotype, and physiological stages on amino acid (AA) pools, protein deposition, and related signaling pathways in different types of skeletal muscles. The study used 48 Landrace pigs and 48 pure-bred Bama mini-pigs assigned to each of 2 dietary treatments: lower/GB (Chinese conventional diet)- or higher/NRC (National Research Council)-protein diet. Diets were fed from 5 weeks of age to respective market weights of each genotype. Samples of biceps femoris muscle (BFM, type I) and longissimus dorsi muscle (LDM, type II) were collected at nursery, growing, and finishing phases according to the physiological stage of each genotype, to determine the AA concentrations, mRNA levels for growth-related genes in muscles, and protein abundances of mechanistic target of rapamycin (mTOR) signaling pathway. Our data showed that the concentrations of most AAs in LDM and BFM of pigs increased (P<0.05) gradually with increasing age. Bama mini-pigs had generally higher (P<0.05) muscle concentrations of flavor-related AA, including Met, Phe, Tyr, Pro, and Ser, compared with Landrace pigs. The mRNA levels for myogenic determining factor, myogenin, myocyte-specific enhancer binding factor 2 A, and myostatin of Bama mini-pigs were higher (P<0.05) than those of Landrace pigs, while total and phosphorylated protein levels for protein kinase B, mTOR, and p70 ribosomal protein S6 kinases (p70S6K), and ratios of p-mTOR/mTOR, p-AKT/AKT, and p-p70S6K/p70S6K were lower (P<0.05). There was a significant pig genotype-dependent effect of dietary protein on the levels for mTOR and p70S6K. When compared with the higher protein-NRC diet, the lower protein-GB diet increased (P<0.05) the levels for mTOR and p70S6K in Bama mini-pigs, but repressed (P<0.05) the level for p70S6K in Landrace pigs. The higher protein-NRC diet increased ratio of p-mTOR/mTOR in Landrace pigs. These findings indicated that the dynamic consequences of AA profile and protein deposition in muscle tissues are the concerted effort of distinctive genotype, nutrient status, age, and muscle type. Our results provide valuable information for animal feeding strategy. PMID:26394157

  14. Signaling Pathways Related to Protein Synthesis and Amino Acid Concentration in Pig Skeletal Muscles Depend on the Dietary Protein Level, Genotype and Developmental Stages.

    PubMed

    Liu, Yingying; Li, Fengna; Kong, Xiangfeng; Tan, Bie; Li, Yinghui; Duan, Yehui; Blachier, François; Hu, Chien-An A; Yin, Yulong

    2015-01-01

    Muscle growth is regulated by the homeostatic balance of the biosynthesis and degradation of muscle proteins. To elucidate the molecular interactions among diet, pig genotype, and physiological stage, we examined the effect of dietary protein concentration, pig genotype, and physiological stages on amino acid (AA) pools, protein deposition, and related signaling pathways in different types of skeletal muscles. The study used 48 Landrace pigs and 48 pure-bred Bama mini-pigs assigned to each of 2 dietary treatments: lower/GB (Chinese conventional diet)- or higher/NRC (National Research Council)-protein diet. Diets were fed from 5 weeks of age to respective market weights of each genotype. Samples of biceps femoris muscle (BFM, type I) and longissimus dorsi muscle (LDM, type II) were collected at nursery, growing, and finishing phases according to the physiological stage of each genotype, to determine the AA concentrations, mRNA levels for growth-related genes in muscles, and protein abundances of mechanistic target of rapamycin (mTOR) signaling pathway. Our data showed that the concentrations of most AAs in LDM and BFM of pigs increased (P<0.05) gradually with increasing age. Bama mini-pigs had generally higher (P<0.05) muscle concentrations of flavor-related AA, including Met, Phe, Tyr, Pro, and Ser, compared with Landrace pigs. The mRNA levels for myogenic determining factor, myogenin, myocyte-specific enhancer binding factor 2 A, and myostatin of Bama mini-pigs were higher (P<0.05) than those of Landrace pigs, while total and phosphorylated protein levels for protein kinase B, mTOR, and p70 ribosomal protein S6 kinases (p70S6K), and ratios of p-mTOR/mTOR, p-AKT/AKT, and p-p70S6K/p70S6K were lower (P<0.05). There was a significant pig genotype-dependent effect of dietary protein on the levels for mTOR and p70S6K. When compared with the higher protein-NRC diet, the lower protein-GB diet increased (P<0.05) the levels for mTOR and p70S6K in Bama mini-pigs, but repressed (P<0.05) the level for p70S6K in Landrace pigs. The higher protein-NRC diet increased ratio of p-mTOR/mTOR in Landrace pigs. These findings indicated that the dynamic consequences of AA profile and protein deposition in muscle tissues are the concerted effort of distinctive genotype, nutrient status, age, and muscle type. Our results provide valuable information for animal feeding strategy. PMID:26394157

  15. Skeletal muscle: an endocrine organ

    PubMed Central

    Pratesi, Alessandra; Tarantini, Francesca; Di Bari, Mauro

    2013-01-01

    Summary Tropism and efficiency of skeletal muscle depend on the complex balance between anabolic and catabolic factors. This balance gradually deteriorates with aging, leading to an age-related decline in muscle quantity and quality, called sarcopenia: this condition plays a central role in physical and functional impairment in late life. The knowledge of the mechanisms that induce sarcopenia and the ability to prevent or counteract them, therefore, can greatly contribute to the prevention of disability and probably also mortality in the elderly. It is well known that skeletal muscle is the target of numerous hormones, but only in recent years studies have shown a role of skeletal muscle as a secretory organ of cytokines and other peptides, denominated myokines (IL6, IL8, IL15, Brain-derived neurotrophic factor, and leukaemia inhibitory factor), which have autocrine, paracrine, or endocrine actions and are deeply involved in inflammatory processes. Physical inactivity promotes an unbalance between these substances towards a pro-inflammatory status, thus favoring the vicious circle of sarcopenia, accumulation of fat – especially visceral – and development of cardiovascular diseases, type 2 diabetes mellitus, cancer, dementia and depression, according to what has been called “the diseasome of physical inactivity”. PMID:23858303

  16. Skeletal muscle satellite cells

    NASA Technical Reports Server (NTRS)

    Schultz, E.; McCormick, K. M.

    1994-01-01

    Evidence now suggests that satellite cells constitute a class of myogenic cells that differ distinctly from other embryonic myoblasts. Satellite cells arise from somites and first appear as a distinct myoblast type well before birth. Satellite cells from different muscles cannot be functionally distinguished from one another and are able to provide nuclei to all fibers without regard to phenotype. Thus, it is difficult to ascribe any significant function to establishing or stabilizing fiber type, even during regeneration. Within a muscle, satellite cells exhibit marked heterogeneity with respect to their proliferative behavior. The satellite cell population on a fiber can be partitioned into those that function as stem cells and those which are readily available for fusion. Recent studies have shown that the cells are not simply spindle shaped, but are very diverse in their morphology and have multiple branches emanating from the poles of the cells. This finding is consistent with other studies indicating that the cells have the capacity for extensive migration within, and perhaps between, muscles. Complexity of cell shape usually reflects increased cytoplasmic volume and organelles including a well developed Golgi, and is usually associated with growing postnatal muscle or muscles undergoing some form of induced adaptive change or repair. The appearance of activated satellite cells suggests some function of the cells in the adaptive process through elaboration and secretion of a product. Significant advances have been made in determining the potential secretion products that satellite cells make. The manner in which satellite cell proliferative and fusion behavior is controlled has also been studied. There seems to be little doubt that cellcell coupling is not how satellite cells and myofibers communicate. Rather satellite cell regulation is through a number of potential growth factors that arise from a number of sources. Critical to the understanding of this form of control is to determine which of the many growth factors that can alter satellite cell behavior in vitro are at work in vivo. Little work has been done to determine what controls are at work after a regeneration response has been initiated. It seems likely that, after injury, growth factors are liberated through proteolytic activity and initiate an activation process whereby cells enter into a proliferative phase. After myofibers are formed, it also seems likely that satellite cell behavior is regulated through diffusible factors arising from the fibers rather than continuous control by circulating factors.(ABSTRACT TRUNCATED AT 400 WORDS).

  17. Skeletal muscle satellite cells.

    PubMed

    Schultz, E; McCormick, K M

    1994-01-01

    Evidence now suggests that satellite cells constitute a class of myogenic cells that differ distinctly from other embryonic myoblasts. Satellite cells arise from somites and first appear as a distinct myoblast type well before birth. Satellite cells from different muscles cannot be functionally distinguished from one another and are able to provide nuclei to all fibers without regard to phenotype. Thus, it is difficult to ascribe any significant function to establishing or stabilizing fiber type, even during regeneration. Within a muscle, satellite cells exhibit marked heterogeneity with respect to their proliferative behavior. The satellite cell population on a fiber can be partitioned into those that function as stem cells and those which are readily available for fusion. Recent studies have shown that the cells are not simply spindle shaped, but are very diverse in their morphology and have multiple branches emanating from the poles of the cells. This finding is consistent with other studies indicating that the cells have the capacity for extensive migration within, and perhaps between, muscles. Complexity of cell shape usually reflects increased cytoplasmic volume and organelles including a well developed Golgi, and is usually associated with growing postnatal muscle or muscles undergoing some form of induced adaptive change or repair. The appearance of activated satellite cells suggests some function of the cells in the adaptive process through elaboration and secretion of a product. Significant advances have been made in determining the potential secretion products that satellite cells make. The manner in which satellite cell proliferative and fusion behavior is controlled has also been studied. There seems to be little doubt that cellcell coupling is not how satellite cells and myofibers communicate. Rather satellite cell regulation is through a number of potential growth factors that arise from a number of sources. Critical to the understanding of this form of control is to determine which of the many growth factors that can alter satellite cell behavior in vitro are at work in vivo. Little work has been done to determine what controls are at work after a regeneration response has been initiated. It seems likely that, after injury, growth factors are liberated through proteolytic activity and initiate an activation process whereby cells enter into a proliferative phase. After myofibers are formed, it also seems likely that satellite cell behavior is regulated through diffusible factors arising from the fibers rather than continuous control by circulating factors.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8209136

  18. Occurrence of a novel acetylated amino acid, N(alpha)-acetylhistidine, in skeletal muscle of freshwater fish and other ectothermic vertebrates.

    PubMed

    Yamada, Shoji; Kawashima, Kazuto; Baba, Kyoko; Oku, Takahiro; Ando, Seiichi

    2009-03-01

    The occurrence of N(alpha)-acetylhistidine (NAH) in skeletal muscle of 91 species of freshwater fish and 9 species of other ectothermic vertebrates was investigated, with consideration of phylogenetic relationships. Of the 91 freshwater fish species examined, 13 species (7 cichlids, 5 anabantids, and 1 catfish) contained considerable amounts (>1 micromol/g) of NAH in their skeletal muscles. The highest level (10.37 micromol/g) of NAH was found in the tissue of Betta splendens (Siamese fighting fish). Moreover, the NAH contents in the tissues of Trichogaster trichopterus (three spot gourami), Kryptopterus bicirrhis (glass catfish), Oreochromis niloticus (Nile tilapia), Mikrogeophagus ramirezi (ram cichlid) and Parachromis managuensis (Guapote tigre) were 3.17-6.16 micromol/g. The skeletal muscle of amphibians (5 species) and reptiles (4 species) had a low level (<0.25 micromol/g) of NAH. The present findings clearly demonstrate NAH as the fifth imidazole-related compound, in addition to histidine, carnosine, anserine and ophidine (balenine), recognized as a major non-protein nitrogenous constituent in the skeletal muscle of vertebrate animals. PMID:19100335

  19. Shark skeletal muscle tropomyosin is a phosphoprotein.

    PubMed

    Hayley, Michael; Chevaldina, Tatiana; Mudalige, Wasana A K A; Jackman, Donna M; Dobbin, Alvin D; Heeley, David H

    2008-01-01

    Shark skeletal muscle tropomyosin is classified as an alpha-type isoform. The chemical structure is characterised by the absence of cysteine and the presence of a sub-stoichiometric amount of covalently bound phosphate. The protein migrates as a single component on a SDS polyacrylamide gel but is resolved into two components by chromatography and electrophoresis both in the presence of urea at mild alkaline pH. The only detectable difference between these components is the presence of phosphoserine in the tropomyosin form of greater net negative charge. Low ionic strength (pH 7) solutions of phosphorylated shark tropomyosin display significantly higher specific viscosity than unphosphorylated, consistent with the presence of a phosphorylation site within the overlap region, serine 283, as well as conservation of the positively charged amino terminal region. Similar observations were made with tropomyosin prepared from the trunk muscle of Atlantic cod. In a steady-state MgATPase assay, thin filaments (Ca2+) reconstituted with shark phosphorylated tropomyosin activate myosin to a greater extent than those composed of unphosphorylated. The difference is attributable chiefly to a change in Vmax. Skeletal muscle tropomyosin is concluded to be phosphorylated in cartilaginous fishes as well as some teleosts. PMID:18763042

  20. Signaling pathways controlling skeletal muscle mass

    PubMed Central

    Egerman, Marc A.

    2014-01-01

    The molecular mechanisms underlying skeletal muscle maintenance involve interplay between multiple signaling pathways. Under normal physiological conditions, a network of interconnected signals serves to control and coordinate hypertrophic and atrophic messages, culminating in a delicate balance between muscle protein synthesis and proteolysis. Loss of skeletal muscle mass, termed “atrophy”, is a diagnostic feature of cachexia seen in settings of cancer, heart disease, chronic obstructive pulmonary disease, kidney disease, and burns. Cachexia increases the likelihood of death from these already serious diseases. Recent studies have further defined the pathways leading to gain and loss of skeletal muscle as well as the signaling events that induce differentiation and post-injury regeneration, which are also essential for the maintenance of skeletal muscle mass. In this review, we summarize and discuss the relevant recent literature demonstrating these previously undiscovered mediators governing anabolism and catabolism of skeletal muscle. PMID:24237131

  1. Aging of Skeletal Muscle Fibers

    PubMed Central

    Miljkovic, Natasa; Lim, Jae-Young; Miljkovic, Iva

    2015-01-01

    Aging has become an important topic for scientific research because life expectancy and the number of men and women in older age groups have increased dramatically in the last century. This is true in most countries of the world including the Republic of Korea and the United States. From a rehabilitation perspective, the most important associated issue is a progressive decline in functional capacity and independence. Sarcopenia is partly responsible for this decline. Many changes underlying the loss of muscle mass and force-generating capacity of skeletal muscle can be understood at the cellular and molecular levels. Muscle size and architecture are both altered with advanced adult age. Further, changes in myofibers include impairments in several physiological domains including muscle fiber activation, excitation-contraction coupling, actin-myosin cross-bridge interaction, energy production, and repair and regeneration. A thorough understanding of these alterations can lead to the design of improved preventative and rehabilitative interventions, such as personalized exercise training programs. PMID:25932410

  2. Channelopathies of skeletal muscle excitability

    PubMed Central

    Cannon, Stephen C.

    2016-01-01

    Familial disorders of skeletal muscle excitability were initially described early in the last century and are now known to be caused by mutations of voltage-gated ion channels. The clinical manifestations are often striking, with an inability to relax after voluntary contraction (myotonia) or transient attacks of severe weakness (periodic paralysis). An essential feature of these disorders is fluctuation of symptoms that are strongly impacted by environmental triggers such as exercise, temperature, or serum K+ levels. These phenomena have intrigued physiologists for decades, and in the past 25 years the molecular lesions underlying these disorders have been identified and mechanistic studies are providing insights for therapeutic strategies of disease modification. These familial disorders of muscle fiber excitability are “channelopathies” caused by mutations of a chloride channel (ClC-1), sodium channel (NaV1.4), calcium channel (CaV1.1) and several potassium channels (Kir2.1, Kir2.6, Kir3.4). This review provides a synthesis of the mechanistic connections between functional defects of mutant ion channels, their impact on muscle excitability, how these changes cause clinical phenotypes, and approaches toward therapeutics. PMID:25880512

  3. Skeletal muscle regeneration in cancer cachexia.

    PubMed

    Bossola, Maurizio; Marzetti, Emanuele; Rosa, Fausto; Pacelli, Fabio

    2016-05-01

    Muscle wasting is the most important phenotypic and clinical feature of cancer cachexia, and the principal cause of impaired physical function, fatigue, and respiratory complications. Muscle loss has been attributed to a variable combination of reduced nutritional intake and an imbalance between anabolic and catabolic processes. It has been suggested that defective skeletal muscle regeneration may also contribute to muscle wasting in cancer patients. However, there is little in vitro or in vivo data available, in either animals or in humans, regarding skeletal muscle regeneration in cancer wasting. The aim of the present review is to define the role of skeletal muscle regeneration in the muscle wasting of cancer patients and to determine possible therapeutic implications. PMID:26857538

  4. Muscle-specific microRNAs in skeletal muscle development.

    PubMed

    Horak, Martin; Novak, Jan; Bienertova-Vasku, Julie

    2016-02-01

    Proper muscle function constitutes a precondition for good heath and an active lifestyle during an individual's lifespan and any deviations from normal skeletal muscle development and its functions may lead to numerous health conditions including e.g. myopathies and increased mortality. It is thus not surprising that there is an increasing need for understanding skeletal muscle developmental processes and the associated molecular pathways, especially as such information could find further uses in therapy. The understanding of complex skeletal muscle developmental networks was broadened with the discovery of microRNA (miRNA) molecules. MicroRNAs are evolutionary conserved small non-coding RNAs capable of negatively regulating gene expression on a post-transcriptional level by means of miRNA-mRNA interaction. Several miRNAs expressed exclusively in muscle have been labeled myomiRs. MyomiRs represent an integral part of skeletal muscle development, i.e. playing a significant role during skeletal muscle proliferation, differentiation and regeneration. The purpose of this review is to provide a summary of current knowledge regarding the involvement of myomiRs in the individual phases of myogenesis and other aspects of skeletal muscle biology, along with an up-to-date list of myomiR target genes and their functions in skeletal muscle and miRNA-related therapeutic approaches and future prospects. PMID:26708096

  5. Co-dependence of genotype and dietary protein intake to affect expression on amino acid/peptide transporters in porcine skeletal muscle.

    PubMed

    Liu, Y; Kong, X; Li, F; Tan, B; Li, Y; Duan, Y; Yin, Y; He, J; Hu, C; Blachier, F; Wu, Guoyao

    2016-01-01

    A total of 96 barrows (48 pure-bred Bama mini-pigs representing fatty genotype, and 48 Landrace pigs representing lean genotype) were randomly assigned to either a low- or adequate-protein treatment diet. The experimental period commenced at 5 weeks of age and extended to the finishing period. After euthanasia, blood and skeletal muscle samples were collected from pigs at the nursery, growing, and finishing phases. Our results indicate that the concentrations of free AAs in the plasma and muscle decreased as the age of the pigs increased. In addition, a strain × growth phase interaction (P < 0.05) was observed for the free AA pool in the plasma and muscle. The low-protein diet upregulated (P < 0.05) the mRNA levels for T1R1/T1R3 involved in glutamate binding, but downregulated (P < 0.05) the mRNA levels for PAT1, PAT2, and ASCT2, which transport neutral AAs into muscles. Bama mini-pigs had higher (P < 0.05) mRNA levels for LAT1, SNAT2, and EAAC1, but a lower (P < 0.05) mRNA level for PepT1, compared with Landrace pigs. Collectively, our findings indicate that adequate provision of dietary protein plays an important role in regulating profiles of free AA pools and expression of key AA/peptide transporters/transceptors in a genotype- and tissue-specific manner. PMID:26255284

  6. Regulation of skeletal muscle perfusion during exercise

    NASA Technical Reports Server (NTRS)

    Delp, M. D.; Laughlin, M. H.

    1998-01-01

    For exercise to be sustained, it is essential that adequate blood flow be provided to skeletal muscle. The local vascular control mechanisms involved in regulating muscle perfusion during exercise include metabolic control, endothelium-mediated control, propagated responses, myogenic control, and the muscle pump. The primary determinant of muscle perfusion during sustained exercise is the metabolic rate of the muscle. Metabolites from contracting muscle diffuse to resistance arterioles and act directly to induce vasodilation, or indirectly to inhibit noradrenaline release from sympathetic nerve endings and oppose alpha-adrenoreceptor-mediated vasoconstriction. The vascular endothelium also releases vasodilator substances (e.g., prostacyclin and nitric oxide) that are prominent in establishing basal vascular tone, but these substances do not appear to contribute to the exercise hyperemia in muscle. Endothelial and smooth muscle cells may also be involved in propagating vasodilator signals along arterioles to parent and daughter vessels. Myogenic autoregulation does not appear to be involved in the exercise hyperemia in muscle, but the rhythmic propulsion of blood from skeletal muscle veins facilitates venous return to the heart and muscle perfusion. It appears that the primary determinants of sustained exercise hyperemia in skeletal muscle are metabolic vasodilation and increased vascular conductance via the muscle pump. Additionally, sympathetic neural control is important in regulating muscle blood flow during exercise.

  7. Skeletal Muscle Autophagy: A New Metabolic Regulator

    PubMed Central

    Neel, Brian A.; Lin, Yuxi; Pessin, Jeffrey E.

    2013-01-01

    Autophagy classically functions as a physiological process to degrade cytoplasmic components, protein aggregates, and/or organelles, as a mechanism for nutrient breakdown, and as a regulator of cellular architecture. Proper autophagic flux is vital for both functional skeletal muscle, which controls support and movement of the skeleton, and muscle metabolism. The role of autophagy as a metabolic regulator in muscle has been previously studied; however, the underlying molecular mechanisms that control autophagy in skeletal muscle have only just begun to emerge. Here, we review recent literature on the molecular pathways controlling skeletal muscle autophagy, and discuss how they connect autophagy to metabolic regulation. We also focus on the implications these studies hold for understanding metabolic and muscle wasting diseases. PMID:24182456

  8. Enhanced skeletal muscle for effective glucose homeostasis.

    PubMed

    Yang, Jinzeng

    2014-01-01

    As the single largest organ in the body, the skeletal muscle is the major site of insulin-stimulated glucose uptake in the postprandial state. Skeletal muscles provide the physiological foundation for physical activities and fitness. Reduced muscle mass and strength is commonly associated with many chronic diseases, including obesity and insulin resistance. The complications of diabetes on skeletal muscle mass and physiology, resulting from either insulin deprivation or insulin resistance, may not be life-threatening, but accelerate the lost physiological functions of glucose homeostasis. The formation of skeletal muscle commences in the embryonic developmental stages at the time of mesoderm generation, where somites are the developmental milestone in musculoskeletal formation. Dramatic skeletal muscle growth occurs during adolescence as a result of muscle fiber hypertrophy since muscle fiber formation is mostly completed before birth. The rate of growth rapidly decelerates in the late stages of adulthood as adipose tissue gradually accumulates more fat when energy intake exceeds expenditure. Physiologically, the key to effective glucose homeostasis is the hormone insulin and insulin sensitivity of target tissues. Enhanced skeletal muscle, by either intrinsic mechanism or physical activity, offers great advantages and benefits in facilitating glucose regulation. One key protein factor named myostatin is a dominant inhibitor of muscle mass. Depression of myostatin by its propeptide or mutated receptor enhances muscle mass effectively. The muscle tissue utilizes a large portion of metabolic energy for its growth and maintenance. We demonstrated that transgenic overexpression of myostatin propeptide in mice fed with a high-fat diet enhanced muscle mass and circulating adiponectin, while the wild-type mice developed obesity and insulin resistance. Enhanced muscle growth has positive effects on fat metabolism through increasing adiponectin expression and its regulations. Molecular studies of the exercise-induced glucose uptake in skeletal muscle also provide insights on auxiliary substances that mimic the plastic adaptations of muscle to exercise so that the body may amplify the effects of exercise in contending physical activity limitations or inactivity. The recent results from the peroxisome proliferator-activated receptor γ coactivator 1α provide a promising therapeutic approach for future metabolic drug development. In summary, enhanced skeletal muscle and fundamental understanding of the biological process are critical for effective glucose homeostasis in metabolic disorders. PMID:24373237

  9. Myostatin in the Pathophysiology of Skeletal Muscle

    PubMed Central

    Carnac, Gilles; Vernus, Barbara; Bonnieu, Anne

    2007-01-01

    Myostatin is an endogenous, negative regulator of muscle growth determining both muscle fiber number and size. The myostatin pathway is conserved across diverse species ranging from zebrafish to humans. Experimental models of muscle growth and regeneration have implicated myostatin as an important mediator of catabolic pathways in muscle cells. Inhibition of this pathway has emerged as a promising therapy for muscle wasting. Here we discuss the recent developments and the controversies in myostatin research, focusing on the molecular and cellular mechanisms underlying the actions of myostatin on skeletal muscle and the potential therapeutic role of myostatin on muscle-related disorders. PMID:19412331

  10. Effects of glucose and amino acid depletions on protein synthetic parameters in liver and skeletal muscle of rats during parenteral nutrition.

    PubMed

    Kikuchi, T; Okamoto, H; Chiku, K; Natori, Y

    1986-12-01

    Rats were nourished by intravenous infusion of four different experimental solutions: total parenteral nutrition (TPN) solution (group I); glucose-depleted TPN solution (group II); amino acid-depleted TPN solution (group III); and glucose- and amino acid-depleted TPN solution (group IV). All except group I animals lost body weight and showed negative nitrogen balance during a 7-day experimental period; glucose-depleted groups II and IV generally suffered more severely than amino acid-depleted group III. However, the concentration of plasma albumin in group III was significantly lower than that in the other groups. The weights of liver and gastrocnemius muscles after 7 days of infusion with different nutrient compositions were fairly well correlated with the RNA/DNA ratios in these tissues. Infusion of nutritionally deficient solutions caused progressive disaggregation of polysomes in both liver and gastrocnemius muscles, indicating variable degrees of impairment of protein synthesis in these tissues. The changes in polysomal profiles were rapid and sensitive; the polysomal disaggregation was evident within one day of infusion with deficient solutions. The determination of polysomal profiles in various tissues may be useful in optimizing the composition of TPN solutions. PMID:3108472

  11. Whole body and skeletal muscle protein turnover in recovery from burns

    PubMed Central

    Porter, Craig; Hurren, Nicholas M; Herndon, David N; Børsheim, Elisabet

    2013-01-01

    Trauma and critical illness are associated with a stress response that results in increased skeletal muscle protein catabolism, which is thought to facilitate the synthesis of acute phase proteins in the liver as well as proteins involved in immune function. What makes burn injury a unique form of trauma is the existence of vast skin lesions, where the majority of afflicted tissue is often surgically excised post injury. Thereafter, recovery is dependent on the formation of a significant quantity of new skin, meaning that the burned patient requires a large and sustained supply of amino acids to facilitate wound healing. Skeletal muscle has the capacity to store surplus glucose and fatty acids within glycogen and triacylglycerol depots respectively, where glycogen and fatty acids can be mobilized during prolonged periods of caloric restriction or heightened metabolic demand (e.g., exercise), to be catabolized in order to maintain cellular ATP availability. Amino acids, on the other hand, are not generally considered to be stored in such a manner within skeletal muscle, i.e., in a temporary pool independent of structural proteins and cellular organelles etc. Subsequently, in response to severe thermal trauma, skeletal muscle assumes the role of an amino acid reserve where muscle protein breakdown and amino acid release from skeletal muscle serves to buffer plasma amino acid concentrations. Interestingly, it seems like aggressive feeding of the severely burned patient may not necessarily supply amino acids in sufficient abundance to normalize skeletal muscle protein metabolism, suggesting that skeletal muscle becomes an essential store of protein in patients suffering from severe burn trauma. In this article, the effects of burn injury on whole body and skeletal muscle protein metabolism will be discussed in an attempt to distill the current understanding of the impact of this debilitating injury on the redistribution of skeletal muscle protein stores. PMID:23386981

  12. Space travel directly induces skeletal muscle atrophy

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H.; Chromiak, J.; Shansky, J.; Del Tatto, M.; Lemaire, J.

    1999-01-01

    Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

  13. Skeletal muscle tuberculosis simultaneously involving multiple sites.

    PubMed

    Neogi, Devdatta S; Bandekar, Shivanand M; Chawla, Lokesh

    2013-03-01

    Tuberculosis (TB) continues to be a public health problem in both developing and industrialized countries. TB of the skeletal muscle is very rare. We present a case of the simultaneous involvement of skeletal muscles in multiple sites in an 11-year-old immune-competent female patient. All physicians should have adequate knowledge of TB and awareness of its atypical presentations to ensure the proper management of such patients. PMID:22561909

  14. Skeletal muscle functions around the clock.

    PubMed

    Mayeuf-Louchart, A; Staels, B; Duez, H

    2015-09-01

    In mammals, the central clock localized in the central nervous system imposes a circadian rhythmicity to all organs. This is achieved thanks to a well-conserved molecular clockwork, involving interactions between several transcription factors, whose pace is conveyed to peripheral tissues through neuronal and humoral signals. The molecular clock plays a key role in the control of numerous physiological processes and takes part in the regulation of metabolism and energy balance. Skeletal muscle is one of the peripheral organs whose function is under the control of the molecular clock. However, although skeletal muscle metabolism and performances display circadian rhythmicity, the role of the molecular clock in the skeletal muscle has remained unappreciated for years. Peripheral organs such as skeletal muscle, and the liver, among others, can be desynchronized from the central clock by external stimuli, such as feeding or exercise, which impose a new rhythm at the organism level. In this review, we discuss our current understanding of the clock in skeletal muscle circadian physiology, focusing on the control of myogenesis and skeletal muscle metabolism. PMID:26332967

  15. Aspects of skeletal muscle modelling.

    PubMed Central

    Epstein, Marcelo; Herzog, Walter

    2003-01-01

    The modelling of skeletal muscle raises a number of philosophical questions, particularly in the realm of the relationship between different possible levels of representation and explanation. After a brief incursion into this area, a list of desiderata is proposed as a guiding principle for the construction of a viable model, including: comprehensiveness, soundness, experimental consistency, predictive ability and refinability. Each of these principles is illustrated by means of simple examples. The presence of internal constraints, such as incompressibility, may lead to counterintuitive results. A one-panel example is exploited to advocate the use of the principle of virtual work as the ideal tool to deal with these situations. The question of stability in the descending limb of the force-length relation is addressed and a purely mechanical analogue is suggested. New experimental results confirm the assumption that fibre stiffness is positive even in the descending limb. The indeterminacy of the force-sharing problem is traditionally resolved by optimizing a, presumably, physically meaningful target function. After presenting some new results in this area, based on a separation theorem, it is suggested that a more fundamental approach to the problem is the abandoning of optimization criteria in favour of an explicit implementation of activation criteria. PMID:14561335

  16. How sex hormones promote skeletal muscle regeneration.

    PubMed

    Velders, Martina; Diel, Patrick

    2013-11-01

    Skeletal muscle regeneration efficiency declines with age for both men and women. This decline impacts on functional capabilities in the elderly and limits their ability to engage in regular physical activity and to maintain independence. Aging is associated with a decline in sex hormone production. Therefore, elucidating the effects of sex hormone substitution on skeletal muscle homeostasis and regeneration after injury or disuse is highly relevant for the aging population, where sarcopenia affects more than 30 % of individuals over 60 years of age. While the anabolic effects of androgens are well known, the effects of estrogens on skeletal muscle anabolism have only been uncovered in recent times. Hence, the purpose of this review is to provide a mechanistic insight into the regulation of skeletal muscle regenerative processes by both androgens and estrogens. Animal studies using estrogen receptor (ER) antagonists and receptor subtype selective agonists have revealed that estrogens act through both genomic and non-genomic pathways to reduce leukocyte invasion and increase satellite cell numbers in regenerating skeletal muscle tissue. Although animal studies have been more conclusive than human studies in establishing a role for sex hormones in the attenuation of muscle damage, data from a number of recent well controlled human studies is presented to support the notion that hormonal therapies and exercise induce added positive effects on functional measures and lean tissue mass. Based on the fact that aging human skeletal muscle retains the ability to adapt to exercise with enhanced satellite cell activation, combining sex hormone therapies with exercise may induce additive effects on satellite cell accretion. There is evidence to suggest that there is a 'window of opportunity' after the onset of a hypogonadal state such as menopause, to initiate a hormonal therapy in order to achieve maximal benefits for skeletal muscle health. Novel receptor subtype selective ligands and selective estrogen and androgen receptor modulators (SERMs, SARMs) promise to reduce health risks associated with classical hormonal therapies, whilst maintaining the positive effects on muscle repair. Dietary supplements containing compounds with structural similarity to estrogens (phytoestrogens) are increasingly used as alternatives to classical hormone-replacement therapies (HRT), but the effects on skeletal muscle are currently largely unknown. Research has started to investigate the combined effects of exercise and alternative HRTs, such as soy isoflavones, on skeletal muscle regenerative processes to provide safer and more efficient therapies to promote muscle regeneration and maintenance of muscle mass and strength in the aging population. PMID:23888432

  17. Uncovering the exercise-related proteome signature in skeletal muscle.

    PubMed

    Padrão, Ana Isabel; Ferreira, Rita; Amado, Francisco; Vitorino, Rui; Duarte, José Alberto

    2016-03-01

    Exercise training has been recommended as a nonpharmacological strategy for the prevention and attenuation of skeletal muscle atrophy in distinct pathophysiological conditions. Despite the well-established phenotypic alterations, the molecular mechanisms underlying exercise-induced skeletal muscle remodeling are poorly characterized. Proteomics based on mass spectrometry have been successfully applied for the characterization of skeletal muscle proteome, representing a pivotal approach for the wide characterization of the molecular networks that lead to skeletal muscle remodeling. Nevertheless, few studies were performed to characterize the exercise-induced proteome remodeling of skeletal muscle, with only six research papers focused on the cross-talk between exercise and pathophysiological conditions. In order to add new insights on the impact of distinct exercise programs on skeletal muscle proteome, molecular network analysis was performed with bioinformatics tools. This analysis highlighted an exercise-related proteome signature characterized by the up-regulation of the capacity for ATP generation, oxygen delivery, antioxidant capacity and regulation of mitochondrial protein synthesis. Chronic endurance training up-regulates the tricarboxylic acid cycle and oxidative phosphorylation system, whereas the release of calcium ion into cytosol and amino acid metabolism are the biological processes up-regulated by a single bout of exercise. Other issues as exercise intensity, load, mode and regimen as well as muscle type also influence the exercise-induced proteome signature. The comprehensive analysis of the molecular networks modulated by exercise training in health and disease, taking in consideration all these variables, might not only support the therapeutic effect of exercise but also highlight novel targets for the development of enhanced pharmacological strategies. PMID:26632760

  18. [Obesity, insulin resistance and skeletal muscle characteristics].

    PubMed

    Torres, S H

    1999-01-01

    Insulin resistance seems to be a metabolic aberration associated with obesity. Impaired insulin action is also central to a cluster of diseases including non-insulin dependent diabetes, hypertension, dyslipidemias and atherosclerosis. Body fat distribution, especially upper body segment obesity is related to insulin-resistance. Glucose uptake is insulin dependent in skeletal muscle and adipose tissue. From a quantitative standpoint, skeletal muscle has the greater impact on whole body glucose economy, therefore the cause of altered insulin sensitivity has been looked for in this tissue. The skeletal muscle is composed of different types of fibers with specific metabolic and circulatory characteristics; type IIB fibers are less insulin-sensitive and their proportion has been related to obesity and insulin resistance. The different factors that may impair insulin action and alter glucose uptake in skeletal muscle are: lower blood flow to muscle, produced by either decreased vasodilation or by increased sympathetic nerve activity; augmented diffusion distance from capillaries to muscle due to a decrease in capillary number or to enlarged muscle cells; decrease of insulin receptors; change in the fatty acid profile of major membrane structural phospholipids; decrease in glucose transporters (GLUT 4) and/or hexokinase; impairment in metabolic routes of glucose in muscle as reduction in glycogen synthase. Also, the high rate of lipolysis present in obesity and in insulin resistance could lead to an impaired glucose oxidation in muscle. PMID:10513036

  19. Myostatin directly regulates skeletal muscle fibrosis.

    PubMed

    Li, Zhao Bo; Kollias, Helen D; Wagner, Kathryn R

    2008-07-11

    Skeletal muscle fibrosis is a major pathological hallmark of chronic myopathies in which myofibers are replaced by progressive deposition of collagen and other extracellular matrix proteins produced by muscle fibroblasts. Recent studies have shown that in the absence of the endogenous muscle growth regulator myostatin, regeneration of muscle is enhanced, and muscle fibrosis is correspondingly reduced. We now demonstrate that myostatin not only regulates the growth of myocytes but also directly regulates muscle fibroblasts. Our results show that myostatin stimulates the proliferation of muscle fibroblasts and the production of extracellular matrix proteins both in vitro and in vivo. Further, muscle fibroblasts express myostatin and its putative receptor activin receptor IIB. Proliferation of muscle fibroblasts, induced by myostatin, involves the activation of Smad, p38 MAPK and Akt pathways. These results expand our understanding of the function of myostatin in muscle tissue and provide a potential target for anti-fibrotic therapies. PMID:18453534

  20. Identification of amino acids associated with skeletal muscle growth in late gestation and at weaning in lambs of well-nourished sheep.

    PubMed

    Sales, F A; Pacheco, D; Blair, H T; Kenyon, P R; Nicholas, G; Senna Salerno, M; McCoard, S A

    2014-11-01

    The objective of this study was to determine the association between intracellular free AA (FAA) profiles in skeletal muscle with muscle growth in twin and singleton fetuses in late pregnancy and at weaning, under an ad libitum feeding regime of the dam. Plasma from singleton- (n = 9) and twin-bearing (n = 10) ewes at d 140 of pregnancy and FAA in the semitendinosus muscle (STM) from the corresponding fetuses were studied. At weaning, intracellular STM FAA concentrations were compared between twins at the same age as singletons (Twin(age); n = 17) and at the same weight as singletons (Twin(wt); n = 17) to that of singletons (n = 20). Twin fetuses were 15% lighter (P = 0.03) with a 20% lighter STM (P = 0.02) compared to singletons. Maternal plasma FAA were similar (P ? 0.17) between singleton- and twin-bearing ewes. Twin fetuses had greater (P < 0.05) plasma concentrations of glutamine, histidine, and methionine and lower (P < 0.05) concentrations of aspartate, citrulline, glutamate, and ornithine compared with singletons. In fetal STM, twins had lower (P < 0.05) concentrations of aspartate and valine and greater (P < 0.01) concentration of methionine. Correlations were found between fetal STM weight and intracellular concentrations of arginine (r = 0.66, P < 0.01) and glutamine (r = 0.49, P < 0.01). Compared to singletons at weaning, Twin(age) were 16% lighter (P < 0.01) and the STM weight was proportionately 16% lighter (P < 0.01). For Twin(wt), the magnitude of the difference for STM weight was reduced to 8% lighter (P = 0.02). Compared to singletons, Twin(age) lambs had greater (P < 0.05) intracellular concentrations of glutamine, histidine, threonine, asparagine, alanine, serine, and glutamate but reduced taurine. The differences in FAA concentrations were less between Twin(wt) and singletons than between Twin(age) and singletons. Positive correlations were found between leucine, lysine, methionine, phenylalanine, proline, threonine, and tyrosine muscle concentration and STM weight at weaning. Males differed from females in intracellular FAA both in late pregnancy and at weaning. Twins had reduced RNA content during pregnancy and at weaning, suggesting a lower capacity for protein accretion. These data suggest that specific FAA concentrations are associated with differences in muscle growth during late pregnancy, notably arginine and glutamine, and reduced protein synthesis capacity. However, the relevance of specific FAA varies according to stage of development and sex of the lamb. PMID:25349352

  1. The benefits of coffee on skeletal muscle.

    PubMed

    Dirks-Naylor, Amie J

    2015-12-15

    Coffee is consumed worldwide with greater than a billion cups of coffee ingested every day. Epidemiological studies have revealed an association of coffee consumption with reduced incidence of a variety of chronic diseases as well as all-cause mortality. Current research has primarily focused on the effects of coffee or its components on various organ systems such as the cardiovascular system, with relatively little attention on skeletal muscle. Summary of current literature suggests that coffee has beneficial effects on skeletal muscle. Coffee has been shown to induce autophagy, improve insulin sensitivity, stimulate glucose uptake, slow the progression of sarcopenia, and promote the regeneration of injured muscle. Much more research is needed to reveal the full scope of benefits that coffee consumption may exert on skeletal muscle structure and function. PMID:26546720

  2. Epigenetic regulation of skeletal muscle metabolism.

    PubMed

    Howlett, Kirsten F; McGee, Sean L

    2016-07-01

    Normal skeletal muscle metabolism is essential for whole body metabolic homoeostasis and disruptions in muscle metabolism are associated with a number of chronic diseases. Transcriptional control of metabolic enzyme expression is a major regulatory mechanism for muscle metabolic processes. Substantial evidence is emerging that highlights the importance of epigenetic mechanisms in this process. This review will examine the importance of epigenetics in the regulation of muscle metabolism, with a particular emphasis on DNA methylation and histone acetylation as epigenetic control points. The emerging cross-talk between metabolism and epigenetics in the context of health and disease will also be examined. The concept of inheritance of skeletal muscle metabolic phenotypes will be discussed, in addition to emerging epigenetic therapies that could be used to alter muscle metabolism in chronic disease states. PMID:27215678

  3. Coaxing stem cells for skeletal muscle repair

    PubMed Central

    McCullagh, Karl J.A.; Perlingeiro, Rita C. R.

    2014-01-01

    Skeletal muscle has a tremendous ability to regenerate, attributed to a well-defined population of muscle stem cells called satellite cells. However, this ability to regenerate diminishes with age and can also be dramatically affected by multiple types of muscle diseases, or injury. Extrinsic and/or intrinsic defects in the regulation of satellite cells are considered to be major determinants for the diminished regenerative capacity. Maintenance and replenishment of the satellite cell pool is one focus for muscle regenerative medicine, which will be discussed. There are other sources of progenitor cells with myogenic capacity, which may also support skeletal muscle repair. However, all of these myogenic cell populations have inherent difficulties and challenges in maintaining or coaxing their derivation for therapeutic purpose. This review will highlight recent reported attributes of these cells and new bioengineering approaches to creating a supply of myogenic stem cells or implants applicable for acute and/or chronic muscle disorders. PMID:25049085

  4. Epigenetic control of skeletal muscle fibre type.

    PubMed

    Baar, K

    2010-08-01

    Adult muscle is extremely plastic. However, the muscle precursor cells associated with those fibres show stable and heritable differences in gene expression indicative of epigenetic imprinting. Epigenetic processes in the development of skeletal muscle have been appreciated for over a decade; however, there are a paucity of studies looking at whether epigenetics determines the phenotype of adult and/or ageing skeletal muscle. This review presents the evidence that epigenetics plays a role in determining adult muscle function and a series of unanswered questions that would greatly increase our understanding of how epigenetics works in adult muscle. With the increased interest in epigenetics, over the next few years this field will begin to unfold in unimaginable directions. PMID:20345412

  5. Inactivity amplifies the catabolic response of skeletal muscle to cortisol

    NASA Technical Reports Server (NTRS)

    Ferrando, A. A.; Stuart, C. A.; Sheffield-Moore, M.; Wolfe, R. R.

    1999-01-01

    Severe injury or trauma is accompanied by both hypercortisolemia and prolonged inactivity or bed rest (BR). Trauma and BR alone each result in a loss of muscle nitrogen, albeit through different metabolic alterations. Although BR alone can result in a 2-3% loss of lean body mass, the effects of severe trauma can be 2- to 3-fold greater. We investigated the combined effects of hypercortisolemia and prolonged inactivity on muscle protein metabolism in healthy volunteers. Six males were studied before and after 14 days of strict BR using a model based on arteriovenous sampling and muscle biopsy. Fractional synthesis and breakdown rates of skeletal muscle protein were also directly calculated. Each assessment of protein metabolism was conducted during a 12-h infusion of hydrocortisone sodium succinate (120 microg/kg x h), resulting in blood cortisol concentrations that mimic severe injury (approximately 31 microg/dL). After 14 days of strict BR, hypercortisolemia increased phenylalanine efflux from muscle by 3-fold (P < 0.05). The augmented negative amino acid balance was the result of an increased muscle protein breakdown (P < 0.05) without a concomitant change in muscle protein synthesis. Muscle efflux of glutamine and alanine increased significantly after bed rest due to a significant increase in de novo synthesis (P < 0.05). Thus, inactivity sensitizes skeletal muscle to the catabolic effects of hypercortisolemia. Furthermore, these effects on healthy volunteers are analogous to those seen after severe injury.

  6. Denervation and reinnervation of skeletal muscle

    NASA Technical Reports Server (NTRS)

    Mayer, R. F.; Max, S. R.

    1983-01-01

    A review is presented of the physiological and biochemical changes that occur in mammalian skeletal muscle after denervation and reinnervation. These changes are compared with those observed after altered motor function. Also considered is the nature of the trophic influence by which nerves control muscle properties. Topics examined include the membrane and contractile properties of denervated and reinnervated muscle; the cholinergic proteins, such as choline acetyltransferase, acetylcholinesterase, and the acetylcholine receptor; and glucose-6-phosphate dehydrogenase.

  7. Skeletal muscle pathology in Huntington's disease

    PubMed Central

    Zielonka, Daniel; Piotrowska, Izabela; Marcinkowski, Jerzy T.; Mielcarek, Michal

    2014-01-01

    Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy (due to increased mechanical load) or atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments. PMID:25339908

  8. Human Skeletal Muscle Health with Spaceflight

    NASA Astrophysics Data System (ADS)

    Trappe, Scott

    2012-07-01

    This lecture will overview the most recent aerobic and resistance exercise programs used by crewmembers while aboard the International Space Station (ISS) for six months and examine its effectiveness for protecting skeletal muscle health. Detailed information on the exercise prescription program, whole muscle size, whole muscle performance, and cellular data obtained from muscle biopsy samples will be presented. Historically, detailed information on the exercise program while in space has not been available. These most recent exercise and muscle physiology findings provide a critical foundation to guide the exercise countermeasure program forward for future long-duration space missions.

  9. Multiple Sclerosis Affects Skeletal Muscle Characteristics

    PubMed Central

    Wens, Inez; Dalgas, Ulrik; Vandenabeele, Frank; Krekels, Maartje; Grevendonk, Lotte; Eijnde, Bert O.

    2014-01-01

    Background The impact of multiple sclerosis (MS) on skeletal muscle characteristics, such as muscle fiber cross sectional area (CSA), fiber type proportion, muscle strength and whole muscle mass, remains conflicting. Methods In this cross sectional study, body composition and muscle strength of the quadriceps were assessed in 34 MS (EDSS: 2.5±0.19) patients and 18 matched healthy controls (HC). Hereafter a muscle biopsy (m.vastus lateralis) was taken. Results Compared to HC, mean muscle fiber CSA of all fibers, as well as CSA of type I, II and IIa fibers were smaller and muscle strength of the quadriceps was lower in MS patients. Whole body composition was comparable between groups. However, compared to HC, the biopsied leg tended to have a higher fat percentage (p = 0.1) and a lower lean mass (p = 0.06) in MS patients. Conclusion MS seems to negatively influence skeletal muscle fiber CSA, muscle strength and muscle mass of the lower limbs of mildly affected MS patients. This emphasises the need for rehabilitation programs focusing on muscle preservation of the lower limb. Trial Registration ClinicalTrials.gov NCT01845896 PMID:25264868

  10. HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology.

    PubMed

    Favier, F B; Britto, F A; Freyssenet, D G; Bigard, X A; Benoit, H

    2015-12-01

    Skeletal muscle is a metabolically active tissue and the major body protein reservoir. Drop in ambient oxygen pressure likely results in a decrease in muscle cells oxygenation, reactive oxygen species (ROS) overproduction and stabilization of the oxygen-sensitive hypoxia-inducible factor (HIF)-1α. However, skeletal muscle seems to be quite resistant to hypoxia compared to other organs, probably because it is accustomed to hypoxic episodes during physical exercise. Few studies have observed HIF-1α accumulation in skeletal muscle during ambient hypoxia probably because of its transient stabilization. Nevertheless, skeletal muscle presents adaptations to hypoxia that fit with HIF-1 activation, although the exact contribution of HIF-2, I kappa B kinase and activating transcription factors, all potentially activated by hypoxia, needs to be determined. Metabolic alterations result in the inhibition of fatty acid oxidation, while activation of anaerobic glycolysis is less evident. Hypoxia causes mitochondrial remodeling and enhanced mitophagy that ultimately lead to a decrease in ROS production, and this acclimatization in turn contributes to HIF-1α destabilization. Likewise, hypoxia has structural consequences with muscle fiber atrophy due to mTOR-dependent inhibition of protein synthesis and transient activation of proteolysis. The decrease in muscle fiber area improves oxygen diffusion into muscle cells, while inhibition of protein synthesis, an ATP-consuming process, and reduction in muscle mass decreases energy demand. Amino acids released from muscle cells may also have protective and metabolic effects. Collectively, these results demonstrate that skeletal muscle copes with the energetic challenge imposed by O2 rarefaction via metabolic optimization. PMID:26298291

  11. Gene Regions Responding to Skeletal Muscle Atrophy

    NASA Technical Reports Server (NTRS)

    Booth, Frank W.

    1997-01-01

    Our stated specific aims for this project were: 1) Identify the region(s) of the mouse IIb myosin heavy chain (MHC) promoter necessary for in vivo expression in mouse fast-twitch muscle, and 2) Identify the region(s) of the mouse IIb MHC promoter responsive to immobilization in mouse slow-twitch muscle in vivo. We sought to address these specific aims by introducing various MHC IIb promoter/reporter gene constructs directly into the tibialis anterior and gastrocnemius muscles of living mice. Although the method of somatic gene transfer into skeletal muscle by direct injection has been successfully used in our laboratory to study the regulation of the skeletal alpha actin gene in chicken skeletal muscle, we had many difficulties utilizing this procedure in the mouse. Because of the small size of the mouse soleus and the difficulty in obtaining consistent results, we elected not to study this muscle as first proposed. Rather, our MHC IIb promoter deletion experiments were performed in the gastrocnemius. Further, we decided to use hindlimb unloading via tail suspension to induce an upregulation of the MHC IIb gene, rather than immobilization of the hindlimbs via plaster casts. This change was made because tail suspension more closely mimics spaceflight, and this procedure in our lab results in a smaller loss of overall body mass than the mouse hindlimb immobilization procedure. This suggests that the stress level during tail suspension is less than during immobilization. This research has provided an important beginning point towards understanding the molecular regulation of the MHC lIb gene in response to unweighting of skeletal muscle Future work will focus on the regulation of MHC IIb mRNA stability in response to altered loading of skeletal muscle

  12. Satellite cells in human skeletal muscle plasticity

    PubMed Central

    Snijders, Tim; Nederveen, Joshua P.; McKay, Bryon R.; Joanisse, Sophie; Verdijk, Lex B.; van Loon, Luc J. C.; Parise, Gianni

    2015-01-01

    Skeletal muscle satellite cells are considered to play a crucial role in muscle fiber maintenance, repair and remodeling. Our knowledge of the role of satellite cells in muscle fiber adaptation has traditionally relied on in vitro cell and in vivo animal models. Over the past decade, a genuine effort has been made to translate these results to humans under physiological conditions. Findings from in vivo human studies suggest that satellite cells play a key role in skeletal muscle fiber repair/remodeling in response to exercise. Mounting evidence indicates that aging has a profound impact on the regulation of satellite cells in human skeletal muscle. Yet, the precise role of satellite cells in the development of muscle fiber atrophy with age remains unresolved. This review seeks to integrate recent results from in vivo human studies on satellite cell function in muscle fiber repair/remodeling in the wider context of satellite cell biology whose literature is largely based on animal and cell models. PMID:26557092

  13. Non-contrast Skeletal Muscle Oximetry

    PubMed Central

    Jie, Zheng; An, Hongyu; Coggan, Andrew R.; Zhang, Xiaodong; Adil, Bashir; Muccigrosso, David; Peterson, Linda R.; Gropler, Robert J.

    2013-01-01

    Purpose The objective of this study was to develop a new non-contrast method to directly quantify regional skeletal muscle oxygenation. Methods The feasibility of the method was examined in five healthy volunteers using a 3T clinical MRI scanner, at rest and during a sustained isometric contraction. The perfusion of skeletal muscle of the calf was measured using an arterial spin labeling method, whereas the oxygen extraction fraction of the muscle was measured using a susceptibility based MRI technique. Results In all volunteers, the perfusion in soleus muscle increased significantly from 6.5 ± 2.0 ml/100g/min at rest to 47.9 ± 7.7 ml/100g/min during exercise (P < 0.05). While the corresponding oxygen extraction fraction did not change significantly, the rate of oxygen consumption increased from 0.43 ± 0.13 to 4.2 ± 1.5 ml/100g/min (P < 0.05). Similar results were observed in gastrocnemius muscle, but with greater oxygen extraction fraction increase than the soleus muscle. Conclusion This is the first MR oximetry developed for quantification of regional skeletal muscle oxygenation. A broad range of medical conditions could benefit from these techniques, including cardiology, gerontology, kinesiology, and physical therapy. PMID:23424006

  14. Mechanotransduction pathways in skeletal muscle hypertrophy.

    PubMed

    Yamada, André Katayama; Verlengia, Rozangela; Bueno Junior, Carlos Roberto

    2012-02-01

    In the last decade, molecular biology has contributed to define some of the cellular events that trigger skeletal muscle hypertrophy. Recent evidence shows that insulin like growth factor 1/phosphatidyl inositol 3-kinase/protein kinase B (IGF-1/PI3K/Akt) signaling is not the main pathway towards load-induced skeletal muscle hypertrophy. During load-induced skeletal muscle hypertrophy process, activation of mTORC1 does not require classical growth factor signaling. One potential mechanism that would activate mTORC1 is increased synthesis of phosphatidic acid (PA). Despite the huge progress in this field, it is still early to affirm which molecular event induces hypertrophy in response to mechanical overload. Until now, it seems that mTORC1 is the key regulator of load-induced skeletal muscle hypertrophy. On the other hand, how mTORC1 is activated by PA is unclear, and therefore these mechanisms have to be determined in the following years. The understanding of these molecular events may result in promising therapies for the treatment of muscle-wasting diseases. For now, the best approach is a good regime of resistance exercise training. The objective of this point-of-view paper is to highlight mechanotransduction events, with focus on the mechanisms of mTORC1 and PA activation, and the role of IGF-1 on hypertrophy process. PMID:22171534

  15. Cytokine Signaling in Skeletal Muscle Wasting.

    PubMed

    Zhou, Jin; Liu, Bin; Liang, Chun; Li, Yangxin; Song, Yao-Hua

    2016-05-01

    Skeletal muscle wasting occurs in a variety of diseases including diabetes, cancer, Crohn's disease, chronic obstructive pulmonary disease (COPD), disuse, and denervation. Tumor necrosis factor α (TNF-α) is involved in mediating the wasting effect. To date, a causal relationship between TNF-α signaling and muscle wasting has been established in animal models. However, results from clinical trials are conflicting. This is partly due to the fact that other factors such as TNF-like weak inducer of apoptosis (TWEAK) and interleukin 6 (IL-6) are also involved in skeletal muscle wasting. Because muscle wasting is often associated with physical inactivity and reduced food intake, therapeutic interventions will be most effective when multiple approaches are used in conjunction with nutritional support and exercise. PMID:27025788

  16. YAP-Mediated Mechanotransduction in Skeletal Muscle

    PubMed Central

    Fischer, Martina; Rikeit, Paul; Knaus, Petra; Coirault, Catherine

    2016-01-01

    Skeletal muscle is not only translating chemical energy into mechanical work, it is also a highly adaptive and regenerative tissue whose architecture and functionality is determined by its mechanical and physical environment. Processing intra- and extracellular mechanical signaling cues contributes to the regulation of cell growth, survival, migration and differentiation. Yes-associated Protein (YAP), a transcriptional coactivator downstream of the Hippo pathway and its paralog, the transcriptional co-activator with PDZ-binding motif (TAZ), were recently found to play a key role in mechanotransduction in various tissues including skeletal muscle. Furthermore, YAP/TAZ modulate myogenesis and muscle regeneration and abnormal YAP activity has been reported in muscular dystrophy and rhabdomyosarcoma. Here, we summarize the current knowledge of mechanosensing and -signaling in striated muscle. We highlight the role of YAP signaling and discuss the different routes and hypotheses of its regulation in the context of mechanotransduction. PMID:26909043

  17. Redox Characterization of Functioning Skeletal Muscle

    PubMed Central

    Zuo, Li; Pannell, Benjamin K.

    2015-01-01

    Skeletal muscle physiology is influenced by the presence of chemically reactive molecules such as reactive oxygen species (ROS). These molecules regulate multiple redox-sensitive signaling pathways that play a critical role in cellular processes including gene expression and protein modification. While ROS have gained much attention for their harmful effects in muscle fatigue and dysfunction, research has also shown ROS to facilitate muscle adaptation after stressors such as physical exercise. This manuscript aims to provide a comprehensive review of the current understanding of redox signaling in skeletal muscle. ROS-induced oxidative stress and its role in the aging process are discussed. Mitochondria have been shown to generate large amounts of ROS during muscular contractions, and thus are susceptible to oxidative stress. ROS can modify proteins located in the mitochondrial membrane leading to cell death and osmotic swelling. ROS also contribute to the necrosis and inflammation of muscle fibers that is associated with muscular diseases including Duchenne muscular dystrophy. It is imperative that future research continues to investigate the exact role of ROS in normal skeletal muscle function as well as muscular dysfunction and disease. PMID:26635624

  18. Oxidative proteome alterations during skeletal muscle ageing

    PubMed Central

    Lourenço dos Santos, Sofia; Baraibar, Martin A.; Lundberg, Staffan; Eeg-Olofsson, Orvar; Larsson, Lars; Friguet, Bertrand

    2015-01-01

    Sarcopenia corresponds to the degenerative loss of skeletal muscle mass, quality, and strength associated with ageing and leads to a progressive impairment of mobility and quality of life. However, the cellular and molecular mechanisms involved in this process are not completely understood. A hallmark of cellular and tissular ageing is the accumulation of oxidatively modified (carbonylated) proteins, leading to a decreased quality of the cellular proteome that could directly impact on normal cellular functions. Although increased oxidative stress has been reported during skeletal muscle ageing, the oxidized protein targets, also referred as to the ‘oxi-proteome’ or ‘carbonylome’, have not been characterized yet. To better understand the mechanisms by which these damaged proteins build up and potentially affect muscle function, proteins targeted by these modifications have been identified in human rectus abdominis muscle obtained from young and old healthy donors using a bi-dimensional gel electrophoresis-based proteomic approach coupled with immunodetection of carbonylated proteins. Among evidenced protein spots, 17 were found as increased carbonylated in biopsies from old donors comparing to young counterparts. These proteins are involved in key cellular functions such as cellular morphology and transport, muscle contraction and energy metabolism. Importantly, impairment of these pathways has been described in skeletal muscle during ageing. Functional decline of these proteins due to irreversible oxidation may therefore impact directly on the above-mentioned pathways, hence contributing to the generation of the sarcopenic phenotype. PMID:26073261

  19. Human skeletal muscle biochemical diversity

    PubMed Central

    Tirrell, Timothy F.; Cook, Mark S.; Carr, J. Austin; Lin, Evie; Ward, Samuel R.; Lieber, Richard L.

    2012-01-01

    SUMMARY The molecular components largely responsible for muscle attributes such as passive tension development (titin and collagen), active tension development (myosin heavy chain, MHC) and mechanosensitive signaling (titin) have been well studied in animals but less is known about their roles in humans. The purpose of this study was to perform a comprehensive analysis of titin, collagen and MHC isoform distributions in a large number of human muscles, to search for common themes and trends in the muscular organization of the human body. In this study, 599 biopsies were obtained from six human cadaveric donors (mean age 83 years). Three assays were performed on each biopsy – titin molecular mass determination, hydroxyproline content (a surrogate for collagen content) and MHC isoform distribution. Titin molecular mass was increased in more distal muscles of the upper and lower limbs. This trend was also observed for collagen. Percentage MHC-1 data followed a pattern similar to collagen in muscles of the upper extremity but this trend was reversed in the lower extremity. Titin molecular mass was the best predictor of anatomical region and muscle functional group. On average, human muscles had more slow myosin than other mammals. Also, larger titins were generally associated with faster muscles. These trends suggest that distal muscles should have higher passive tension than proximal ones, and that titin size variability may potentially act to ‘tune’ the protein's mechanotransduction capability. PMID:22786631

  20. Human skeletal muscle biochemical diversity.

    PubMed

    Tirrell, Timothy F; Cook, Mark S; Carr, J Austin; Lin, Evie; Ward, Samuel R; Lieber, Richard L

    2012-08-01

    The molecular components largely responsible for muscle attributes such as passive tension development (titin and collagen), active tension development (myosin heavy chain, MHC) and mechanosensitive signaling (titin) have been well studied in animals but less is known about their roles in humans. The purpose of this study was to perform a comprehensive analysis of titin, collagen and MHC isoform distributions in a large number of human muscles, to search for common themes and trends in the muscular organization of the human body. In this study, 599 biopsies were obtained from six human cadaveric donors (mean age 83 years). Three assays were performed on each biopsy - titin molecular mass determination, hydroxyproline content (a surrogate for collagen content) and MHC isoform distribution. Titin molecular mass was increased in more distal muscles of the upper and lower limbs. This trend was also observed for collagen. Percentage MHC-1 data followed a pattern similar to collagen in muscles of the upper extremity but this trend was reversed in the lower extremity. Titin molecular mass was the best predictor of anatomical region and muscle functional group. On average, human muscles had more slow myosin than other mammals. Also, larger titins were generally associated with faster muscles. These trends suggest that distal muscles should have higher passive tension than proximal ones, and that titin size variability may potentially act to 'tune' the protein's mechanotransduction capability. PMID:22786631

  1. Skeletal muscle metabolism in hypokinetic rats

    NASA Technical Reports Server (NTRS)

    Tischler, M. E.

    1984-01-01

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

  2. Advances and challenges in skeletal muscle angiogenesis.

    PubMed

    Olfert, I Mark; Baum, Oliver; Hellsten, Ylva; Egginton, Stuart

    2016-02-01

    The role of capillaries is to serve as the interface for delivery of oxygen and removal of metabolites to/from tissues. During the past decade there has been a proliferation of studies that have advanced our understanding of angiogenesis, demonstrating that tissue capillary supply is under strict control during health but poorly controlled in disease, resulting in either excessive capillary growth (pathological angiogenesis) or losses in capillarity (rarefaction). Given that skeletal muscle comprises nearly 40% of body mass in humans, skeletal muscle capillary density has a significant impact on metabolism, endocrine function, and locomotion and is tightly regulated at many different levels. Skeletal muscle is also high adaptable and thus one of the few organ systems that can be experimentally manipulated (e.g., by exercise) to study physiological regulation of angiogenesis. This review will focus on the methodological concerns that have arisen in determining skeletal muscle capillarity and highlight the concepts that are reshaping our understanding of the angio-adaptation process. We also summarize selected new findings (physical influences, molecular changes, and ultrastructural rearrangement of capillaries) that identify areas of future research with the greatest potential to expand our understanding of how angiogenesis is normally regulated, and that may also help to better understand conditions of uncontrolled (pathological) angiogenesis. PMID:26608338

  3. Actions of scorpion venom on skeletal muscle

    PubMed Central

    Adam, K. R.; Weiss, C.

    1959-01-01

    A protein-like constituent of scorpion venom produced effects on the skeletal muscle fibre resembling those of citrate, lack of calcium or veratrine. These effects could be diminished by the addition of calcium. They do not appear to be due to the formation of a non-ionized complex with calcium. PMID:13791719

  4. Tissue engineering skeletal muscle for orthopaedic applications

    NASA Technical Reports Server (NTRS)

    Payumo, Francis C.; Kim, Hyun D.; Sherling, Michael A.; Smith, Lee P.; Powell, Courtney; Wang, Xiao; Keeping, Hugh S.; Valentini, Robert F.; Vandenburgh, Herman H.

    2002-01-01

    With current technology, tissue-engineered skeletal muscle analogues (bioartificial muscles) generate too little active force to be clinically useful in orthopaedic applications. They have been engineered genetically with numerous transgenes (growth hormone, insulinlike growth factor-1, erythropoietin, vascular endothelial growth factor), and have been shown to deliver these therapeutic proteins either locally or systemically for months in vivo. Bone morphogenetic proteins belonging to the transforming growth factor-beta superfamily are osteoinductive molecules that drive the differentiation pathway of mesenchymal cells toward the chondroblastic or osteoblastic lineage, and stimulate bone formation in vivo. To determine whether skeletal muscle cells endogenously expressing bone morphogenetic proteins might serve as a vehicle for systemic bone morphogenetic protein delivery in vivo, proliferating skeletal myoblasts (C2C12) were transduced with a replication defective retrovirus containing the gene for recombinant human bone morphogenetic protein-6 (C2BMP-6). The C2BMP-6 cells constitutively expressed recombinant human bone morphogenetic protein-6 and synthesized bioactive recombinant human bone morphogenetic protein-6, based on increased alkaline phosphatase activity in coincubated mesenchymal cells. C2BMP-6 cells did not secrete soluble, bioactive recombinant human bone morphogenetic protein-6, but retained the bioactivity in the cell layer. Therefore, genetically-engineered skeletal muscle cells might serve as a platform for long-term delivery of osteoinductive bone morphogenetic proteins locally.

  5. Advances and challenges in skeletal muscle angiogenesis

    PubMed Central

    Baum, Oliver; Hellsten, Ylva; Egginton, Stuart

    2015-01-01

    The role of capillaries is to serve as the interface for delivery of oxygen and removal of metabolites to/from tissues. During the past decade there has been a proliferation of studies that have advanced our understanding of angiogenesis, demonstrating that tissue capillary supply is under strict control during health but poorly controlled in disease, resulting in either excessive capillary growth (pathological angiogenesis) or losses in capillarity (rarefaction). Given that skeletal muscle comprises nearly 40% of body mass in humans, skeletal muscle capillary density has a significant impact on metabolism, endocrine function, and locomotion and is tightly regulated at many different levels. Skeletal muscle is also high adaptable and thus one of the few organ systems that can be experimentally manipulated (e.g., by exercise) to study physiological regulation of angiogenesis. This review will focus on the methodological concerns that have arisen in determining skeletal muscle capillarity and highlight the concepts that are reshaping our understanding of the angio-adaptation process. We also summarize selected new findings (physical influences, molecular changes, and ultrastructural rearrangement of capillaries) that identify areas of future research with the greatest potential to expand our understanding of how angiogenesis is normally regulated, and that may also help to better understand conditions of uncontrolled (pathological) angiogenesis. PMID:26608338

  6. Development of Sensory Receptors in Skeletal Muscle

    NASA Technical Reports Server (NTRS)

    DeSantis, Mark

    2000-01-01

    The two major goals for this project is to (1) examine the hindlimb walking pattern of offspring from the Flight dams as compared with offspring of the ground control groups from initiation of walking up to two months thereafter; and (2) examine skeletal muscle.

  7. Heat stress inhibits skeletal muscle hypertrophy

    PubMed Central

    Frier, Bruce C.; Locke, Marius

    2007-01-01

    Heat shock proteins (Hsps) are molecular chaperones that aid in protein synthesis and trafficking and have been shown to protect cells/tissues from various protein damaging stressors. To determine the extent to which a single heat stress and the concurrent accumulation of Hsps influences the early events of skeletal muscle hypertrophy, Sprague-Dawley rats were heat stressed (42°C, 15 minutes) 24 hours prior to overloading 1 plantaris muscle by surgical removal of the gastrocnemius muscle. The contralateral plantaris muscles served as controls. Heat-stressed and/or overloaded plantaris muscles were assessed for muscle mass, total muscle protein, muscle protein concentration, Type I myosin heavy chain (Type I MHC) content, as well as Hsp72 and Hsp25 content over the course of 7 days following removal of the gastrocnemius muscle. As expected, in non–heat-stressed animals, muscle mass, total muscle protein and MHC I content were significantly increased (P < 0.05) following overload. In addition, Hsp25 and Hsp72 increased significantly after 2 and 3 days of overload, respectively. A prior heat stress–elevated Hsp25 content to levels similar to those measured following overload alone, but heat stress–induced Hsp72 content was increased significantly greater than was elicited by overload alone. Moreover, overloaded muscles from animals that experienced a prior heat stress showed a lower muscle mass increase at 5 and 7 days; a reduced total muscle protein elevation at 3, 5, and 7 days; reduced protein concentration; and a diminished Type I MHC content accumulation at 3, 5, and 7 days relative to non– heat-stressed animals. These data suggest that a prior heat stress and/or the consequent accumulation of Hsps may inhibit increases in muscle mass, total muscle protein content, and Type I MHC in muscles undergoing hypertrophy. PMID:17688192

  8. Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice

    PubMed Central

    Jackson, Kathryn C.; Wohlers, Lindsay M.; Lovering, Richard M.; Schuh, Rosemary A.; Maher, Amy C.; Bonen, Arend; Koves, Timothy R.; Ilkayeva, Olga; Thomson, David M.; Muoio, Deborah M.

    2013-01-01

    Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile. PMID:23193112

  9. AMINO ACIDS AUGMENT MUSCLE PROTEIN SYNTHESIS IN NEONATAL PIGS DURING ENDOTOXEMIA BY MODULATING TRANSLATION INITIATION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In adults, sepsis reduces protein synthesis in skeletal muscle by restraining translation. The effect of sepsis on amino acid-stimulated muscle protein synthesis has not been determined in neonates, a population who is highly anabolic and whose muscle protein synthesis rates are uniquely sensitive ...

  10. Dysregulation of skeletal muscle protein metabolism by alcohol.

    PubMed

    Steiner, Jennifer L; Lang, Charles H

    2015-05-01

    Alcohol abuse, either by acute intoxication or prolonged excessive consumption, leads to pathological changes in many organs and tissues including skeletal muscle. As muscle protein serves not only a contractile function but also as a metabolic reserve for amino acids, which are used to support the energy needs of other tissues, its content is tightly regulated and dynamic. This review focuses on the etiology by which alcohol perturbs skeletal muscle protein balance and thereby over time produces muscle wasting and weakness. The preponderance of data suggest that alcohol primarily impairs global protein synthesis, under basal conditions as well as in response to several anabolic stimuli including growth factors, nutrients, and muscle contraction. This inhibitory effect of alcohol is mediated, at least in part, by a reduction in mTOR kinase activity via a mechanism that remains poorly defined but likely involves altered protein-protein interactions within mTOR complex 1. Furthermore, alcohol can exacerbate the decrement in mTOR and/or muscle protein synthesis present in other catabolic states. In contrast, alcohol-induced changes in muscle protein degradation, either global or via specific modulation of the ubiquitin-proteasome or autophagy pathways, are relatively inconsistent and may be model dependent. Herein, changes produced by acute intoxication versus chronic ingestion are contrasted in relation to skeletal muscle metabolism, and limitations as well as opportunities for future research are discussed. As the proportion of more economically developed countries ages and chronic illness becomes more prevalent, a better understanding of the etiology of biomedical consequences of alcohol use disorders is warranted. PMID:25759394

  11. Skeletal muscle adaptations and muscle genomics of performance horses.

    PubMed

    Rivero, José-Luis L; Hill, Emmeline W

    2016-03-01

    Skeletal muscles in horses are characterised by specific adaptations, which are the result of the natural evolution of the horse as a grazing animal, centuries of selective breeding and the adaptability of this tissue in response to training. These adaptations include an increased muscle mass relative to body weight, a great locomotor efficiency based upon an admirable muscle-tendon architectural design and an adaptable fibre-type composition with intrinsic shortening velocities greater than would be predicted from an animal of comparable body size. Furthermore, equine skeletal muscles have a high mitochondrial volume that permits a higher whole animal aerobic capacity, as well as large intramuscular stores of energy substrates (glycogen in particular). Finally, high buffer and lactate transport capacities preserve muscles against fatigue during anaerobic exercise. Many of these adaptations can improve with training. The publication of the equine genome sequence in 2009 has provided a major advance towards an improved understanding of equine muscle physiology. Equine muscle genomics studies have revealed a number of genes associated with elite physical performance and have also identified changes in structural and metabolic genes following exercise and training. Genes involved in muscle growth, muscle contraction and specific metabolic pathways have been found to be functionally relevant for the early performance evaluation of elite athletic horses. The candidate genes discussed in this review are important for a healthy individual to improve performance. However, muscle performance limiting conditions are widespread in horses and many of these conditions are also genetically influenced. PMID:26831154

  12. Treatment of Skeletal Muscle Injury: A Review

    PubMed Central

    Baoge, L.; Van Den Steen, E.; Rimbaut, S.; Philips, N.; Witvrouw, E.; Almqvist, K. F.; Vanderstraeten, G.; Vanden Bossche, L. C.

    2012-01-01

    Skeletal muscle injuries are the most common sports-related injuries and present a challenge in primary care and sports medicine. Most types of muscle injuries would follow three stages: the acute inflammatory and degenerative phase, the repair phase and the remodeling phase. Present conservative treatment includes RICE (rest, ice, compression, elevation), nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy. However, if use improper, NSAIDs may suppress an essential inflammatory phase in the healing of injured skeletal muscle. Furthermore, it remains controversial whether or not they have adverse effects on the healing process or on the tensile strength. However, several growth factors might promote the regeneration of injured skeletal muscle, many novel treatments have involved on enhancing complete functional recovery. Exogenous growth factors have been shown to regulate satellite cell proliferation, differentiation and fusion in myotubes in vivo and in vitro, TGF-?1 antagonists behave as inhibitors of TGF-?1. They prevent collagen deposition and block formation of muscle fibrosis, so that a complete functional recovery can be achieved. PMID:24977084

  13. Effect of GABA on oxidative stress in the skeletal muscles and plasma free amino acids in mice fed high-fat diet.

    PubMed

    Xie, Z X; Xia, S F; Qiao, Y; Shi, Y H; Le, G W

    2015-06-01

    Increased levels of plasma free amino acids (pFAAs) can disturb the blood glucose levels in patients with obesity, diabetes mellitus and metabolic syndrome (MS) and are associated with enhanced protein oxidation. Oxidation of proteins, especially in the muscles, can promote protein degradation and elevate the levels of pFAAs. Gamma-aminobutyric acid (GABA), a food additive, can reduce high-fat diet (HFD)-induced hyperglycaemia; however, the mechanisms remain unclear. The aim of this study was to evaluate the effects of GABA on protein oxidation and pFAAs changes. One hundred male C57BL/6 mice were randomly divided into five groups that were fed with control diet, HFD and HFD supplied with 0.2%, 0.12% and 0.06% GABA in drinking water for 20 weeks respectively. HFD feeding led to muscular oxidative stress, protein oxidation, pFAA disorders, hyperglycaemia and augmented plasma GABA levels. Treatment with GABA restored normally fasting blood glucose level and dose-dependently inhibited body weight gains, muscular oxidation and protein degradation. While medium and low doses of GABA mitigated HFD-induced pFAA disorders, the high dose of GABA deteriorated the pFAA disorders. Medium dose of GABA increased the levels of GABA, but high dose of GABA reduced the levels of plasma GABA and increased the activity of succinic semialdehyde dehydrogenase in the liver. Therefore, treatment with GABA mitigated HFD-induced hyperglycaemia probably by repairing HFD-induced muscular oxidative stress and pFAA disorders in mice. Our data also suggest that an optimal dose of GABA is crucial for the prevention of excess GABA-related decrease in the levels of pFAA and GABA as well as obesity. PMID:25266692

  14. Cellular Players in Skeletal Muscle Regeneration

    PubMed Central

    Ceafalan, Laura Cristina; Popescu, Bogdan Ovidiu; Hinescu, Mihail Eugen

    2014-01-01

    Skeletal muscle, a tissue endowed with remarkable endogenous regeneration potential, is still under focused experimental investigation mainly due to treatment potential for muscle trauma and muscular dystrophies. Resident satellite cells with stem cell features were enthusiastically described quite a long time ago, but activation of these cells is not yet controlled by any medical interventions. However, after thorough reports of their existence, survival, activation, and differentiation there are still many questions to be answered regarding the intimate mechanism of tissue regeneration. This review delivers an up-to-date inventory of the main known key players in skeletal muscle repair, revealed by various models of tissue injuries in mechanical trauma, toxic lesions, and muscular dystrophy. A better understanding of the spatial and temporal relationships between various cell populations, with different physical or paracrine interactions and phenotype changes induced by local or systemic signalling, might lead to a more efficient approach for future therapies. PMID:24779022

  15. Skeletal muscle ventricles for total heart replacement.

    PubMed Central

    Pochettino, A; Spanta, A D; Hammond, R L; Anderson, D R; Bridges, C R; Samet, P; Niinami, H; Hohenhaus, E; Salmons, S; Stephenson, L W

    1990-01-01

    Skeletal muscle ventricles (SMV) were constructed from canine left latissimus dorsi muscle. The animals were divided into three groups: group A (n = 5), SMVs rested 4 weeks without electrical conditioning; group B (n = 6), SMVs rested 4 weeks and then electrically conditioned for 6 weeks; group C (n = 5), SMVs rested 18 weeks without electrical conditioning. At the end of each protocol, the SMVs were acutely tested by connecting them to a mock-circulation device. The SMVs in group C developed stroke work at physiologic preloads superior to any previously reported, as high as 194% of left ventricular stroke work at afterloads of 80 mmHg. The SMVs in group B developed work outputs equivalent to 53% of the left ventricle, which is still more than four times that of the right ventricle. The results show that it is possible to harvest sufficient work from skeletal muscle ventricles to fully replace cardiac function at physiologic preloads. PMID:2396886

  16. Oxidative system in aged skeletal muscle

    PubMed Central

    Buonocore, Daniela; Rucci, Sara; Vandoni, Matteo; Negro, Massimo; Marzatico, Fulvio

    2011-01-01

    Summary Aging is an inevitable biological process that is characterized by a general decline in the physiological and biochemical functions of the major systems. In the case of the neuromuscular system, reductions in strength and mobility cause a deterioration in motor performance, impaired mobility and disability. At the cellular level, aging is caused by a progressive decline in mitochondrial function that results in the accumulation of reactive oxygen species (ROS). As the level of oxidative stress in skeletal muscle increases with age, the age-process is characterized by an imbalance between an increase in ROS production in the organism, and antioxidant defences as a whole. We have reviewed the literature on oxidative stress in aging human skeletal muscles, and to assesss the impact of differences in physiological factors (sex, fiber composition, muscle type and function). PMID:23738253

  17. Oxidative system in aged skeletal muscle.

    PubMed

    Buonocore, Daniela; Rucci, Sara; Vandoni, Matteo; Negro, Massimo; Marzatico, Fulvio

    2011-07-01

    Aging is an inevitable biological process that is characterized by a general decline in the physiological and biochemical functions of the major systems. In the case of the neuromuscular system, reductions in strength and mobility cause a deterioration in motor performance, impaired mobility and disability. At the cellular level, aging is caused by a progressive decline in mitochondrial function that results in the accumulation of reactive oxygen species (ROS). As the level of oxidative stress in skeletal muscle increases with age, the age-process is characterized by an imbalance between an increase in ROS production in the organism, and antioxidant defences as a whole. We have reviewed the literature on oxidative stress in aging human skeletal muscles, and to assesss the impact of differences in physiological factors (sex, fiber composition, muscle type and function). PMID:23738253

  18. Pannexin 1 channels in skeletal muscles

    PubMed Central

    Cea, Luis A.; Riquelme, Manuel A.; Vargas, Anibal A.; Urrutia, Carolina; Sez, Juan C.

    2014-01-01

    Normal myotubes and adult innervated skeletal myofibers express the glycoprotein pannexin1 (Panx1). Six of them form a gap junction hemichannel-like structure that connects the cytoplasm with the extracellular space; here they will be called Panx1 channels. These are poorly selective channels permeable to ions, small metabolic substrate, and signaling molecules. So far little is known about the role of Panx1 channels in muscles but skeletal muscles of Panx1?/? mice do not show an evident phenotype. Innervated adult fast and slow skeletal myofibers show Panx1 reactivity in close proximity to dihydropyridine receptors in the sarcolemma of T-tubules. These Panx1 channels are activated by electrical stimulation and extracellular ATP. Panx1 channels play a relevant role in potentiation of muscle contraction because they allow release of ATP and uptake of glucose, two molecules required for this response. In support of this notion, the absence of Panx1 abrogates the potentiation of muscle contraction elicited by repetitive electrical stimulation, which is reversed by exogenously applied ATP. Phosphorylation of Panx1 Thr and Ser residues might be involved in Panx1 channel activation since it is enhanced during potentiation of muscle contraction. Under denervation, Panx1 levels are upregulated and this partially explains the reduction in electrochemical gradient, however its absence does not prevent denervation-induced atrophy but prevents the higher oxidative state. Panx1 also forms functional channels at the cell surface of myotubes and their functional state has been associated with intracellular Ca2+ signals and regulation of myotube plasticity evoked by electrical stimulation. We proposed that Panx1 channels participate as ATP channels and help to keep a normal oxidative state in skeletal muscles. PMID:24782784

  19. Interactive effects of glutamine and gamma-aminobutyric acid on growth performance and skeletal muscle amino acid metabolism of 22-42-day-old broilers exposed to hot environment

    NASA Astrophysics Data System (ADS)

    Hu, Hong; Bai, Xi; Shah, Assar Ali; Dai, Sifa; Wang, Like; Hua, Jinling; Che, Chuanyan; He, Shaojun; Wen, Aiyou; Jiang, Jinpeng

    2015-10-01

    The present experiment was conducted to investigate the interactive effects between dietary glutamine (Gln, 0 and 5 g/kg) and gamma-aminobutyric acid (GABA, 0 and 100 mg/kg) on growth performance and amino acid (AA) metabolism of broilers under hot environment. A total of 360 22-day-old Arbor Acres male chickens were randomly assigned to five treatment groups under thermoneutral chamber (PC, 23 °C) and cyclic heat stress (HS, 30-34 °C cycling) conditions. Compared with the PC group, cyclic HS decreased (P < 0.05) daily weight gain (DWG), daily feed consumption (DFC), the concentrations of Gln, glutamate (Glu), and GABA, and the activities of glutaminase and glutamic acid decarboxylase (GAD) in breast muscle at 28, 35, and 42 days, while it increased (P < 0.05) the activities of glutamine synthetase (GS) and gamma-aminobutyric acid transaminase (GABA-T) at 28, 35, and 42 days. Dietary Gln and GABA improved (P < 0.05) DWG and DFC of broilers under cyclic HS during 28-42 days. In breast muscle, the Gln supplementation increased (P < 0.05) the concentrations of Gln (28, 35, and 42 days), Glu (28, 35, and 42 days), and GABA (42 days) and the activities of glutaminase (28, 35, and 42 days) and GAD (28, 35, and 42 days) but decreased (P < 0.05) GS activities at 28, 35, and 42 days and GABA-T activities at 28 days. The addition of GABA increased (P < 0.05) the concentrations of Gln and Glu and activities of glutaminase and GAD, while it decreased (P < 0.05) GABA-T activities at 28, 35, and 42 days. Significant interactions (P < 0.05) between Gln and GABA were found on breast skeletal muscle Gln concentrations, glutaminase activities, GS activities at 28 and 35 days, and DWG, GABA concentrations, and GABA-T activities at 28, 35, and 42 days in broilers under cyclic HS. In conclusion, the present results indicated that the interactions of exogenous Gln and GABA could offer a potential nutritional strategy to prevent HS-related depression in skeletal muscle Gln and GABA metabolism of broilers.

  20. Interactive effects of glutamine and gamma-aminobutyric acid on growth performance and skeletal muscle amino acid metabolism of 22-42-day-old broilers exposed to hot environment.

    PubMed

    Hu, Hong; Bai, Xi; Shah, Assar Ali; Dai, Sifa; Wang, Like; Hua, Jinling; Che, Chuanyan; He, Shaojun; Wen, Aiyou; Jiang, Jinpeng

    2016-06-01

    The present experiment was conducted to investigate the interactive effects between dietary glutamine (Gln, 0 and 5 g/kg) and gamma-aminobutyric acid (GABA, 0 and 100 mg/kg) on growth performance and amino acid (AA) metabolism of broilers under hot environment. A total of 360 22-day-old Arbor Acres male chickens were randomly assigned to five treatment groups under thermoneutral chamber (PC, 23 °C) and cyclic heat stress (HS, 30-34 °C cycling) conditions. Compared with the PC group, cyclic HS decreased (P < 0.05) daily weight gain (DWG), daily feed consumption (DFC), the concentrations of Gln, glutamate (Glu), and GABA, and the activities of glutaminase and glutamic acid decarboxylase (GAD) in breast muscle at 28, 35, and 42 days, while it increased (P < 0.05) the activities of glutamine synthetase (GS) and gamma-aminobutyric acid transaminase (GABA-T) at 28, 35, and 42 days. Dietary Gln and GABA improved (P < 0.05) DWG and DFC of broilers under cyclic HS during 28-42 days. In breast muscle, the Gln supplementation increased (P < 0.05) the concentrations of Gln (28, 35, and 42 days), Glu (28, 35, and 42 days), and GABA (42 days) and the activities of glutaminase (28, 35, and 42 days) and GAD (28, 35, and 42 days) but decreased (P < 0.05) GS activities at 28, 35, and 42 days and GABA-T activities at 28 days. The addition of GABA increased (P < 0.05) the concentrations of Gln and Glu and activities of glutaminase and GAD, while it decreased (P < 0.05) GABA-T activities at 28, 35, and 42 days. Significant interactions (P < 0.05) between Gln and GABA were found on breast skeletal muscle Gln concentrations, glutaminase activities, GS activities at 28 and 35 days, and DWG, GABA concentrations, and GABA-T activities at 28, 35, and 42 days in broilers under cyclic HS. In conclusion, the present results indicated that the interactions of exogenous Gln and GABA could offer a potential nutritional strategy to prevent HS-related depression in skeletal muscle Gln and GABA metabolism of broilers. PMID:26493197

  1. Nutritional regulation of mTOR signaling in skeletal muscle of neonates in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The post-prandial rise in both amino acids and insulin independently stimulate protein synthesis in the rapidly growing skeletal muscle of the neonate. Leucine, in particular, is important in mediating the response to amino acids. We have shown that a physiological rise in leucine, but not isoleuc...

  2. Sexual dimorphism in skeletal muscle protein turnover.

    PubMed

    Smith, Gordon I; Mittendorfer, Bettina

    2016-03-15

    Skeletal muscle is the major constituent of lean body mass and essential for the body's locomotor function. Women have less muscle mass (and more body fat) than men and are therefore not able to exert the same absolute maximal force as men. The difference in body composition between the sexes is evident from infancy but becomes most marked after puberty (when boys experience an accelerated growth spurt) and persists into old age. During early adulthood until approximately the fourth decade of life, muscle mass is relatively stable, both in men and women, but then begins to decline, and the rate of loss is slower in women than in men. In this review we discuss the underlying mechanisms responsible for the age-associated sexual dimorphism in muscle mass (as far as they have been elucidated to date) and highlight areas that require more research to advance our understanding of the control of muscle mass throughout life. PMID:26702024

  3. Calcineurin and skeletal muscle growth.

    PubMed

    Michel, Robin N; Dunn, Shannon E; Chin, Eva R

    2004-05-01

    Recruitment determines the profile of fibre-type-specific genes expressed across the range of muscle fibres associated with slow, fast fatigue-resistant and fast fatiguable motor units. Downstream signalling pathways activated by neural signalling and mechanical load have been the focus of intensive research in past years. It is now known that Ca(2+)-dependent calcineurin-nuclear factor of activated T cells and insulin-like growth factor 1 pathways and their downstream mediators contribute to these adaptive responses. These pathways regulate gene expression through muscle-specific (myocyte-enhancing factor 2, myoblast determination protein) and non-specific (nuclear factor of activated T cell 2, GATA-2) transcription factors. Transcriptional signals activated with increased contractile activity result in altered expression of fibre-type specific genes, including the myosin heavy chain isoforms and oxidative and glycolytic enzymes and a net change in muscle fibre-type composition. In contrast, transcriptional signals activated by increased load bearing result in hypertrophy or a growth response, a component of which involves satellite cell recruitment and fusion with existing adult myofibres. Calcineurin has been identified as a key mediator in the hypertrophic response, and the current challenge has been to determine the downstream target genes of this pathway. Exciting new data have emerged, showing that myostatin, a negative regulator of muscle growth, and utrophin, a cytoskeletal protein important in maintaining membrane integrity, are downstream targets of calcineurin signalling. Increased understanding of these mediators of muscle growth may provide strategies for the development of effective therapeutics to counter muscle weakness and muscular dystrophy. PMID:15294053

  4. Role of skeletal muscle in mandible development.

    PubMed

    Rot, Irena; Mardesic-Brakus, Snjezana; Costain, Willard J; Saraga-Babic, Mirna; Kablar, Boris

    2014-11-01

    As a continuation of the previous study on palate development (Rot and Kablar, 2013), here we explore the relationship between the secondary cartilage mandibular condyles (parts of the temporomandibular joint) and the contributions (mechanical and secretory) from the adjacent skeletal musculature. Previous analysis of Myf5-/-:MyoD-/- mouse fetuses lacking skeletal muscle demonstrated the importance of muscle contraction and static loading in mouse skeletogenesis. Among abnormal skeletal features, micrognathia (mandibular hypoplasia) was detected: small, bent and posteriorly displaced mandible. As an example of Waddingtonian epigenetics, we suggest that muscle, in addition to acting via mechanochemical signal transduction pathways, networks and promoters, also exerts secretory stimuli on skeleton. Our goal is to identify candidate molecules at that muscle-mandible interface. By employing Systematic Subtractive Microarray Analysis approach, we compared gene expression between mandibles of amyogenic and wild type mouse fetuses and we identified up- and down-regulated genes. This step was followed by a bioinformatics approach and consultation of web-accessible mouse databases. We searched for individual tissue-specific gene expression and distribution, and for the functional effects of mutations in a particular gene. The database search tools allowed us to generate a set of candidate genes with involvement in mandibular development: Cacna1s, Ckm, Des, Mir300, Myog and Tnnc1. We also performed mouse-to-human translational experiments and found analogies. In the light of our findings we discuss various players in mandibular morphogenesis and make an argument for the need to consider mandibular development as a consequence of reciprocal epigenetic interactions of both skeletal and non-skeletal compartments. PMID:24867377

  5. Wave biomechanics of the skeletal muscle

    NASA Astrophysics Data System (ADS)

    Rudenko, O. V.; Sarvazyan, A. P.

    2006-12-01

    Results of acoustic measurements in skeletal muscle are generalized. It is shown that assessment of the pathologies and functional condition of the muscular system is possible with the use of shear waves. The velocity of these waves in muscles is much smaller than the velocity of sound; therefore, a higher symmetry type is formed for them. In the presence of a preferential direction (along muscle fibers), it is characterized by only two rather than five (as in usual media with the same anisotropy) moduli of elasticity. A covariant form of the corresponding wave equation is presented. It is shown that dissipation properties of skeletal muscles can be controlled by contracting them isometrically. Pulsed loads (shocks) and vibrations are damped differently, depending on their frequency spectrum. Characteristic frequencies on the order of tens and hundreds of hertz are attenuated due to actin-myosin bridges association/dissociation dynamics in the contracted muscle. At higher (kilohertz) frequencies, when the muscle is tensed, viscosity of the tissue increases by a factor of several tens because of the increase in friction experienced by fibrillar structures as they move relative to the surrounding liquid; the tension of the fibers changes the hydrodynamic conditions of the flow around them. Finally, at higher frequencies, the attenuation is associated with the rheological properties of biological molecules, in particular, with their conformational dynamics in the wave field. Models that describe the controlled shock dissipation mechanisms are proposed. Corresponding solutions are found, including those that allow for nonlinear effects.

  6. Skeletal Muscle Tissue Engineering: Methods to Form Skeletal Myotubes and Their Applications

    PubMed Central

    Ostrovidov, Serge; Hosseini, Vahid; Ahadian, Samad; Fujie, Toshinori; Parthiban, Selvakumar Prakash; Ramalingam, Murugan; Bae, Hojae; Kaji, Hirokazu

    2014-01-01

    Skeletal muscle tissue engineering (SMTE) aims to repair or regenerate defective skeletal muscle tissue lost by traumatic injury, tumor ablation, or muscular disease. However, two decades after the introduction of SMTE, the engineering of functional skeletal muscle in the laboratory still remains a great challenge, and numerous techniques for growing functional muscle tissues are constantly being developed. This article reviews the recent findings regarding the methodology and various technical aspects of SMTE, including cell alignment and differentiation. We describe the structure and organization of muscle and discuss the methods for myoblast alignment cultured in vitro. To better understand muscle formation and to enhance the engineering of skeletal muscle, we also address the molecular basics of myogenesis and discuss different methods to induce myoblast differentiation into myotubes. We then provide an overview of different coculture systems involving skeletal muscle cells, and highlight major applications of engineered skeletal muscle tissues. Finally, potential challenges and future research directions for SMTE are outlined. PMID:24320971

  7. Conchotome and needle percutaneous biopsy of skeletal muscle.

    PubMed Central

    Dietrichson, P; Coakley, J; Smith, P E; Griffiths, R D; Helliwell, T R; Edwards, R H

    1987-01-01

    Percutaneous muscle biopsy is an important and acceptable technique in the study of conditions involving human skeletal muscle. A review of 436 conchotome and needle muscle biopsies obtained over 18 months in this centre is presented. Images PMID:3694206

  8. Skeletal muscle mitochondrial energetic efficiency and aging.

    PubMed

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2015-01-01

    Aging is associated with a progressive loss of maximal cell functionality, and mitochondria are considered a key factor in aging process, since they determine the ATP availability in the cells. Mitochondrial performance during aging in skeletal muscle is reported to be either decreased or unchanged. This heterogeneity of results could partly be due to the method used to assess mitochondrial performance. In addition, in skeletal muscle the mitochondrial population is heterogeneous, composed of subsarcolemmal and intermyofibrillar mitochondria. Therefore, the purpose of the present review is to summarize the results obtained on the functionality of the above mitochondrial populations during aging, taking into account that the mitochondrial performance depends on organelle number, organelle activity, and energetic efficiency of the mitochondrial machinery in synthesizing ATP from the oxidation of fuels. PMID:25970752

  9. Role of skeletal muscle proteoglycans during myogenesis.

    PubMed

    Brandan, Enrique; Gutierrez, Jaime

    2013-08-01

    Skeletal muscle formation during development and the adult mammal consists of a highly organised and regulated the sequence of cellular processes intending to form or repair muscle tissue. This sequence includes, cell proliferation, migration, and differentiation. Proteoglycans (PGs), macromolecules formed by a core protein and glycosaminoglycan chains (GAGs) present a great diversity of functions explained by their capacity to interact with different ligands and receptors forming part of their signalling complex and/or protecting them from proteolytic cleavage. Particularly attractive is the function of the different types of PGs present at the neuromuscular junction (NMJ). This review is focussed on the advances reached to understand the role of PGs during myogenesis and skeletal muscular dystrophies. PMID:23583522

  10. Skeletal Muscle Mitochondrial Energetic Efficiency and Aging

    PubMed Central

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2015-01-01

    Aging is associated with a progressive loss of maximal cell functionality, and mitochondria are considered a key factor in aging process, since they determine the ATP availability in the cells. Mitochondrial performance during aging in skeletal muscle is reported to be either decreased or unchanged. This heterogeneity of results could partly be due to the method used to assess mitochondrial performance. In addition, in skeletal muscle the mitochondrial population is heterogeneous, composed of subsarcolemmal and intermyofibrillar mitochondria. Therefore, the purpose of the present review is to summarize the results obtained on the functionality of the above mitochondrial populations during aging, taking into account that the mitochondrial performance depends on organelle number, organelle activity, and energetic efficiency of the mitochondrial machinery in synthesizing ATP from the oxidation of fuels. PMID:25970752

  11. Tissue Engineered Strategies for Skeletal Muscle Injury

    PubMed Central

    Longo, Umile Giuseppe; Loppini, Mattia; Berton, Alessandra; Spiezia, Filippo; Maffulli, Nicola; Denaro, Vincenzo

    2012-01-01

    Skeletal muscle injuries are common in athletes, occurring with direct and indirect mechanisms and marked residual effects, such as severe long-term pain and physical disability. Current therapy consists of conservative management including RICE protocol (rest, ice, compression and elevation), nonsteroidal anti-inflammatory drugs, and intramuscular corticosteroids. However, current management of muscle injuries often does not provide optimal restoration to preinjury status. New biological therapies, such as injection of platelet-rich plasma and stem-cell-based therapy, are appealing. Although some studies support PRP application in muscle-injury management, reasons for concern persist, and further research is required for a standardized and safe use of PRP in clinical practice. The role of stem cells needs to be confirmed, as studies are still limited and inconsistent. Further research is needed to identify mechanisms involved in muscle regeneration and in survival, proliferation, and differentiation of stem cells. PMID:25098362

  12. Skeletal Muscle Mitochondria and Aging: A Review

    PubMed Central

    Peterson, Courtney M.; Johannsen, Darcy L.; Ravussin, Eric

    2012-01-01

    Aging is characterized by a progressive loss of muscle mass and muscle strength. Declines in skeletal muscle mitochondria are thought to play a primary role in this process. Mitochondria are the major producers of reactive oxygen species, which damage DNA, proteins, and lipids if not rapidly quenched. Animal and human studies typically show that skeletal muscle mitochondria are altered with aging, including increased mutations in mitochondrial DNA, decreased activity of some mitochondrial enzymes, altered respiration with reduced maximal capacity at least in sedentary individuals, and reduced total mitochondrial content with increased morphological changes. However, there has been much controversy over measurements of mitochondrial energy production, which may largely be explained by differences in approach and by whether physical activity is controlled for. These changes may in turn alter mitochondrial dynamics, such as fusion and fission rates, and mitochondrially induced apoptosis, which may also lead to net muscle fiber loss and age-related sarcopenia. Fortunately, strategies such as exercise and caloric restriction that reduce oxidative damage also improve mitochondrial function. While these strategies may not completely prevent the primary effects of aging, they may help to attenuate the rate of decline. PMID:22888430

  13. Development of Sensory Receptors in Skeletal Muscle

    NASA Technical Reports Server (NTRS)

    DeSantis, Mark

    2000-01-01

    There were two major goals for my project. One was to examine the hindlimb walking pattern of offspring from the Flight dams as compared with offspring of the ground control groups from initiation of walking up to two months thereafter. This initial goal was subsequently modified so that additional developmental measures were taken (e.g. body weight, eye opening) as the progeny developed, and the study period was lengthened to eighty days. Also videotapes taken shortly after the pregnant Flight dams returned to Earth were scored for locomotor activity and compared to those for the Synchronous control dams at the same stage of pregnancy. The second goal was to examine skeletal muscle. Selected hindlimb skeletal muscles were to be identified, weighed, and examined for the presence and integrity of muscle receptors, (both muscle spindles and tendon organs), at the level of the light and electron microscope. Muscles were examined from rats that were at fetal (G20), newborn (postnatal day 1 or P1, where P1 = day of birth), and young adult (approx. P100) stages. At the present time data from only the last group of rats (i.e. P100) has been completely examined.

  14. Effect of limb immobilization on skeletal muscle

    NASA Technical Reports Server (NTRS)

    Booth, F. W.

    1982-01-01

    Current knowledge and questions remaining concerning the effects of limb immobilization on skeletal muscle is reviewed. The most dramatic of these effects is muscle atrophy, which has been noted in cases of muscles fixed at or below their resting length. Immobilization is also accompanied by a substantial decrease in motoneuronal discharges, which results in the conversion of slow-twitch muscle to muscle with fast-twitch characteristics. Sarcolemma effects include no change or a decrease in resting membrane potential, the appearance of extrajunctional acetylcholine receptors, and no change in acetylcholinesterase activity. Evidence of changes in motoneuron after hyperpolarization characteristics suggests that the muscle inactivity is responsible for neuronal changes, rather than vice versa. The rate of protein loss from atrophying muscles is determined solely by the first-order rate constant for degradation. Various other biochemical and functional changes have been noted, including decreased insulin responsiveness and protein synthesis. The model of limb immobilization may also be useful for related studies of muscle adaptation.

  15. Skeletal muscle disease: patterns of MRI appearances

    PubMed Central

    Theodorou, D J; Theodorou, S J; Kakitsubata, Y

    2012-01-01

    Although the presumptive diagnosis of skeletal muscle disease (myopathy) may be made on the basis of clinical–radiological correlation in many cases, muscle biopsy remains the cornerstone of diagnosis. Myopathy is suspected when patients complain that the involved muscle is painful and tender, when they experience difficulty performing tasks that require muscle strength or when they develop various systemic manifestations. Because the cause of musculoskeletal pain may be difficult to determine clinically in many cases, MRI is increasingly utilised to assess the anatomical location, extent and severity of several pathological conditions affecting muscle. Infectious, inflammatory, traumatic, neurological, neoplastic and iatrogenic conditions can cause abnormal signal intensity on MRI. Although diverse, some diseases have similar MRI appearances, whereas others present distinct patterns of signal intensity abnormality. In general, alterations in muscle signal intensity fall into one of three cardinal patterns: muscle oedema, fatty infiltration and mass lesion. Because some of the muscular disorders may require medical or surgical treatment, correct diagnosis is essential. In this regard, MRI features, when correlated with clinical and laboratory findings as well as findings from other methods such as electromyography, may facilitate correct diagnosis. This article will review and illustrate the spectrum of MRI appearances in several primary and systemic disorders affecting muscle, both common and uncommon. The aim of this article is to provide radiologists and clinicians with a collective, yet succinct and useful, guide to a wide array of myopathies. PMID:22960244

  16. Aging impairs skeletal muscle mitochondrial bioenergetic function.

    PubMed

    Figueiredo, Pedro A; Powers, Scott K; Ferreira, Rita M; Appell, Hans Joachim; Duarte, José A

    2009-01-01

    This study investigated the influence of age on the functional status of mitochondria isolated from skeletal muscle of C57BL/6 mice aged 3 and 18 months. We hypothesized that skeletal muscle mitochondria isolated from aged animals will exhibit a decreased respiratory function. Mitochondrial respiratory functional measures (ie, State 3 and 4 respiration, respiratory control ratio and number of nanomoles of ADP phosphorylated by nanomoles of O(2) consumed per mitochondrion) and biochemical markers of oxidative damage (aconitase activity, protein carbonyl derivatives, sulfhydryl groups, and malondialdehyde) were measured in isolated mitochondrial suspensions. Along with traditional tests of mitochondrial function, an in vitro repetitive ADP-stimulation test was used to evaluate the mitochondrial capacity to reestablish the homeostatic balance between successive ADP stimulations. The number of mitochondria per mitochondrial suspension, calculated by transmission electron microscopy, was used to normalize functional and biochemical data. Our results confirm the existence of an age-associated decline in mitochondrial function of mixed skeletal muscle, which is significantly correlated with higher levels of mitochondrial oxidative damage. PMID:19196905

  17. Metastases of esophageal carcinoma to skeletal muscle: single center experience.

    PubMed

    Cincibuch, Jan; Mysliveček, Miroslav; Melichar, Bohuslav; Neoral, Cestmír; Metelková, Iva; Zezulová, Michaela; Procházková-Študentová, Hana; Flodr, Patrik; Zlevorová, Miloslava; Aujeský, René; Cwiertka, Karel

    2012-09-21

    Metastases of esophageal carcinoma to the skeletal muscle are rare, but the incidence may be increasing because of better diagnosis resulting from widespread use of positron emission tomography/computed tomography (PET/CT). A cohort of 205 patients with esophageal carcinoma treated at our center who had PET/CT between 2006 and 2010 was retrospectively evaluated for the presence of skeletal muscle metastases. Four patients had skeletal muscle metastases of esophageal carcinoma, including two patients with squamous cell carcinoma. In another patient with squamous cell carcinoma of the esophagus and synchronous skeletal muscle metastases, muscle metastases were subsequently shown to be related to second primary pancreatic adenocarcinoma. In all cases, skeletal muscle metastases were the first manifestation of systemic disease. In three patients palliation was obtained with the combination of external beam radiation therapy, systemic chemotherapy or surgical resection. Skeletal muscle metastases are a rare complication of esophageal carcinoma. PMID:23002370

  18. Engineering of aligned skeletal muscle by micropatterning

    PubMed Central

    Huang, Ngan F; Lee, Randall J; Li, Song

    2010-01-01

    Tissue engineered skeletal muscle has tremendous potential for the treatment of muscular injury or muscular dysfunction. However, in vitro methods to generate skeletal muscle with physiologically aligned myofiber structure remains limited. To develop a robust in vitro model that resembles the physiologically aligned structure of muscle fibers, we fabricated micropatterned polymer membranes of poly(dimethylsiloxane) (PDMS) with parallel microgrooves, and then examined the effect of micropatterning on myoblast cellular organization and the cell fusion process. In comparison to the myoblasts on non-patterned PDMS films, myoblasts on micropatterned PDMS films had well-organized F-actin assembly in close proximity to the direction of microgrooves, along with enhanced levels of myotube formation at early time points. The increase of cell cycle regulator p21WAF/Cip1 and the organized interactions of N-cadherin in myoblasts on micropatterned surfaces may contribute to the enhanced formation of myotubes. Similar results of cellular alignment was observed when myoblasts were cultured on microfluidically patterned poly(2-hydroxyethyl methacrylate) (pHEMA) microgrooves, and the micropatterns were found to detach from the Petri dish over time. To apply this technology for generating aligned tissue-like muscle constructs, we developed a methodology to transfer the aligned myotubes to biodegradable collagen gels. Histological analysis revealed the persistence of aligned cellular organization in the collagen gels. Together, these results demonstrate that micropatterned PDMS or pHEMA can promote cell alignment and fusion along the direction of the microgrooves, and this platform can be utilized to transfer aligned myotubes on biodegradable hydrogels. This study highlights the importance of spatial cues in creating aligned skeletal muscle for tissue engineering and muscular regeneration applications. PMID:20182581

  19. Dietary lysine affected the expression of genes related to lipid metabolism in skeletal muscle of finishing pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It has been reported that some amino acids can function as signaling molecules to regulate skeletal muscle growth in mammals. This study was conducted to identify those genes that may be regulated by amino acid lysine and responsible for muscle growth and meat quality of pigs. Nine crossbred barrows...

  20. Phosphorylation of human skeletal muscle myosin

    SciTech Connect

    Houston, M.E.; Lingley, M.D.; Stuart, D.S.; Hoffman-Goetz, L.

    1986-03-01

    Phosphorylation of the P-light chains (phosphorylatable light chains) in human skeletal muscle myosin was studied in vitro and in vivo under resting an d contracted conditions. biopsy samples from rested vastus lateralis muscle of male and female subjects were incubated in oxygenated physiological solution at 30/sup 0/C. Samples frozen following a quiescent period showed the presence of only unphosphorylated P-light chains designated LC2f (light chain two of fast myosin) CL2s and LC2s'(light chains two of slow myosin). Treatment with caffeine (10 mM) or direct electrical stimulation resulted in the appearance of three additional bands which were identified as the phosphorylated forms of the P-light chains i.e. LC2f-P, LC2s-P and LC2s'-P. The presence of phosphate was confirmed by prior incubation with (/sup 30/P) orthophosphate. Muscle samples rapidly frozen from resting vastus lateralis muscle revealed the presence of unphosphorylated and phosphorylated P-light chains in approximately equal ratios. Muscle samples rapidly frozen following a maximal 10 second isometric contraction showed virtually only phosphorylated fast and slow P-light chains. These results reveal that the P-light chains in human fast and slow myosin may be rapidly phosphorylated, but the basal level of phosphorylation in rested human muscle considerably exceeds that observed in animal muscles studied in vitro or in situ.

  1. GLUT-3 expression in human skeletal muscle

    NASA Technical Reports Server (NTRS)

    Stuart, C. A.; Wen, G.; Peng, B. H.; Popov, V. L.; Hudnall, S. D.; Campbell, G. A.

    2000-01-01

    Muscle biopsy homogenates contain GLUT-3 mRNA and protein. Before these studies, it was unclear where GLUT-3 was located in muscle tissue. In situ hybridization using a midmolecule probe demonstrated GLUT-3 within all muscle fibers. Fluorescent-tagged antibody reacting with affinity-purified antibody directed at the carboxy-terminus demonstrated GLUT-3 protein in all fibers. Slow-twitch muscle fibers, identified by NADH-tetrazolium reductase staining, possessed more GLUT-3 protein than fast-twitch fibers. Electron microscopy using affinity-purified primary antibody and gold particle-tagged second antibody showed that the majority of GLUT-3 was in association with triads and transverse tubules inside the fiber. Strong GLUT-3 signals were seen in association with the few nerves that traversed muscle sections. Electron microscopic evaluation of human peripheral nerve demonstrated GLUT-3 within the axon, with many of the particles related to mitochondria. GLUT-3 protein was found in myelin but not in Schwann cells. GLUT-1 protein was not present in nerve cells, axons, myelin, or Schwann cells but was seen at the surface of the peripheral nerve in the perineurium. These studies demonstrated that GLUT-3 mRNA and protein are expressed throughout normal human skeletal muscle, but the protein is predominantly found in the triads of slow-twitch muscle fibers.

  2. Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation

    PubMed Central

    Haldar, Saptarsi M.; Jeyaraj, Darwin; Anand, Priti; Zhu, Han; Lu, Yuan; Prosdocimo, Domenick A.; Eapen, Betty; Kawanami, Daiji; Okutsu, Mitsuharu; Brotto, Leticia; Fujioka, Hisashi; Kerner, Janos; Rosca, Mariana G.; McGuinness, Owen P.; Snow, Rod J.; Russell, Aaron P.; Gerber, Anthony N.; Bai, Xiaodong; Yan, Zhen; Nosek, Thomas M.; Brotto, Marco; Hoppel, Charles L.; Jain, Mukesh K.

    2012-01-01

    The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids. PMID:22493257

  3. Working around the clock: circadian rhythms and skeletal muscle

    PubMed Central

    Zhang, Xiping; Dube, Thomas J.

    2009-01-01

    The study of the circadian molecular clock in skeletal muscle is in the very early stages. Initial research has demonstrated the presence of the molecular clock in skeletal muscle and that skeletal muscle of a clock-compromised mouse, Clock mutant, exhibits significant disruption in normal expression of many genes required for adult muscle structure and metabolism. In light of the growing association between the molecular clock, metabolism, and metabolic disease, it will also be important to understand the contribution of circadian factors to normal metabolism, metabolic responses to muscle training, and contribution of the molecular clock in muscle-to-muscle disease (e.g., insulin resistance). Consistent with the potential for the skeletal muscle molecular clock modulating skeletal muscle physiology, there are findings in the literature that there is significant time-of-day effects for strength and metabolism. Additionally, there is some recent evidence that temporal specificity is important for optimizing training for muscular performance. While these studies do not prove that the molecular clock in skeletal muscle is important, they are suggestive of a circadian contribution to skeletal muscle function. The application of well-established models of skeletal muscle research in function and metabolism with available genetic models of molecular clock disruption will allow for more mechanistic understanding of potential relationships. PMID:19696362

  4. FGFR1 inhibits skeletal muscle atrophy associated with hindlimb suspension

    PubMed Central

    Eash, John; Olsen, Aaron; Breur, Gert; Gerrard, Dave; Hannon, Kevin

    2007-01-01

    Background Skeletal muscle atrophy can occur under many different conditions, including prolonged disuse or immobilization, cachexia, cushingoid conditions, secondary to surgery, or with advanced age. The mechanisms by which unloading of muscle is sensed and translated into signals controlling tissue reduction remains a major question in the field of musculoskeletal research. While the fibroblast growth factors (FGFs) and their receptors are synthesized by, and intimately involved in, embryonic skeletal muscle growth and repair, their role maintaining adult muscle status has not been examined. Methods We examined the effects of ectopic expression of FGFR1 during disuse-mediated skeletal muscle atrophy, utilizing hindlimb suspension and DNA electroporation in mice. Results We found skeletal muscle FGF4 and FGFR1 mRNA expression to be modified by hind limb suspension,. In addition, we found FGFR1 protein localized in muscle fibers within atrophying mouse muscle which appeared to be resistant to atrophy. Electroporation and ectopic expression of FGFR1 significantly inhibited the decrease in muscle fiber area within skeletal muscles of mice undergoing suspension induced muscle atrophy. Ectopic FGFR1 expression in muscle also significantly stimulated protein synthesis in muscle fibers, and increased protein degradation in weight bearing muscle fibers. Conclusion These results support the theory that FGF signaling can play a role in regulation of postnatal skeletal muscle maintenance, and could offer potentially novel and efficient therapeutic options for attenuating muscle atrophy during aging, illness and spaceflight. PMID:17425786

  5. Role of microRNAs in skeletal muscle hypertrophy

    PubMed Central

    Hitachi, Keisuke; Tsuchida, Kunihiro

    2014-01-01

    Skeletal muscle comprises approximately 40% of body weight, and is important for locomotion, as well as for metabolic homeostasis. Adult skeletal muscle mass is maintained by a fine balance between muscle protein synthesis and degradation. In response to cytokines, nutrients, and mechanical stimuli, skeletal muscle mass is increased (hypertrophy), whereas skeletal muscle mass is decreased (atrophy) in a variety of conditions, including cancer cachexia, starvation, immobilization, aging, and neuromuscular disorders. Recent studies have determined two important signaling pathways involved in skeletal muscle mass. The insulin-like growth factor-1 (IGF-1)/Akt pathway increases skeletal muscle mass via stimulation of protein synthesis and inhibition of protein degradation. By contrast, myostatin signaling negatively regulates skeletal muscle mass by reducing protein synthesis. In addition, the discovery of microRNAs as novel regulators of gene expression has provided new insights into a multitude of biological processes, especially in skeletal muscle physiology. We summarize here the current knowledge of microRNAs in the regulation of skeletal muscle hypertrophy, focusing on the IGF-1/Akt pathway and myostatin signaling. PMID:24474938

  6. The abundance and activation of mTORC1 regulators in skeletal muscle of neonatal pigs are modulated by insulin, amino acids, and age

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previously we demonstrated that the insulin (INS) and amino acid (AA) -induced activation of the mammalian target of rapamycin complex 1 (mTORC1) is developmentally regulated in neonatal pigs. This study aimed to determine the effects of the post-prandial rise in INS and AA on the activation and abu...

  7. Abundance of amino acid transporters involved in mTORC1 activation in skeletal muscle of neonatal pigs is developmentally regulated

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previously we demonstrated that the insulinand amino acid-induced activation of the mammalian target of rapamycin complex 1 (mTORC1) is developmentally regulated in neonatal pigs. Recent studies have indicated that members of the System A transporter (SNAT2), the System N transporter (SNAT3), the Sy...

  8. Primary sacrococcygeal chordoma with unusual skeletal muscle metastasis

    PubMed Central

    Vu, Lisa; Haygood, Tamara Miner

    2015-01-01

    Chordomas are rare neoplasms that do not often metastasize. Of the small percent that do metastasize, they very infrequently involve skeletal muscle. Only a few cases of skeletal muscle metastases have been reported in the literature. We report an unusual case of a patient with a primary sacrococcygeal chordoma who experienced a long period of remission but who subsequently developed recurrence and multiple metastatic lesions to skeletal muscles including the deltoid, triceps, and pectineus.

  9. Effects of regular exercise training on skeletal muscle contractile function

    NASA Technical Reports Server (NTRS)

    Fitts, Robert H.

    2003-01-01

    Skeletal muscle function is critical to movement and one's ability to perform daily tasks, such as eating and walking. One objective of this article is to review the contractile properties of fast and slow skeletal muscle and single fibers, with particular emphasis on the cellular events that control or rate limit the important mechanical properties. Another important goal of this article is to present the current understanding of how the contractile properties of limb skeletal muscle adapt to programs of regular exercise.

  10. Prolonged stimulation of muscle protein synthesis by leucine in neonates is dependent on amino acid availability

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The rise in amino acids and insulin after a meal independently stimulate protein synthesis in skeletal muscle of neonates by activating the intracellular signalling pathways that regulate mRNA translation. Leucine, in particular, is important in mediating the response to amino acids. Previously, w...

  11. Regulation of protein synthesis by amino acids in muscle of neonates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The marked increase in skeletal muscle mass during the neonatal period is largely due to a high rate of postprandial protein synthesis that is modulated by an enhanced sensitivity to insulin and amino acids. The amino acid signaling pathway leading to the stimulation of protein synthesis has not bee...

  12. The molecular basis for load-induced skeletal muscle hypertrophy.

    PubMed

    Marcotte, George R; West, Daniel W D; Baar, Keith

    2015-03-01

    In a mature (weight neutral) animal, an increase in muscle mass only occurs when the muscle is loaded sufficiently to cause an increase in myofibrillar protein balance. A tight relationship between muscle hypertrophy, acute increases in protein balance, and the activity of the mechanistic target of rapamycin complex 1 (mTORC1) was demonstrated 15 years ago. Since then, our understanding of the signals that regulate load-induced hypertrophy has evolved considerably. For example, we now know that mechanical load activates mTORC1 in the same way as growth factors, by moving TSC2 (a primary inhibitor of mTORC1) away from its target (the mTORC activator) Rheb. However, the kinase that phosphorylates and moves TSC2 is different in the two processes. Similarly, we have learned that a distinct pathway exists whereby amino acids activate mTORC1 by moving it to Rheb. While mTORC1 remains at the forefront of load-induced hypertrophy, the importance of other pathways that regulate muscle mass are becoming clearer. Myostatin, is best known for its control of developmental muscle size. However, new mechanisms to explain how loading regulates this process are suggesting that it could play an important role in hypertrophic muscle growth as well. Last, new mechanisms are highlighted for how β2 receptor agonists could be involved in load-induced muscle growth and why these agents are being developed as non-exercise-based therapies for muscle atrophy. Overall, the results highlight how studying the mechanism of load-induced skeletal muscle mass is leading the development of pharmaceutical interventions to promote muscle growth in those unwilling or unable to perform resistance exercise. PMID:25359125

  13. The Molecular Basis for Load-Induced Skeletal Muscle Hypertrophy

    PubMed Central

    Marcotte, George R.; West, Daniel W.D.; Baar, Keith

    2016-01-01

    In a mature (weight neutral) animal, an increase in muscle mass only occurs when the muscle is loaded sufficiently to cause an increase in myofibrillar protein balance. A tight relationship between muscle hypertrophy, acute increases in protein balance, and the activity of the mechanistic target of rapamycin complex 1 (mTORC1) was demonstrated 15 years ago. Since then, our understanding of the signals that regulate load-induced hypertrophy has evolved considerably. For example, we now know that mechanical load activates mTORC1 in the same way as growth factors, by moving TSC2 (a primary inhibitor of mTORC1) away from its target (the mTORC activator) Rheb. However, the kinase that phosphorylates and moves TSC2 is different in the two processes. Similarly, we have learned that a distinct pathway exists whereby amino acids activate mTORC1 by moving it to Rheb. While mTORC1 remains at the forefront of load-induced hypertrophy, the importance of other pathways that regulate muscle mass are becoming clearer. Myostatin, is best known for its control of developmental muscle size. However, new mechanisms to explain how loading regulates this process are suggesting that it could play an important role in hypertrophic muscle growth as well. Lastly, new mechanisms are highlighted for how β2 receptor agonists could be involved in load-induced muscle growth and why these agents are being developed as non-exercise-based therapies for muscle atrophy. Overall, the results highlight how studying the mechanism of load-induced skeletal muscle mass is leading the development of pharmaceutical interventions to promote muscle growth in those unwilling or unable to perform resistance exercise. PMID:25359125

  14. Circadian rhythms, the molecular clock, and skeletal muscle.

    PubMed

    Harfmann, Brianna D; Schroder, Elizabeth A; Esser, Karyn A

    2015-04-01

    Circadian rhythms are the approximate 24-h biological cycles that function to prepare an organism for daily environmental changes. They are driven by the molecular clock, a transcriptional:translational feedback mechanism that in mammals involves the core clock genes Bmal1, Clock, Per1/2, and Cry1/2. The molecular clock is present in virtually all cells of an organism. The central clock in the suprachiasmatic nucleus (SCN) has been well studied, but the clocks in the peripheral tissues, such as heart and skeletal muscle, have just begun to be investigated. Skeletal muscle is one of the largest organs in the body, comprising approximately 45% of total body mass. More than 2300 genes in skeletal muscle are expressed in a circadian pattern, and these genes participate in a wide range of functions, including myogenesis, transcription, and metabolism. The circadian rhythms of skeletal muscle can be entrained both indirectly through light input to the SCN and directly through time of feeding and activity. It is critical for the skeletal muscle molecular clock not only to be entrained to the environment but also to be in synchrony with rhythms of other tissues. When circadian rhythms are disrupted, the observed effects on skeletal muscle include fiber-type shifts, altered sarcomeric structure, reduced mitochondrial respiration, and impaired muscle function. Furthermore, there are detrimental effects on metabolic health, including impaired glucose tolerance and insulin sensitivity, which skeletal muscle likely contributes to considering it is a key metabolic tissue. These data indicate a critical role for skeletal muscle circadian rhythms for both muscle and systems health. Future research is needed to determine the mechanisms of molecular clock function in skeletal muscle, identify the means by which skeletal muscle entrainment occurs, and provide a stringent comparison of circadian gene expression across the diverse tissue system of skeletal muscle. PMID:25512305

  15. Circadian Rhythms, the Molecular Clock, and Skeletal Muscle

    PubMed Central

    Harfmann, Brianna D.; Schroder, Elizabeth A.; Esser, Karyn A.

    2015-01-01

    Circadian rhythms are the approximate 24-h biological cycles that function to prepare an organism for daily environmental changes. They are driven by the molecular clock, a transcriptional:translational feedback mechanism that in mammals involves the core clock genes Bmal1, Clock, Per1/2, and Cry1/2. The molecular clock is present in virtually all cells of an organism. The central clock in the suprachiasmatic nucleus (SCN) has been well studied, but the clocks in the peripheral tissues, such as heart and skeletal muscle, have just begun to be investigated. Skeletal muscle is one of the largest organs in the body, comprising approximately 45% of total body mass. More than 2300 genes in skeletal muscle are expressed in a circadian pattern, and these genes participate in a wide range of functions, including myogenesis, transcription, and metabolism. The circadian rhythms of skeletal muscle can be entrained both indirectly through light input to the SCN and directly through time of feeding and activity. It is critical for the skeletal muscle molecular clock not only to be entrained to the environment but also to be in synchrony with rhythms of other tissues. When circadian rhythms are disrupted, the observed effects on skeletal muscle include fiber-type shifts, altered sarcomeric structure, reduced mitochondrial respiration, and impaired muscle function. Furthermore, there are detrimental effects on metabolic health, including impaired glucose tolerance and insulin sensitivity, which skeletal muscle likely contributes to considering it is a key metabolic tissue. These data indicate a critical role for skeletal muscle circadian rhythms for both muscle and systems health. Future research is needed to determine the mechanisms of molecular clock function in skeletal muscle, identify the means by which skeletal muscle entrainment occurs, and provide a stringent comparison of circadian gene expression across the diverse tissue system of skeletal muscle. PMID:25512305

  16. Skeletal muscle myosin is the autoantigen for experimental autoimmune myositis.

    PubMed

    Nemoto, Hiroshi; Bhopale, Mahendra K; Constantinescu, Cris S; Schotland, Donald; Rostami, Abdolmohamad

    2003-06-01

    Experimental autoimmune myositis (EAM) is a rodent model for human inflammatory muscle disease (IMD). It can be induced by immunization of rodents with skeletal muscle homogenate and adjuvant. The specific myositogenic autoantigen has not been clearly identified although some evidence points to skeletal muscle myosin. In this report we strengthen this evidence, showing that Lewis rats immunized with purified skeletal muscle myosin develop EAM with the same pattern and severity as EAM induced by whole rabbit skeletal muscle homogenate (WRM). Multiple inflammatory lesions are detected histopathologically in the biceps, quadriceps, and gastrocnemius muscles. Myosin-reactive T cells from animals immunized either with myosin or with WRM have similar patterns of antigen-induced proliferation. The results show that myosin, a component of skeletal muscle, is at least one autoantigen in EAM. PMID:12782010

  17. Modeling of the Skeletal Muscle Microcirculation

    NASA Astrophysics Data System (ADS)

    Jacobitz, Frank; Beth, Christophe; Salado, Jerome

    2004-11-01

    Numerical simulations of blood flow in a microvascular network require extensive modeling. This contribution focuses on the reconstruction of a complete network topology from microscopic images of rat skeletal muscle and skeletal muscle fascia. The bifurcating network is composed of a feeding arterial network, a collecting venous network, and bundles of capillaries. Multiple topologies of each network component are recontructed and statistical properties of the network, such as distributions of vessel diameters, vessel lengths, and branching patters are determined. Particular attention has been paid to venous vessel loops that are observed only in the muscle fascia. The flow in the microvessel network is then computed. In the simulations, the microvessels are distensible by pressure, and the arterioles are actively contractile. The blood has non-Newtonian apparent viscosity. Models of each of these properties have previously been determined and are used in the computations. The method of indefinite admittances is used to compute the flow in the network. The apparent viscosity is computed from the local hematocrit, which is found using a combination of breadth first search and Dykstra's algorithms. The computations allow the determination of additional properties of the network, such as flow velocities, shear stresses, and hematocrit.

  18. [Skeletal muscle: from development to function].

    PubMed

    Imbesi, R; D'Agata, V; Musumeci, G; Castrogiovanni, P

    2014-01-01

    Aim of this minireview was to focus attention on some aspects of myogenesis, differentiation and metabolism of muscle in mammals (rodents and humans), and to summarize current knowledge on the issue referring to both our experimental contributions and those of other authors.Particular attention was directed at both the mesodermal stem cells, elements of the early embryonic period, and the regulatory genes. It was also discussed the crucial role of several growth factors, such as myogenin and bFGF, and substances of vital importance to the regulation of contraction: somatomedins [Insulin-like Growth Factors (IGF-I and IGF-II)], interleukin-15 (IL -15), transferrin (Tf), catecholamines (CA). A no secondary role in the metabolism of skeletal muscle is played by serotonin (5-HT) and its precursor [L-tryptophan (L-Tp)]. The presence of L-Tp, in the diet of growing rats, seems to be crucial for protein synthesis and for the increase in the number of mitochondria. It has also highlighted the role played by certain hormones: growth hormone (GH), thyroid hormones (T3 and T4), sex steroids on metabolism, growth and differentiation of skeletal muscle. PMID:24589951

  19. The impact of severe burn injury on skeletal muscle mitochondrial function

    PubMed Central

    Porter, Craig; Herndon, David N; Sidossis, Labros S; Borsheim, Elisabet

    2013-01-01

    Severe burn injury induces a pathophysiological response that affects almost every physiological system within the body. Inflammation, hypermetabolism, muscle wasting, and insulin resistance are all hallmarks of the pathophysiological response to burn injury, with perturbations in metabolism known to persist for several years post injury. Skeletal muscle is the main depot of lean tissue within the body and as the primary site of peripheral glucose disposal, plays an important role in metabolic regulation. Following a large burn, skeletal muscle functions as and endogenous amino acid store, providing substrates for more pressing functions post burn, such as the synthesis of acute phase proteins and the deposition of new skin. Subsequently, burn patients become cachexic, which is associated with poor outcomes in terms of metabolic health and functional capacity. While a loss of skeletal muscle contractile proteins per se will no doubt negatively impact functional capacity, detriments in skeletal muscle quality, i.e. a loss in mitochondrial number and/or function may be quantitatively just as important. The goal of this review article is to summarize the current understanding of the impact of burn injury on skeletal muscle mitochondrial content and function, to offer direction for future research concerning skeletal muscle mitochondrial function in patients with severe burns, and to renew interest in the role of these organelles in metabolic dysfunction following burn injury. PMID:23664225

  20. Molecular networks in skeletal muscle plasticity.

    PubMed

    Hoppeler, Hans

    2016-01-01

    The skeletal muscle phenotype is subject to considerable malleability depending on use as well as internal and external cues. In humans, low-load endurance-type exercise leads to qualitative changes of muscle tissue characterized by an increase in structures supporting oxygen delivery and consumption, such as capillaries and mitochondria. High-load strength-type exercise leads to growth of muscle fibers dominated by an increase in contractile proteins. In endurance exercise, stress-induced signaling leads to transcriptional upregulation of genes, with Ca(2+) signaling and the energy status of the muscle cells sensed through AMPK being major input determinants. Several interrelated signaling pathways converge on the transcriptional co-activator PGC-1α, perceived to be the coordinator of much of the transcriptional and post-transcriptional processes. Strength training is dominated by a translational upregulation controlled by mTORC1. mTORC1 is mainly regulated by an insulin- and/or growth-factor-dependent signaling cascade as well as mechanical and nutritional cues. Muscle growth is further supported by DNA recruitment through activation and incorporation of satellite cells. In addition, there are several negative regulators of muscle mass. We currently have a good descriptive understanding of the molecular mechanisms controlling the muscle phenotype. The topology of signaling networks seems highly conserved among species, with the signaling outcome being dependent on the particular way individual species make use of the options offered by the multi-nodal networks. As a consequence, muscle structural and functional modifications can be achieved by an almost unlimited combination of inputs and downstream signaling events. PMID:26792332

  1. Osmoregulatory processes and skeletal muscle metabolism

    NASA Astrophysics Data System (ADS)

    Boschmann, Michael; Gottschalk, Simone; Adams, Frauke; Luft, Friedrich C.; Jordan, Jens

    Prolonged microgravity during space flight is associated with a decrease in blood and extracellular volume. These changes in water and electrolyte balance might activate catabolic processes which contribute finally to the loss of muscle and bone mass and strength. Recently, we found a prompt increase that energy expenditure by about 30% in both normal and overweight men and women after drinking 500 ml water. This effect is mediated by an increased sympathetic nervous system activity, obviously secondary to stimulation of osmosensitive afferent neurons in the liver, and skeletal muscle is possibly one effector organ. Therefore, we tested the hypothesis that this thermogenic response to water is accompanied by a stimulation of aerobic glucose metabolism in skeletal muscle. To this end, 16 young healthy volunteers (8 men) were studied. After an overnight fast (12h), a microdialysis probe was implanted into the right M. quadriceps femoris vastus lateralis and subsequently perfused with Ringer's solution (+50 mM ethanol). After 1h, volunteers were asked to drink 500 ml water (22° C) followed by continuing microdialysis for another 90 min. Dialysates (15 min fractions) were analyzed for [ethanol], [glucose], [lactate], [pyruvate], and [glycerol] in order to assess changes in muscle tissue perfusion (ethanol dilution technique), glycolysis and lipolysis. Blood samples were taken and heart rate (HR) and blood pressure (BP) were monitored. Neither HR and systolic and diastolic BP, nor plasma [glucose], [lactate], [insulin], and [C peptide] changed significantly after water drinking. Also, tissue perfusion and dialysate [glucose] did not change significantly. However, dialysate [lactate] increased by about 10 and 20% and dialysate [pyruvate] by about 100 and 200% in men and women, respectively. In contrast, dialysate [glycerol] decreased by about 30 and 20% in men and women, respectively. Therefore, drinking of 500 ml water stimulates aerobic glucose metabolism and inhibits lipolysis in skeletal muscle and this to a greater extent in women than men. These insulin-like effects after water drinking originate possibly from regulatory cell volume swelling in osmosensitive organs such as muscle. Therefore, a well-balanced water homeostasis might be important for preventing catabolic processes during long-term space expeditions.

  2. Myofibrillogenesis in Skeletal Muscle Cells in Zebrafish

    PubMed Central

    Sanger, Joseph W.; Wang, Jushuo; Holloway, Beth; Du, Aiping; Sanger, Jean M.

    2009-01-01

    The “premyofibril” model of myofibrillogenesis, based on observations in cultured avian muscle cells, proposes that mature myofibrils are preceded by two intermediary structures: premyofibrils and nascent myofibrils. To determine if this model applies to zebrafish skeletal muscle development, we stained developing embryos with antibodies to sarcomeric alpha-actinin and myosin II. In the youngest muscle cells, sarcomeric alpha-actinin and non-muscle myosin II were each localized in linear arrays of small bands that resembled the premyofibrils in avian myocytes. The distribution of muscle–specific myosin II began as scattered short filaments followed in time by overlapping bundles of filaments and organized A-bands in the older somites. Alpha-actinin organization changed from small z-bodies to beaded Z-bands and ordered Z-bands in myofibrils that extended the length of the elongating somites. In older somites with mature myofibrils, premyofibrils were also present at the ends of the mature myofibrils, suggesting that as the cells and somites grew longer, premyofibrils were involved in the elongation of existing mature myofibrils. Fluorescence Recovery After Photobleaching showed that the exchange of proteins (actin, alpha-actinin, FATZ, myotilin and telethonin) between sarcoplasm and the Z-bands of mature myofibrils in zebrafish resembled that seen for the same proteins in cultured avian myotubes, suggesting that myofibril assembly and maintenance in zebrafish share common properties with avian muscle. PMID:19382198

  3. Skeletal muscle responses to unloading in humans

    NASA Technical Reports Server (NTRS)

    Dudley, G.; Tesch, P.; Hather, B.; Adams, G.; Buchanan, P.

    1992-01-01

    This study examined the effects of unloading on skeletal muscle structure. Method: Eight subjects walked on crutches for six weeks with a 110 cm elevated sole on the right shoe. This removed weight bearing by the left lower limb. Magnetic resonance imaging of both lower limbs and biopsies of the left m. vastus laterallis (VL) were used to study muscle structure. Results: Unloading decreased (P less than 0.05) muscle cross-sectional areas (CSA) of the knee extensors 16 percent. The knee flexors showed about 1/2 of this response (-7 percent, P less than 0.05). The three vasti muscles each showed decreases (P less than 0.05) of about 15 percent. M. rectus femoris did not change. Mean fiber CSA in VL decreased (P less than 0.05) 14 percent with type 2 and type 1 fibers showing reductions of 15 and 11 percent respectively. The ankle extensors showed a 20 percent decrease (P less than 0.05) in CSA. The reduction for the 'fast' m. gastrocnemius was 27 percent compared to the 18 percent decrease for the 'slow' soleus. Summary: The results suggest that decreases in muscle CSA are determined by the relative change in impact loading history because atrophy was (1) greater in extensor than flexor muscles, (2) at least as great in fast as compared to slow muscles or fibers, and (3) not dependent on single or multi-joint function. They also suggest that the atrophic responses to unloading reported for lower mammals are quantitatively but not qualitatively similar to those of humans.

  4. Structure-function relationship of skeletal muscle provides inspiration for design of new artificial muscle

    NASA Astrophysics Data System (ADS)

    Gao, Yingxin; Zhang, Chi

    2015-03-01

    A variety of actuator technologies have been developed to mimic biological skeletal muscle that generates force in a controlled manner. Force generation process of skeletal muscle involves complicated biophysical and biochemical mechanisms; therefore, it is impossible to replace biological muscle. In biological skeletal muscle tissue, the force generation of a muscle depends not only on the force generation capacity of the muscle fiber, but also on many other important factors, including muscle fiber type, motor unit recruitment, architecture, structure and morphology of skeletal muscle, all of which have significant impact on the force generation of the whole muscle or force transmission from muscle fibers to the tendon. Such factors have often been overlooked, but can be incorporated in artificial muscle design, especially with the discovery of new smart materials and the development of innovative fabrication and manufacturing technologies. A better understanding of the physiology and structure-function relationship of skeletal muscle will therefore benefit the artificial muscle design. In this paper, factors that affect muscle force generation are reviewed. Mathematical models used to model the structure-function relationship of skeletal muscle are reviewed and discussed. We hope the review will provide inspiration for the design of a new generation of artificial muscle by incorporating the structure-function relationship of skeletal muscle into the design of artificial muscle.

  5. Amino acids augment muscle protein synthesis in neonatal pigs during acute endotoxemia by stimulating mTOR-dependent translation initiation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In skeletal muscle of adults, sepsis reduces protein synthesis by depressing translation initiation and induces resistance to branched-chain amino acid stimulation. Normal neonates maintain a high basal muscle protein synthesis rate that is sensitive to amino acid stimulation. In the present study...

  6. mTORC1 and the regulation of skeletal muscle anabolism and mass.

    TOXLINE Toxicology Bibliographic Information

    Adegoke OA; Abdullahi A; Tavajohi-Fini P

    2012-06-01

    The mass and integrity of skeletal muscle is vital to whole-body substrate metabolism and health. Indeed, defects in muscle metabolism and functions underlie or exacerbate diseases like diabetes, rheumatoid arthritis, and cancer. Physical activity and nutrition are the 2 most important environmental factors that can affect muscle health. At the molecular level, the mammalian target of rapamycin complex 1 (mTORC1) is a critical signalling complex that regulates muscle mass. In response to nutrition and resistance exercise, increased muscle mass and activation of mTORC1 occur in parallel. In this review, we summarize recent findings on mTORC1 and its regulation in skeletal muscle in response to resistance exercise, alone or in combination with intake of protein or amino acids. Because increased activity of the complex is implicated in the development of muscle insulin resistance, obesity, and some cancers (e.g., ovarian, breast), drugs that target mTORC1 are being developed or are in clinical trials. However, various cancers are associated with extensive muscle wasting, due in part to tumour burden and malnutrition. This muscle wasting may also be a side effect of anticancer drugs. Because loss of muscle mass is associated not only with metabolic abnormalities but also dose limiting toxicity, we review the possible implications for skeletal muscle of long-term inhibition of mTORC1, especially in muscle wasting conditions.

  7. mTORC1 and the regulation of skeletal muscle anabolism and mass.

    PubMed

    Adegoke, Olasunkanmi A J; Abdullahi, Abdikarim; Tavajohi-Fini, Pegah

    2012-06-01

    The mass and integrity of skeletal muscle is vital to whole-body substrate metabolism and health. Indeed, defects in muscle metabolism and functions underlie or exacerbate diseases like diabetes, rheumatoid arthritis, and cancer. Physical activity and nutrition are the 2 most important environmental factors that can affect muscle health. At the molecular level, the mammalian target of rapamycin complex 1 (mTORC1) is a critical signalling complex that regulates muscle mass. In response to nutrition and resistance exercise, increased muscle mass and activation of mTORC1 occur in parallel. In this review, we summarize recent findings on mTORC1 and its regulation in skeletal muscle in response to resistance exercise, alone or in combination with intake of protein or amino acids. Because increased activity of the complex is implicated in the development of muscle insulin resistance, obesity, and some cancers (e.g., ovarian, breast), drugs that target mTORC1 are being developed or are in clinical trials. However, various cancers are associated with extensive muscle wasting, due in part to tumour burden and malnutrition. This muscle wasting may also be a side effect of anticancer drugs. Because loss of muscle mass is associated not only with metabolic abnormalities but also dose limiting toxicity, we review the possible implications for skeletal muscle of long-term inhibition of mTORC1, especially in muscle wasting conditions. PMID:22509811

  8. Satellite cell proliferation in adult skeletal muscle

    NASA Technical Reports Server (NTRS)

    Booth, Frank W. (Inventor); Thomason, Donald B. (Inventor); Morrison, Paul R. (Inventor); Stancel, George M. (Inventor)

    1995-01-01

    Novel methods of retroviral-mediated gene transfer for the in vivo corporation and stable expression of eukaryotic or prokaryotic foreign genes in tissues of living animals is described. More specifically, methods of incorporating foreign genes into mitotically active cells are disclosed. The constitutive and stable expression of E. coli .beta.-galactosidase gene under the promoter control of the Moloney murine leukemia virus long terminal repeat is employed as a particularly preferred embodiment, by way of example, establishes the model upon which the incorporation of a foreign gene into a mitotically-active living eukaryotic tissue is based. Use of the described methods in therapeutic treatments for genetic diseases, such as those muscular degenerative diseases, is also presented. In muscle tissue, the described processes result in genetically-altered satellite cells which proliferate daughter myoblasts which preferentially fuse to form a single undamaged muscle fiber replacing damaged muscle tissue in a treated animal. The retroviral vector, by way of example, includes a dystrophin gene construct for use in treating muscular dystrophy. The present invention also comprises an experimental model utilizable in the study of the physiological regulation of skeletal muscle gene expression in intact animals.

  9. Modelling skeletal muscle fibre orientation arrangement.

    PubMed

    Lu, Y T; Zhu, H X; Richmond, S; Middleton, J

    2011-12-01

    Skeletal muscle tissues have complex geometries. In addition, the complex fibre orientation arrangement makes it quite difficult to create an accurate finite element muscle model. There are many possible ways to specify the complex fibre orientations in a finite element model, for example defining a local element coordinate system. In this paper, an alternative method using ABAQUS, which is combination of the finite element method and the non-uniform rational B-spline solid representation, is proposed to calculate the initial fibre orientations. The initial direction of each muscle fibre is specified as the tangent direction of the NURBS curve which the fibre lies on, and the directions of the deformed fibres are calculated from the initial fibre directions, the deformation gradients and the fibre stretch ratios. Several examples are presented to demonstrate the ability of the proposed method. Results show that the proposed method is able to characterise both the muscle complex fibre orientation arrangement and its complex mechanical response. PMID:20924862

  10. Skeletal muscle stem cells from animals I. Basic cell biology

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle stem cells from food-producing animals have been of interest to agricultural life scientists seeking to develop a better understanding of the molecular regulation of lean tissue (skeletal muscle protein hypertrophy) and intramuscular fat (marbling) development. Enhanced understanding...

  11. Growth factor involvement in tension-induced skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman W.

    1987-01-01

    New muscle tissue culture techniques were developed to grow embryonic skeletal myofibers which are able to differentiate into more adultlike myofibers. Studies on mechanical simulation of cultured muscle cell growth will now be more directly applicable to mechanically-induced growth in adult muscle, and lead to better models for understanding muscle tissue atrophy caused by disuse in the microgravity of space.

  12. Insulin and Amino Acids Are Critical Regulators of Neonatal Muscle Growth

    PubMed Central

    Davis, Teresa A.

    2009-01-01

    Newborn humans and animals grow at very rapid rates because they use the protein that they eat very efficiency to increase body protein mass. This high efficiency of protein deposition in neonates is largely due to their ability to markedly increase the amount of protein synthesized in their muscles when they eat. This enhanced stimulation of muscle protein synthesis after eating is mediated by the rise in the hormone, insulin, and the rise in amino acids, which are the building blocks of protein. Intracellular signaling components that respond to insulin and amino acids have been identified and these have been shown to be involved in the feeding-induced stimulation of protein synthesis in skeletal muscle of the neonate. The enhanced activation of these intracellular signaling components in neonatal muscle contributes to the high rate of muscle protein synthesis and rapid gain in skeletal muscle mass in newborns. PMID:19360138

  13. Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways.

    PubMed

    Long, Yun Chau; Cheng, Zhiyong; Copps, Kyle D; White, Morris F

    2011-02-01

    Coordination of skeletal muscle growth and metabolism with nutrient availability is critical for metabolic homeostasis. To establish the role of insulin-like signaling in this process, we used muscle creatine kinase (MCK)-Cre to disrupt expression of insulin receptor substrates Irs1 and Irs2 in mouse skeletal/cardiac muscle. In 2-week-old mice, skeletal muscle masses and insulin responses were slightly affected by Irs1, but not Irs2, deficiency. In contrast, the combined deficiency of Irs1 and Irs2 (MDKO mice) severely reduced skeletal muscle growth and Akt→mTOR signaling and caused death by 3 weeks of age. Autopsy of MDKO mice revealed dilated cardiomyopathy, reflecting the known requirement of insulin-like signaling for cardiac function (P. G. Laustsen et al., Mol. Cell. Biol. 27:1649-1664, 2007). Impaired growth and function of MDKO skeletal muscle were accompanied by increased Foxo-dependent atrogene expression and amino acid release. MDKO mice were resistant to injected insulin, and their isolated skeletal muscles showed decreased insulin-stimulated glucose uptake. Glucose utilization in MDKO mice and isolated skeletal muscles was shifted from oxidation to lactate production, accompanied by an elevated AMP/ATP ratio that increased AMP-activated protein kinase (AMPK)→acetyl coenzyme A carboxylase (ACC) phosphorylation and fatty acid oxidation. Thus, insulin-like signaling via Irs1/2 is essential to terminate skeletal muscle catabolic/fasting pathways in the presence of adequate nutrition. PMID:21135130

  14. Identification of a novel tropomodulin isoform, skeletal tropomodulin, that caps actin filament pointed ends in fast skeletal muscle.

    PubMed

    Almenar-Queralt, A; Lee, A; Conley, C A; Ribas de Pouplana, L; Fowler, V M

    1999-10-01

    Tropomodulin (E-Tmod) is an actin filament pointed end capping protein that maintains the length of the sarcomeric actin filaments in striated muscle. Here, we describe the identification and characterization of a novel tropomodulin isoform, skeletal tropomodulin (Sk-Tmod) from chickens. Sk-Tmod is 62% identical in amino acid sequence to the previously described chicken E-Tmod and is the product of a different gene. Sk-Tmod isoform sequences are highly conserved across vertebrates and constitute an independent group in the tropomodulin family. In vitro, chicken Sk-Tmod caps actin and tropomyosin-actin filament pointed ends to the same extent as does chicken E-Tmod. However, E- and Sk-Tmods differ in their tissue distribution; Sk-Tmod predominates in fast skeletal muscle fibers, lens, and erythrocytes, while E-Tmod is found in heart and slow skeletal muscle fibers. Additionally, their expression is developmentally regulated during chicken breast muscle differentiation with Sk-Tmod replacing E-Tmod after hatching. Finally, in skeletal muscle fibers that coexpress both Sk- and E-Tmod, they are recruited to different actin filament-containing cytoskeletal structures within the cell: myofibrils and costameres, respectively. All together, these observations support the hypothesis that vertebrates have acquired different tropomodulin isoforms that play distinct roles in vivo. PMID:10497209

  15. Omega-3 Fatty Acids and Skeletal Muscle Health

    PubMed Central

    Jeromson, Stewart; Gallagher, Iain J.; Galloway, Stuart D. R.; Hamilton, D. Lee

    2015-01-01

    Skeletal muscle is a plastic tissue capable of adapting and mal-adapting to physical activity and diet. The response of skeletal muscle to adaptive stimuli, such as exercise, can be modified by the prior nutritional status of the muscle. The influence of nutrition on skeletal muscle has the potential to substantially impact physical function and whole body metabolism. Animal and cell based models show that omega-3 fatty acids, in particular those of marine origin, can influence skeletal muscle metabolism. Furthermore, recent human studies demonstrate that omega-3 fatty acids of marine origin can influence the exercise and nutritional response of skeletal muscle. These studies show that the prior omega-3 status influences not only the metabolic response of muscle to nutrition, but also the functional response to a period of exercise training. Omega-3 fatty acids of marine origin therefore have the potential to alter the trajectory of a number of human diseases including the physical decline associated with aging. We explore the potential molecular mechanisms by which omega-3 fatty acids may act in skeletal muscle, considering the n-3/n-6 ratio, inflammation and lipidomic remodelling as possible mechanisms of action. Finally, we suggest some avenues for further research to clarify how omega-3 fatty acids may be exerting their biological action in skeletal muscle. PMID:26610527

  16. Omega-3 Fatty Acids and Skeletal Muscle Health.

    PubMed

    Jeromson, Stewart; Gallagher, Iain J; Galloway, Stuart D R; Hamilton, D Lee

    2015-11-01

    Skeletal muscle is a plastic tissue capable of adapting and mal-adapting to physical activity and diet. The response of skeletal muscle to adaptive stimuli, such as exercise, can be modified by the prior nutritional status of the muscle. The influence of nutrition on skeletal muscle has the potential to substantially impact physical function and whole body metabolism. Animal and cell based models show that omega-3 fatty acids, in particular those of marine origin, can influence skeletal muscle metabolism. Furthermore, recent human studies demonstrate that omega-3 fatty acids of marine origin can influence the exercise and nutritional response of skeletal muscle. These studies show that the prior omega-3 status influences not only the metabolic response of muscle to nutrition, but also the functional response to a period of exercise training. Omega-3 fatty acids of marine origin therefore have the potential to alter the trajectory of a number of human diseases including the physical decline associated with aging. We explore the potential molecular mechanisms by which omega-3 fatty acids may act in skeletal muscle, considering the n-3/n-6 ratio, inflammation and lipidomic remodelling as possible mechanisms of action. Finally, we suggest some avenues for further research to clarify how omega-3 fatty acids may be exerting their biological action in skeletal muscle. PMID:26610527

  17. Amino acid metabolism in leg muscle after an endotoxin injection in healthy volunteers.

    PubMed

    Vesali, Rokhsareh F; Klaude, Maria; Rooyackers, Olav; Wernerman, Jan

    2005-02-01

    Decreased plasma amino acid concentrations and increased net release of amino acids from skeletal muscle, especially for glutamine, are common features in critically ill patients. A low dose of endotoxin administered to healthy volunteers was used as a human model for the initial phase of sepsis to study the early metabolic response to sepsis. Six healthy male volunteers were studied in the postabsorptive state. Blood samples from the forearm artery and femoral vein were taken during 4 h before and 4 h after an intravenous endotoxin injection (4 ng/kg body wt). In addition, muscle biopsies from the leg muscle were taken. Plasma concentration of the total sum of amino acids decreased by 19% (P = 0.001) and of glutamine by 25% (P = 0.004) the 3rd h after endotoxin administration. At the same time, muscle concentrations of the sum of amino acids and glutamine decreased by 11% (P = 0.05) and 9% (P = 0.09), respectively. In parallel, the efflux from the leg increased by 35% (P = 0.004) for the total sum of amino acids and by 43% (P = 0.05) for glutamine. In conclusion, intravenous endotoxin administration to healthy volunteers, used as a model for the initial phase of sepsis, resulted in a decrease in plasma amino acid concentrations. At the same time, amino acid concentrations in muscle tissue decreased, whereas the efflux of amino acids from leg skeletal muscle increased. PMID:15367399

  18. Strategies for functional bioscaffold-based skeletal muscle reconstruction

    PubMed Central

    Sicari, Brian M.; Dziki, Jenna L.

    2015-01-01

    Tissue engineering and regenerative medicine-based strategies for the reconstruction of functional skeletal muscle tissue have included cellular and acellular approaches. The use of acellular biologic scaffold material as a treatment for volumetric muscle loss (VML) in five patients has recently been reported with a generally favorable outcome. Further studies are necessary for a better understanding of the mechanism(s) behind acellular bioscaffold-mediated skeletal muscle repair, and for combination cell-based/bioscaffold based approaches. The present overview highlights the current thinking on bioscaffold-based remodeling including the associated mechanisms and the future of scaffold-based skeletal muscle reconstruction. PMID:26605302

  19. Skeletal Muscle Metastasis from Renal Cell Carcinoma

    PubMed Central

    Haygood, Tamara Miner; Sayyouh, Mohamed; Wong, Jason; Lin, Jennifer C.; Matamoros, Aurelio; Sandler, Carl; Madewell, John E.

    2015-01-01

    Objectives: This study aimed to raise radiologists’ awareness of skeletal muscle metastases (SMM) in renal cell carcinoma (RCC) cases and to clarify their imaging appearance. Methods: A retrospective analysis was undertaken of 21 patients between 44–75 years old with 72 SMM treated from January 1990 to May 2009 at the MD Anderson Cancer Center in Houston, Texas, USA. Additionally, 37 patients with 44 SMM from a literature review were analysed. Results: Among the 21 patients, the majority of SMM were asymptomatic and detected via computed tomography (CT). Mean metastasis size was 18.3 mm and the most common site was the trunk muscles (83.3%). The interval between discovery of the primary tumour and metastasis detection ranged up to 234 months. Peripheral enhancement (47.1%) was the most common post-contrast CT pattern and non-contrasted CT lesions were often isodense. Magnetic resonance imaging (MRI) characteristics were varied. Five lesions with available T1-weighted pre-contrast images were hyperintense to the surrounding muscle. Other organ metastases were present in 20 patients. Of the 44 SMM reported in the literature, the majority were symptomatic. Average metastasis size was 53.4 mm and only 20.5% of SMM were in trunk muscles. The average interval between tumour discovery and metastasis detection was 101 months. Other organ metastases were recorded in 17 out of 29 patients. Conclusion: SMM should always be considered in patients with RCC, even well after primary treatment. SMM from RCC may be invisible on CT without intravenous contrast; contrast-enhanced studies are therefore recommended. SMM are often hyperintense to the surrounding muscle on T1-weighted MRI scans. PMID:26357552

  20. Growth factor involvement in tension-induced skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H. H.

    1987-01-01

    Muscle tissue culture techniques were developed to grow skeletal myofibers which differentiate into more adult-like myofibers. Mechanical simulation studies of these muscle cells in a newly developed mechanical cell simulator can now be performed to study growth processes in skeletal muscle. Conditions in the mechanical cell simulator were defined where mechanical activity can either prevent muscle wasting or stimulate muscle growth. The role of endogenous and exogenous growth factors in tension-induced muscle growth is being investigated under the defined conditions of tissue culture.

  1. Autophagic cellular responses to physical exercise in skeletal muscle.

    PubMed

    Tam, Bjorn T; Siu, Parco M

    2014-05-01

    Autophagy is an evolutionarily conserved biological process that functions to recycle protein aggregate and malfunctioned organelles. The activation of autophagy can be stimulated by a number of ways including infection, caloric restriction, and physical exercise. In addition to cellular metabolism and cell survival/death machinery, autophagy plays an important role in the maintenance of cellular homeostasis in skeletal muscle especially during physical exercise in which energy demand can be extremely high. By degrading macromolecules and subcellular organelles through the fusion of autophagosomes and lysosomes, useful materials such as amino acids can be released and re-used to sustain normal metabolism in cells. Autophagy is suggested to be involved in glucose and lipid metabolism and is proposed to be a critical physiological process in the regulation of intracellular metabolism. The effects of physical exercise on autophagy have been investigated. Although physical exercise has been demonstrated to be an autophagic inducer, cellular autophagic responses to exercise in skeletal muscle appear to be varied in different exercise protocols and disease models. It is also not known whether the exercise-induced beneficial health consequences involve the favorable modulation of cellular autophagy. Furthermore, the cellular mechanisms of exercise-induced autophagy still remain largely unclear. In this review article, we discuss the general principle of autophagy, cellular signaling of autophagy, autophagic responses to acute and chronic aerobic exercise, and the potential cross-talks among autophagy, mitochondrial biogenesis, and ubiquitination. This article aims to stimulate further studies in exercise and autophagy. PMID:24549475

  2. Skeletal muscle insulin resistance in endocrine disease.

    PubMed

    Peppa, Melpomeni; Koliaki, Chrysi; Nikolopoulos, Panagiotis; Raptis, Sotirios A

    2010-01-01

    We summarize the existing literature data concerning the involvement of skeletal muscle (SM) in whole body glucose homeostasis and the contribution of SM insulin resistance (IR) to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS), adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism. PMID:20300436

  3. Physiology and metabolism of tissue-engineered skeletal muscle.

    PubMed

    Cheng, Cindy S; Davis, Brittany N J; Madden, Lauran; Bursac, Nenad; Truskey, George A

    2014-09-01

    Skeletal muscle is a major target for tissue engineering, given its relative size in the body, fraction of cardiac output that passes through muscle beds, as well as its key role in energy metabolism and diabetes, and the need for therapies for muscle diseases such as muscular dystrophy and sarcopenia. To date, most studies with tissue-engineered skeletal muscle have utilized murine and rat cell sources. On the other hand, successful engineering of functional human muscle would enable different applications including improved methods for preclinical testing of drugs and therapies. Some of the requirements for engineering functional skeletal muscle include expression of adult forms of muscle proteins, comparable contractile forces to those produced by native muscle, and physiological force-length and force-frequency relations. This review discusses the various strategies and challenges associated with these requirements, specific applications with cultured human myoblasts, and future directions. PMID:24912506

  4. Syndecans in skeletal muscle development, regeneration and homeostasis.

    PubMed

    Pisconti, Addolorata; Bernet, Jennifer D; Olwin, Bradley B

    2012-01-01

    Skeletal muscle is a highly dynamic tissue that can change in size in response to physiological demands and undergo successful regeneration even upon extensive injury. A population of resident stem cells, termed satellite cells, accounts for skeletal muscle plasticity, maintenance and regeneration. Mammalian satellite cells, generated from muscle precursor cells during development, are maintained quiescent in the musculature throughout a lifespan, but ready to activate, proliferate and differentiate into myocytes upon demand. Syndecans are transmembrane heparan sulfate proteoglycans expressed in muscle precursors during embryonic development and in satellite cells during postnatal life. In the last decades a number of crucial functions for syndecans in myogenesis and muscle disease have been described. Here we review the current knowledge of the multiple roles played by syndecans in the skeletal muscle of several animal models and explore future perspectives for human muscle health, with a focus on muscle aging and muscular dystrophy. PMID:23738267

  5. Physiology and Metabolism of Tissue Engineered Skeletal Muscle

    PubMed Central

    Cheng, Cindy S.; Davis, Brittany N.J.; Madden, Lauran; Bursac, Nenad; Truskey, George A.

    2014-01-01

    Skeletal muscle is a major target for tissue engineering, given its relative size in the body, fraction of cardiac output that passes through muscle beds, as well as its key role in energy metabolism and diabetes, and the need for therapies for muscle diseases such as muscular dystrophy and sarcopenia. To date, most studies with tissue-engineered skeletal muscle have utilized murine and rat cell sources. On the other hand, successful engineering of functional human muscle would enable different applications including improved methods for preclinical testing of drugs and therapies. Some of the requirements for engineering functional skeletal muscle include expression of adult forms of muscle proteins, comparable contractile forces to those produced by native muscle, and physiological force-length and force-frequency relations. This review discusses the various strategies and challenges associated with these requirements, specific applications with cultured human myoblasts, and future directions. PMID:24912506

  6. Skeletal muscle metabolism in hypokinetic rats

    NASA Technical Reports Server (NTRS)

    Tischler, Marc E.

    1993-01-01

    This grant focused on the mechanisms of metabolic changes associated with unweighting atrophy and reduced growth of hind limb muscles of juvenile rats. Metabolic studies included a number of different areas. Amino acid metabolic studies placed particular emphasis on glutamine and branched-chain amino acid metabolism. These studies were an outgrowth of understanding stress effects and the role of glucocorticoids in these animals. Investigations on protein metabolism were largely concerned with selective loss of myofibrillar proteins and the role of muscle proteolysis. These investigations lead to finding important differences from denervation and atrophy and to define the roles of cytosolic versus lysosomal proteolysis in these atrophy models. A major outgrowth of these studies was demonstrating an ability to prevent atrophy of the unweighted muscle for at least 24 hours. A large amount of work concentrated on carbohydrate metabolism and its regulation by insulin and catecholamines. Measurements focused on glucose transport, glycogen metabolism, and glucose oxidation. The grant was used to develop an important new in situ approach for studying protein metabolism, glucose transport, and hormonal effects which involves intramuscular injection of various agents for up to 24 hours. Another important consequence of this project was the development and flight of Physiological-Anatomical Rodent Experiment-1 (PARE-1), which was launched aboard Space Shuttle Discovery in September 1991. Detailed descriptions of these studies can be found in the 30 peer-reviewed publications, 15 non-reviewed publications, 4 reviews and 33 abstracts (total 82 publications) which were or are scheduled to be published as a result of this project. A listing of these publications grouped by area (i.e. amino acid metabolism, protein metabolism, carbohydrate metabolism, and space flight studies) are included.

  7. Satellite Cell Heterogeneity in Skeletal Muscle Homeostasis.

    PubMed

    Tierney, Matthew T; Sacco, Alessandra

    2016-06-01

    The cellular turnover required for skeletal muscle maintenance and repair is mediated by resident stem cells, also termed satellite cells. Satellite cells normally reside in a quiescent state, intermittently entering the cell cycle to fuse with neighboring myofibers and replenish the stem cell pool. However, the mechanisms by which satellite cells maintain the precise balance between self-renewal and differentiation necessary for long-term homeostasis remain unclear. Recent work has supported a previously unappreciated heterogeneity in the satellite cell compartment that may underlie the observed variability in cell fate and function. In this review, we examine the work supporting this notion as well as the potential governing principles, developmental origins, and principal determinants of satellite cell heterogeneity. PMID:26948993

  8. Inhibition of skeletal muscle development: less differentiation gives more muscle.

    PubMed

    Füchtbauer, Ernst-Martin

    2002-01-01

    The fact that stem cells have to be protected from premature differentiation is true for many organs in the developing embryo and the adult organism. However, there are several arguments that this is particularly important for (skeletal) muscle. There are some evolutionary arguments that muscle is a "default" pathway for mesodermal cells, which has to be actively prevented in order to allow cells to differentiate into other tissues. Myogenic cells originate from very small areas of the embryo where only a minor portion of these cells is supposed to differentiate. Differentiated muscle fibres are unconditionally post-mitotic, leaving undifferentiated stem cells as the only source of regeneration. The mechanical usage of muscle and its superficial location in the vertebrate body makes regeneration a frequently used mechanism. Looking at the different inhibitory mechanisms that have been found within the past 10 or so years, it appears as if evolution has taken this issue very serious. At all possible levels we find regulatory mechanisms that help to fine tune the differentiation of myogenic cells. Secreted molecules specifying different populations of somitic cells, diffusing or membrane-bound signals among fellow myoblasts, modulating molecules within the extracellular matrix and last, but not least, a changing set of activating and repressing cofactors. We have come a long way from the simple model of MyoD just to be turned on at the right time in the right cell. PMID:12132393

  9. Protein-Sparing Effect in Skeletal Muscle of Growth Hormone Treatment in Critically Ill Patients

    PubMed Central

    Gamrin, Lena; Essn, Pia; Hultman, Eric; McNurlan, Margaret A.; Garlick, Peter J.; Wernerman, Jan

    2000-01-01

    Objective To investigate the effect of growth hormone (GH) treatment on skeletal muscle protein catabolism in patients with multiple organ failure in the intensive care unit (ICU). Summary Background Data Skeletal muscle depletion affects the incidence of complications and the length of hospital stay. A protein-sparing effect of GH treatment in skeletal muscle of long-term ICU patients was hypothesized. Methods Twenty critically ill ICU patients were randomized to treatment with GH (0.3 U/kg/day) or as controls. Percutaneous muscle biopsy samples were taken before and after a 5-day treatment period starting on day 3 to 42 of the patients ICU stay. Protein content, protein synthesis, water, nucleic acids, and free amino acids in muscle were analyzed. Results The protein content decreased by 8% 11% in the control patients, with no significant change in the GH group. The fractional synthesis rate of muscle proteins increased in the GH group by 33% 48%, and muscle free glutamine increased by 207% 327% in the GH group. Total intramuscular water increased by 12% 14% in the control group as a result of an increase in extracellular water of 67% 86%; these increases were not seen in the GH group. In contrast, the intracellular water increased by 6% 8% in the GH group. Conclusion Treatment with GH for 5 days in patients with multiple organ failure stimulated muscle protein synthesis, increased muscle free glutamine, and increased intracellular muscle water. PMID:10749620

  10. Microfluidic devices for construction of contractile skeletal muscle microtissues.

    PubMed

    Shimizu, Kazunori; Araki, Hiroyuki; Sakata, Kohei; Tonomura, Wataru; Hashida, Mitsuru; Konishi, Satoshi

    2015-02-01

    Cell-culture microchips mimicking tissue/organ-specific functions are required as alternatives to animal testing for drug discovery and disease models. Although three-dimensional (3D) cell culture microfluidic devices can create more biologically relevant cellular microenvironments and higher throughput analysis platforms of cell behavior than conventional techniques, devices for skeletal muscle cells have not been developed. In the present study, we aimed to develop microfluidic devices for 3D cultures of skeletal muscle cells. Skeletal muscle cells mixed with a collagen type-I solution was introduced into the microchannel for cells (MC-C) and was gelated. Then, the medium was introduced into the microchannel for medium (MC-M). During this process, connecting microchannels (Con-MCs) prevented leakage of the collagen solution mixed with cells from MC-C to MC-M and supplied the nutrients from the medium in MC-M to the cells in MC-C. Skeletal muscle microtissues cultured in the microchannel for a week consisted of myotubes were confirmed by histological analysis and immunofluorescence staining. The skeletal muscle microtissues in the microchannel contracted in response to externally applied electrical stimulation (1 and 50 Hz). These results indicate that the functional skeletal muscle microtissues were constructed in the microchannel. Thus, the microfluidic device for culturing 3D skeletal muscle microtissues presented in this study has a potential to be used for drug discovery and toxicological tests. PMID:25085533

  11. Time course of gene expression during mouse skeletal muscle hypertrophy.

    PubMed

    Chaillou, Thomas; Lee, Jonah D; England, Jonathan H; Esser, Karyn A; McCarthy, John J

    2013-10-01

    The purpose of this study was to perform a comprehensive transcriptome analysis during skeletal muscle hypertrophy to identify signaling pathways that are operative throughout the hypertrophic response. Global gene expression patterns were determined from microarray results on days 1, 3, 5, 7, 10, and 14 during plantaris muscle hypertrophy induced by synergist ablation in adult mice. Principal component analysis and the number of differentially expressed genes (cutoffs ≥2-fold increase or ≥50% decrease compared with control muscle) revealed three gene expression patterns during overload-induced hypertrophy: early (1 day), intermediate (3, 5, and 7 days), and late (10 and 14 days) patterns. Based on the robust changes in total RNA content and in the number of differentially expressed genes, we focused our attention on the intermediate gene expression pattern. Ingenuity Pathway Analysis revealed a downregulation of genes encoding components of the branched-chain amino acid degradation pathway during hypertrophy. Among these genes, five were predicted by Ingenuity Pathway Analysis or previously shown to be regulated by the transcription factor Kruppel-like factor-15, which was also downregulated during hypertrophy. Moreover, the integrin-linked kinase signaling pathway was activated during hypertrophy, and the downregulation of muscle-specific micro-RNA-1 correlated with the upregulation of five predicted targets associated with the integrin-linked kinase pathway. In conclusion, we identified two novel pathways that may be involved in muscle hypertrophy, as well as two upstream regulators (Kruppel-like factor-15 and micro-RNA-1) that provide targets for future studies investigating the importance of these pathways in muscle hypertrophy. PMID:23869057

  12. Time course of gene expression during mouse skeletal muscle hypertrophy

    PubMed Central

    Lee, Jonah D.; England, Jonathan H.; Esser, Karyn A.; McCarthy, John J.

    2013-01-01

    The purpose of this study was to perform a comprehensive transcriptome analysis during skeletal muscle hypertrophy to identify signaling pathways that are operative throughout the hypertrophic response. Global gene expression patterns were determined from microarray results on days 1, 3, 5, 7, 10, and 14 during plantaris muscle hypertrophy induced by synergist ablation in adult mice. Principal component analysis and the number of differentially expressed genes (cutoffs ≥2-fold increase or ≥50% decrease compared with control muscle) revealed three gene expression patterns during overload-induced hypertrophy: early (1 day), intermediate (3, 5, and 7 days), and late (10 and 14 days) patterns. Based on the robust changes in total RNA content and in the number of differentially expressed genes, we focused our attention on the intermediate gene expression pattern. Ingenuity Pathway Analysis revealed a downregulation of genes encoding components of the branched-chain amino acid degradation pathway during hypertrophy. Among these genes, five were predicted by Ingenuity Pathway Analysis or previously shown to be regulated by the transcription factor Kruppel-like factor-15, which was also downregulated during hypertrophy. Moreover, the integrin-linked kinase signaling pathway was activated during hypertrophy, and the downregulation of muscle-specific micro-RNA-1 correlated with the upregulation of five predicted targets associated with the integrin-linked kinase pathway. In conclusion, we identified two novel pathways that may be involved in muscle hypertrophy, as well as two upstream regulators (Kruppel-like factor-15 and micro-RNA-1) that provide targets for future studies investigating the importance of these pathways in muscle hypertrophy. PMID:23869057

  13. Exercise and the Regulation of Skeletal Muscle Hypertrophy.

    PubMed

    McGlory, Chris; Phillips, Stuart M

    2015-01-01

    Skeletal muscle is a critical organ serving as the primary site for postprandial glucose disposal and the generation of contractile force. The size of human skeletal muscle mass is dependent upon the temporal relationship between changes in muscle protein synthesis (MPS) and muscle protein breakdown. The aim of this chapter is to review our current understanding of how resistance exercise influences protein turnover with a specific emphasis on the molecular factors regulating MPS. We also will discuss recent data relating to the prescription of resistance exercise to maximize skeletal muscle hypertrophy. Finally, we evaluate the impact of age and periods of disuse on the loss of muscle mass and the controversy surround the etiology of muscle disuse atrophy. PMID:26477914

  14. Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy.

    PubMed

    Sartorelli, Vittorio; Fulco, Marcella

    2004-08-01

    The maintenance of adult skeletal muscle mass is ensured by physical exercise. Accordingly, physiological and pathological situations characterized by either impaired motor neuron activity, reduced gravity (microgravity during space flights), or reduced physical activity result in loss of muscle mass. Furthermore, a plethora of clinical conditions, including cancer, sepsis, diabetes, and AIDS, are associated with varying degrees of muscle atrophy. The cellular and molecular pathways responsible for maintaining the skeletal muscle mass are not well defined. Nonetheless, studies aimed at the understanding of the mechanisms underlying either muscular atrophy or hypertrophy have begun to identify the physiological determinants and clarify the molecular pathways responsible for the maintenance of muscle mass. PMID:15292521

  15. Skeletal Muscle Stem Cells from Animals I. Basic Cell Biology

    PubMed Central

    Dodson, Michael V.; Hausman, Gary J.; Guan, LeLuo; Du, Min; Rasmussen, Theodore P.; Poulos, Sylvia P.; Mir, Priya; Bergen, Werner G.; Fernyhough, Melinda E.; McFarland, Douglas C.; Rhoads, Robert P.; Soret, Beatrice; Reecy, James M.; Velleman, Sandra G.; Jiang, Zhihua

    2010-01-01

    Skeletal muscle stem cells from food-producing animals are of interest to agricultural life scientists seeking to develop a better understanding of the molecular regulation of lean tissue (skeletal muscle protein hypertrophy) and intramuscular fat (marbling) development. Enhanced understanding of muscle stem cell biology and function is essential for developing technologies and strategies to augment the metabolic efficiency and muscle hypertrophy of growing animals potentially leading to greater efficiency and reduced environmental impacts of animal production, while concomitantly improving product uniformity and consumer acceptance and enjoyment of muscle foods. PMID:20827399

  16. Arginylation of myosin heavy chain regulates skeletal muscle strength

    PubMed Central

    Cornachione, Anabelle S.; Leite, Felipe S.; Wang, Junling; Leu, Nicolae A.; Kalganov, Albert; Volgin, Denys; Han, Xuemei; Xu, Tao; Cheng, Yu-Shu; Yates, John R. R.; Rassier, Dilson E.; Kashina, Anna

    2014-01-01

    Protein arginylation is a post-translational modification with an emerging global role in the regulation of actin cytoskeleton. To test the role of arginylation in the skeletal muscle, we generated a mouse model with Ate1 knockout driven by skeletal muscle-specific creatine kinase (Ckmm) promoter. Such Ckmm-Ate1 mice were viable and outwardly normal, however their skeletal muscle strength was significantly reduced compared to the control. Mass spectrometry of the isolated skeletal myofibrils showed a limited set of proteins arginylated on specific sites, including myosin heavy chain. Atomic force microscopy measurements of the contractile strength in individual myofibrils and isolated myosin filaments from these mice showed a significant reduction of contractile forces, which, in the case of the myosin filaments could be fully rescued by re-arginylation with purified Ate1. Our results demonstrate that arginylation regulates force production in the muscle and exerts a direct effect on muscle strength through arginylation of myosin. PMID:25017061

  17. Circulating protein synthesis rates reveal skeletal muscle proteome dynamics

    PubMed Central

    Shankaran, Mahalakshmi; King, Chelsea L.; Angel, Thomas E.; Holmes, William E.; Li, Kelvin W.; Colangelo, Marc; Price, John C.; Turner, Scott M.; Bell, Christopher; Hamilton, Karyn L.; Miller, Benjamin F.; Hellerstein, Marc K.

    2015-01-01

    Here, we have described and validated a strategy for monitoring skeletal muscle protein synthesis rates in rodents and humans over days or weeks from blood samples. We based this approach on label incorporation into proteins that are synthesized specifically in skeletal muscle and escape into the circulation. Heavy water labeling combined with sensitive tandem mass spectrometric analysis allowed integrated synthesis rates of proteins in muscle tissue across the proteome to be measured over several weeks. Fractional synthesis rate (FSR) of plasma creatine kinase M-type (CK-M) and carbonic anhydrase 3 (CA-3) in the blood, more than 90% of which is derived from skeletal muscle, correlated closely with FSR of CK-M, CA-3, and other proteins of various ontologies in skeletal muscle tissue in both rodents and humans. Protein synthesis rates across the muscle proteome generally changed in a coordinate manner in response to a sprint interval exercise training regimen in humans and to denervation or clenbuterol treatment in rodents. FSR of plasma CK-M and CA-3 revealed changes and interindividual differences in muscle tissue proteome dynamics. In human subjects, sprint interval training primarily stimulated synthesis of structural and glycolytic proteins. Together, our results indicate that this approach provides a virtual biopsy, sensitively revealing individualized changes in proteome-wide synthesis rates in skeletal muscle without a muscle biopsy. Accordingly, this approach has potential applications for the diagnosis, management, and treatment of muscle disorders. PMID:26657858

  18. Circulating protein synthesis rates reveal skeletal muscle proteome dynamics.

    PubMed

    Shankaran, Mahalakshmi; King, Chelsea L; Angel, Thomas E; Holmes, William E; Li, Kelvin W; Colangelo, Marc; Price, John C; Turner, Scott M; Bell, Christopher; Hamilton, Karyn L; Miller, Benjamin F; Hellerstein, Marc K

    2016-01-01

    Here, we have described and validated a strategy for monitoring skeletal muscle protein synthesis rates in rodents and humans over days or weeks from blood samples. We based this approach on label incorporation into proteins that are synthesized specifically in skeletal muscle and escape into the circulation. Heavy water labeling combined with sensitive tandem mass spectrometric analysis allowed integrated synthesis rates of proteins in muscle tissue across the proteome to be measured over several weeks. Fractional synthesis rate (FSR) of plasma creatine kinase M-type (CK-M) and carbonic anhydrase 3 (CA-3) in the blood, more than 90% of which is derived from skeletal muscle, correlated closely with FSR of CK-M, CA-3, and other proteins of various ontologies in skeletal muscle tissue in both rodents and humans. Protein synthesis rates across the muscle proteome generally changed in a coordinate manner in response to a sprint interval exercise training regimen in humans and to denervation or clenbuterol treatment in rodents. FSR of plasma CK-M and CA-3 revealed changes and interindividual differences in muscle tissue proteome dynamics. In human subjects, sprint interval training primarily stimulated synthesis of structural and glycolytic proteins. Together, our results indicate that this approach provides a virtual biopsy, sensitively revealing individualized changes in proteome-wide synthesis rates in skeletal muscle without a muscle biopsy. Accordingly, this approach has potential applications for the diagnosis, management, and treatment of muscle disorders. PMID:26657858

  19. Applications of skeletal muscle progenitor cells for neuromuscular diseases.

    PubMed

    Hosoyama, Tohru; Van Dyke, Jonathan; Suzuki, Masatoshi

    2012-01-01

    Neuromuscular diseases affect skeletal muscle and/or nervous control resulting in direct disruption of skeletal muscle and muscle pathology, or nervous system disruption which indirectly disrupts muscle function. Stem cell-based therapy is well-recognized as a promising approach for several types of diseases including those affecting the neuromuscular system. To design a successful therapeutic strategy, it is important to choose the most appropriate stem cell type. Skeletal muscle progenitor cells (SMPCs), also called myogenic progenitors, can contribute to muscle regeneration, differentiate into skeletal muscles, and are valuable cells for therapeutic application. Different types of stem/progenitor cells, including satellite cells, side population cells, muscle derived stem cells, mesenchymal stem cells, myogenic pericytes, and mesoangioblasts, have been identified as possible cell resources of SMPCs. Furthermore, recent advances in stem cell biology allow us to use embryonic stem cells and induced pluripotent stem cells for SMPC derivation. When skeletal muscle is chosen as a target of cell transplantation, the possible criteria for choosing the "best" progenitor/stem cell include preparation strategies, efficiency of intramuscular integration, method of cellular delivery, and functional improvement of the muscle after cell transplantation. Here, we discuss recent findings on various types of SMPCs and their promise for future clinical translation in neuromuscular diseases. PMID:23671812

  20. The activation of nutrient signaling components leading to mRNA translation in skeletal muscle of neonatal pigs is developmentally regulated

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin and amino acids (AA) can act independently to stimulate skeletal muscle protein synthesis in neonatal pigs. To elucidate the role of development in the AA-induced activation of nutrient signaling components leading to translation in skeletal muscle, a balanced AA mixture was infused into fa...

  1. The activation of insulin signaling components leading to mRNA translation in skeletal muscle of neonatal pigs is developmentally regulated

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin and amino acids can act independently to stimulate skeletal muscle protein synthesis in neonatal pigs. The purpose of this study was to elucidate the developmental regulation of the activation of signaling components leading to protein synthesis in skeletal muscle that is induced by insulin...

  2. Leucine and alpha-Ketoisocaproic acid, but not norleucine, stimulate skeletal muscle protein synthesis in neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The branched-chain amino acid, leucine, acts as a nutrient signal to stimulate protein synthesis in skeletal muscle of young pigs. However, the chemical structure responsible for this effect has not been identified. We have shown that the other branched-chain amino acids, isoleucine and valine, are ...

  3. Glucose stimulates protein synthesis in skeletal muscle of neonatal pigs through an AMPK- and mTOR-independent process

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle protein synthesis is elevated in neonates in part due to an enhanced response to the rise in insulin and amino acids after eating. In vitro studies suggest that glucose plays a role in protein synthesis regulation. To determine whether glucose, independently of insulin and amino acid...

  4. Rapamycin blocks leucine-induced protein synthesis by suppressing mTORC1 activation in skeletal muscle of neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle in the neonate grows at a rapid rate due in part to an enhanced sensitivity to the postprandial rise in amino acids, particularly leucine (Leu). To elucidate the molecular mechanism by which Leu stimulates protein synthesis in neonatal muscle, overnight fasted 7-day-old piglets were...

  5. Leucine stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing mTORC1 activation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle in the neonate grows at a rapid rate due in part to an enhanced sensitivity to the postprandial rise in amino acids, particularly leucine. To elucidate the molecular mechanism by which leucine stimulates protein synthesis in neonatal muscle, overnight-fasted 7-day-old piglets were tr...

  6. Postnatal ontogeny of skeletal muscle protein synthesis in pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The neonatal period is characterized by rapid growth and elevated rates of synthesis and accretion of skeletal muscle proteins. The fractional rate of muscle protein synthesis is very high at birth and declines rapidly with development. The elevated capacity for muscle protein synthesis in the neo...

  7. Molecular events in skeletal muscle during disuse atrophy

    NASA Technical Reports Server (NTRS)

    Kandarian, Susan C.; Stevenson, Eric J.

    2002-01-01

    This review summarizes the current knowledge of the molecular processes underlying skeletal muscle atrophy due to disuse. Because the processes involved with muscle wasting due to illness are similar to disuse, this literature is used for comparison. Areas that are ripe for further study and that will advance our understanding of muscle atrophy are suggested.

  8. Postnatal ontogeny of skeletal muscle protein synthesis in pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The neonatal period is characterized by rapid growth and elevated rates of synthesis and accretion of skeletal muscle proteins. The fractional rate of muscle protein synthesis is very high at birth and declines rapidly with age. The elevated capacity for muscle protein synthesis in the neonatal pig ...

  9. Coordination of metabolic plasticity in skeletal muscle.

    PubMed

    Hood, David A; Irrcher, Isabella; Ljubicic, Vladimir; Joseph, Anna-Maria

    2006-06-01

    Skeletal muscle is a highly malleable tissue, capable of pronounced metabolic and morphological adaptations in response to contractile activity (i.e. exercise). Each bout of contractile activity results in a coordinated alteration in the expression of a variety of nuclear DNA and mitochondrial DNA (mtDNA) gene products, leading to phenotypic adaptations. This results in an increase in muscle mitochondrial volume and changes in organelle composition, referred to as mitochondrial biogenesis. The functional consequence of this biogenesis is an improved resistance to fatigue. Signals initiated by the exercise bout involve changes in intracellular Ca2+ as well as alterations in energy status (i.e. ATP/ADP ratio) and the consequent activation of downstream kinases such as AMP kinase and Ca2+-calmodulin-activated kinases. These kinases activate transcription factors that bind DNA to affect the transcription of genes, the most evident manifestation of which occurs during the post-exercise recovery period when energy metabolism is directed toward anabolism, rather than contractile activity. An important protein that is affected by exercise is the transcriptional coactivator PGC-1alpha, which cooperates with multiple transcription factors to induce the expression of nuclear genes encoding mitochondrial proteins. Once translated in the cytosol, these mitochondrially destined proteins are imported into the mitochondrial outer membrane, inner membrane or matrix space via specific import machinery transport components. Contractile activity affects the expression of the import machinery, as well as the kinetics of import, thus facilitating the entry of newly synthesized proteins into the expanding organelle. An important set of proteins that are imported are the mtDNA transcription factors, which influence the expression and replication of mtDNA. While mtDNA contributes only 13 proteins to the synthesis of the organelle, these proteins are vital for the proper assembly of multi-subunit complexes of the respiratory chain, when combined with nuclear-encoded protein subunits. The expansion of skeletal muscle mitochondria during organelle biogenesis involves the assembly of an interconnected network system (i.e. a mitochondrial reticulum). This expansion of membrane size is influenced by the balance between mitochondrial fusion and fission. Thus, mitochondrial biogenesis is an adaptive process that requires the coordination of multiple cellular events, including the transcription of two genomes, the synthesis of lipids and proteins and the stoichiometric assembly of multisubunit protein complexes into a functional respiratory chain. Impairments at any step can lead to defective electron transport, a subsequent failure of ATP production and an inability to maintain energy homeostasis. PMID:16731803

  10. AMP-activated protein kinase regulates nicotinamide phosphoribosyl transferase expression in skeletal muscle

    PubMed Central

    Brandauer, Josef; Vienberg, Sara G; Andersen, Marianne A; Ringholm, Stine; Risis, Steve; Larsen, Per S; Kristensen, Jonas M; Frøsig, Christian; Leick, Lotte; Fentz, Joachim; Jørgensen, Sebastian; Kiens, Bente; Wojtaszewski, Jørgen F P; Richter, Erik A; Zierath, Juleen R; Goodyear, Laurie J; Pilegaard, Henriette; Treebak, Jonas T

    2013-01-01

    Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown. To this end, we assessed whether exercise training- or 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (AICAR)-mediated increases in skeletal muscle Nampt abundance are AMPK dependent. One-legged knee-extensor exercise training in humans increased Nampt protein by 16% (P < 0.05) in the trained, but not the untrained leg. Moreover, increases in Nampt mRNA following acute exercise or AICAR treatment (P < 0.05 for both) were maintained in mouse skeletal muscle lacking a functional AMPK α2 subunit. Nampt protein was reduced in skeletal muscle of sedentary AMPK α2 kinase dead (KD), but 6.5 weeks of endurance exercise training increased skeletal muscle Nampt protein to a similar extent in both wild-type (WT) (24%) and AMPK α2 KD (18%) mice. In contrast, 4 weeks of daily AICAR treatment increased Nampt protein in skeletal muscle in WT mice (27%), but this effect did not occur in AMPK α2 KD mice. In conclusion, functional α2-containing AMPK heterotrimers are required for elevation of skeletal muscle Nampt protein, but not mRNA induction. These findings suggest AMPK plays a post-translational role in the regulation of skeletal muscle Nampt protein abundance, and further indicate that the regulation of cellular energy charge and nutrient sensing is mechanistically related. PMID:23918774

  11. Training-induced apoptosis in skeletal muscle.

    PubMed

    Boffi, F M; Cittar, J; Balskus, G; Muriel, M; Desmaras, E

    2002-09-01

    Apoptosis or programmed cell death is a genetically controlled response of cells to commit suicide and is associated with DNA fragmentation or laddering. The common inducers of apoptosis include Ca2+i and oxygen free radicals/oxidative stress, which are also implicated in the pathogenesis of exercise-induced myopathies. To examine training-induced apoptosis, Thoroughbred horses were subjected to 3 months training programme on a treadmill. At the end of the training programme venous blood samples were taken for a creatine kinase (CK) assay. In addition, muscle biopsy samples were obtained for a membrane lipid peroxidation measurement by malondialdehyde (MDA) assay and for apoptosis detection. Apoptosis was studied by visualising the apoptotic myocytes on the paraffin sections by the modified TUNEL method. DNA laddering was evaluated by subjecting the DNA obtained from the biopsies to 1.5% agarose gel electrophoresis. There was a significant increase (P<0.05) of protein-bound MDA, and a nonsignificant trend (P = 0.14) for the control group to have higher levels of CK compared to the trained group. Under light microscopy, percentage of the TUNEL positive cells was higher (P<0.001) in the training group. This result was corroborated with the findings of DNA fragmentation by gel electrophoresis, which showed higher ladders of DNA band at the same group. In conclusion, these results clearly demonstrate that there is training-induced apoptosis in skeletal muscle. It is probable that apoptosis allows the work/recovery/rebound/supercompensation cycle, when unaccustomed muscle cells activate programmed cell death and are replaced by new and stronger cells, which is the mechanism for training-induced increases in fitness. PMID:12405700

  12. Skeletal Muscle Phospholipid Metabolism Regulates Insulin Sensitivity and Contractile Function.

    PubMed

    Funai, Katsuhiko; Lodhi, Irfan J; Spears, Larry D; Yin, Li; Song, Haowei; Klein, Samuel; Semenkovich, Clay F

    2016-02-01

    Skeletal muscle insulin resistance is an early defect in the development of type 2 diabetes. Lipid overload induces insulin resistance in muscle and alters the composition of the sarcoplasmic reticulum (SR). To test the hypothesis that skeletal muscle phospholipid metabolism regulates systemic glucose metabolism, we perturbed choline/ethanolamine phosphotransferase 1 (CEPT1), the terminal enzyme in the Kennedy pathway of phospholipid synthesis. In C2C12 cells, CEPT1 knockdown altered SR phospholipid composition and calcium flux. In mice, diet-induced obesity, which decreases insulin sensitivity, increased muscle CEPT1 expression. In high-fat diet-fed mice with skeletal muscle-specific knockout of CEPT1, systemic and muscle-based approaches demonstrated increased muscle insulin sensitivity. In CEPT1-deficient muscles, an altered SR phospholipid milieu decreased sarco/endoplasmic reticulum Ca(2+) ATPase-dependent calcium uptake, activating calcium-signaling pathways known to improve insulin sensitivity. Altered muscle SR calcium handling also rendered these mice exercise intolerant. In obese humans, surgery-induced weight loss increased insulin sensitivity and decreased skeletal muscle CEPT1 protein. In obese humans spanning a spectrum of metabolic health, muscle CEPT1 mRNA was inversely correlated with insulin sensitivity. These results suggest that high-fat feeding and obesity induce CEPT1, which remodels the SR to preserve contractile function at the expense of insulin sensitivity. PMID:26512026

  13. Whole-mount immunostaining of Drosophila skeletal muscle.

    PubMed

    Hunt, Liam C; Demontis, Fabio

    2013-12-01

    Skeletal muscle undergoes marked functional decay during aging in humans, but the cell biological mechanisms responsible for this process are only partly known. Age-related muscle dysfunction is also a feature of aging in the fruit fly Drosophila melanogaster. Here we describe a detailed step-by-step protocol, which takes place over 3 d, for whole-mount immunostaining of Drosophila flight muscle. The skeletal muscle is fixed and permeabilized without any tissue freezing and dehydration so that antigens are accessible for staining with appropriate antibodies and the overall tissue ultrastructure is well preserved. This technique can be used to identify age-related cellular changes driving skeletal muscle aging and for characterizing models of human muscle disease in Drosophila. PMID:24232251

  14. Dissemination of Walker 256 carcinoma cells to rat skeletal muscle

    SciTech Connect

    Ueoka, H.; Hayashi, K.; Namba, T.; Grob, D.

    1986-03-05

    After injection of 10/sup 6/ Walker 256 carcinoma cells labelled with /sup 125/I-5-iodo-2'-deoxyuridine into the tail vein, peak concentration in skeletal muscle was 46 cells/g at 60 minutes, which was lower than 169202, 1665, 555, 198 and 133 cells/g, respectively, at 30 or 60 minutes in lung, liver, spleen, kidney and heart. Because skeletal muscle constitutes 37.4% of body weight, the total number of tumor cells was 2323 cells, which was much greater than in spleen, kidney and heart with 238, 271, and 85 cells, respectively, and only less than in lung and liver, at 222857 and 11700 cells, respectively. The total number in skeletal muscle became greater than in liver at 4 hours and than in lung at 24 hours. Ten minutes after injection of 7.5 x 10/sup 6/ Walker 256 carcinoma cells into the abdominal aorta of rats, a mean of 31 colony-forming cells were recovered from the gastrocnemius, while 106 cells were recovered from the lung after injection into the tail vein. These results indicate that a large number of viable tumor cells can be arrested in skeletal muscle through circulation. The rare remote metastasis of malignancies into skeletal muscle despite constantly circulating tumor cells does not appear to be due to poor dissemination of tumor cells into muscle but due to unhospitable environment of skeletal muscle.

  15. Long-term leucine induced stimulation of muscle protein synthesis is amino acid dependent

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Infusing leucine for 1 h increases skeletal muscle protein synthesis in the neonate, but this is not sustained for 2 h unless the corresponding fall in amino acids is prevented. This study aimed to determine whether a continuous leucine infusion can stimulate protein synthesis for a prolonged period...

  16. Angiopoietin-1 enhances skeletal muscle regeneration in mice.

    PubMed

    Mofarrahi, Mahroo; McClung, Joseph M; Kontos, Christopher D; Davis, Elaine C; Tappuni, Bassman; Moroz, Nicolay; Pickett, Amy E; Huck, Laurent; Harel, Sharon; Danialou, Gawiyou; Hussain, Sabah N A

    2015-04-01

    Activation of muscle progenitor cell myogenesis and endothelial cell angiogenesis is critical for the recovery of skeletal muscle from injury. Angiopoietin-1 (Ang-1), a ligand of Tie-2 receptors, enhances angiogenesis and skeletal muscle satellite cell survival; however, its role in skeletal muscle regeneration after injury is unknown. We assessed the effects of Ang-1 on fiber regeneration, myogenesis, and angiogenesis in injured skeletal muscle (tibialis anterior, TA) in mice. We also assessed endogenous Ang-1 levels and localization in intact and injured TA muscles. TA fiber injury was triggered by cardiotoxin injection. Endogenous Ang-1 mRNA levels immediately decreased in response to cardiotoxin then increased during the 2 wk. Ang-1 protein was expressed in satellite cells, both in noninjured and recovering TA muscles. Positive Ang-1 staining was present in blood vessels but not in nerve fibers. Four days after the initiation of injury, injection of adenoviral Ang-1 into injured muscles resulted in significant increases in in situ TA muscle contractility, muscle fiber regeneration, and capillary density. In cultured human skeletal myoblasts, recombinant Ang-1 protein increased survival, proliferation, migration, and differentiation into myotubes. The latter effect was associated with significant upregulation of the expression of the myogenic regulatory factors MyoD and Myogenin and certain genes involved in cell cycle regulation. We conclude that Ang-1 strongly enhances skeletal muscle regeneration in response to fiber injury and that this effect is mediated through induction of the myogenesis program in muscle progenitor cells and the angiogenesis program in endothelial cells. PMID:25608750

  17. Secretomics for skeletal muscle cells: a discovery of novel regulators?

    PubMed

    Yoon, Jong Hyuk; Kim, Jaeyoon; Song, Parkyong; Lee, Taehoon G; Suh, Pann-Ghill; Ryu, Sung Ho

    2012-05-01

    Metabolic tissues, including skeletal muscle, adipose tissue and the digestive system, dynamically secrete various factors depending on the metabolic state, communicate with each other and orchestrate functions to maintain body homeostasis. Skeletal muscle secretes cytokines such as interleukin-6 (IL-6), IL-15, fibroblast growth factor-21 (FGF21) and IL-8. These compounds, myokines, play important roles in biological homeostasis such as energy metabolism, angiogenesis and myogenesis. New technological advances have allowed secretomics - analysis of the secretome - to be performed. The application of highly sensitive mass spectrometry makes qualitative and quantitative analysis of the secretome of skeletal muscle possible. Secretory proteins derived from skeletal muscle cells under various conditions were analyzed, and many important factors were suggested. In-depth studies of the secretome from metabolic cells in various conditions are strongly recommended. This study will provide information on methods of novel communication between metabolic tissues. PMID:22781747

  18. Mitochondrial and Skeletal Muscle Health with Advancing Age

    PubMed Central

    Konopka, Adam R.; Nair, K. Sreekumaran

    2013-01-01

    With increasing age there is a temporal relationship between the decline of mitochondrial and skeletal muscle volume, quality and function (i.e., health). Reduced mitochondrial mRNA expression, protein abundance, and protein synthesis rates appear to promote the decline of mitochondrial protein quality and function. Decreased mitochondrial function is suspected to impede energy demanding processes such as skeletal muscle protein turnover, which is critical for maintaining protein quality and thus skeletal muscle health with advancing age. The focus of this review was to discuss promising human physiological systems underpinning the decline of mitochondrial and skeletal muscle health with advancing age while highlighting therapeutic strategies such as aerobic exercise and caloric restriction for combating age-related functional impairments. PMID:23684888

  19. Leucine-enriched essential amino acids attenuate muscle soreness and improve muscle protein synthesis after eccentric contractions in rats.

    PubMed

    Kato, Hiroyuki; Suzuki, Hiromi; Mimura, Masako; Inoue, Yoshiko; Sugita, Mayu; Suzuki, Katsuya; Kobayashi, Hisamine

    2015-06-01

    Eccentric exercise results in prolonged muscle weakness and muscle soreness, which are typical symptoms of muscle damage. Recovery from muscle damage is related to mammalian target of rapamycin (mTOR) activity. Leucine-enriched essential amino acids (LEAAs) stimulate muscle protein synthesis via activation of the mTOR pathway. Therefore, we investigated the effect of LEAAs on muscle protein synthesis and muscle soreness after eccentric contractions (EC). Male Sprague-Dawley rats (9-11 weeks old) were administered an LEAA solution (AminoL40; containing 40 % leucine and 60 % other essential amino acids) at 1 g/kg body weight or distilled water (control) 30 min before and 10 min after EC. Tibialis anterior (TA) muscle was exposed to 500 EC by electrical stimulation under anesthesia. The fractional synthesis rate (FSR; %/h) in the TA muscle was measured by incorporating L-[ring-(2)H5] phenylalanine into skeletal muscle protein. Muscle soreness was evaluated by the paw withdrawal threshold using the Randal-Selitto test with some modifications from 1 to 3 days after EC. The FSR in the EC-control group (0.147 ± 0.016 %/h) was significantly lower than in the sedentary group (0.188 ± 0.016 %/h, p < 0.05). AminoL40 administration significantly mitigated the EC-induced impairment of the FSR (0.172 ± 0.018 %/h). EC decreased the paw withdrawal threshold at 1 and 2 days after EC, which indicated that EC induced muscle soreness. Furthermore, AminoL40 administration alleviated the decreased paw withdrawal threshold. These findings suggest that LEAA supplementation improves the rate of muscle protein synthesis and ameliorates muscle soreness after eccentric exercise. PMID:25772815

  20. Structure and Function of the Skeletal Muscle Extracellular Matrix

    PubMed Central

    Gillies, Allison R.; Lieber, Richard L.

    2011-01-01

    The skeletal muscle extracellular matrix (ECM) plays an important role in muscle fiber force transmission, maintenance, and repair. In both injured and diseased states, ECM adapts dramatically, a property thathas clinical manifestations and alters muscle function. Here, we review the structure, composition, and mechanical properties of skeletal muscle ECM, describe the cells that contribute to the maintenance of the ECM and, finally, overview changes that occur with pathology. New scanning electron micrographs of ECM structure are also presented with hypotheses about ECM structure-function relationships. Detailed structure-function relationships of the ECM have yet to be defined and, as a result, we propose areas for future studies. PMID:21949456

  1. The influence of skeletal muscle on systemic aging and lifespan.

    PubMed

    Demontis, Fabio; Piccirillo, Rosanna; Goldberg, Alfred L; Perrimon, Norbert

    2013-12-01

    Epidemiological studies in humans suggest that skeletal muscle aging is a risk factor for the development of several age-related diseases such as metabolic syndrome, cancer, Alzheimer's and Parkinson's disease. Here, we review recent studies in mammals and Drosophila highlighting how nutrient- and stress-sensing in skeletal muscle can influence lifespan and overall aging of the organism. In addition to exercise and indirect effects of muscle metabolism, growing evidence suggests that muscle-derived growth factors and cytokines, known as myokines, modulate systemic physiology. Myokines may influence the progression of age-related diseases and contribute to the intertissue communication that underlies systemic aging. PMID:23802635

  2. The effects of obesity on skeletal muscle regeneration

    PubMed Central

    Akhmedov, Dmitry; Berdeaux, Rebecca

    2013-01-01

    Obesity and metabolic disorders such as type 2 diabetes mellitus are accompanied by increased lipid deposition in adipose and non-adipose tissues including liver, pancreas, heart and skeletal muscle. Recent publications report impaired regenerative capacity of skeletal muscle following injury in obese mice. Although muscle regeneration has not been thoroughly studied in obese and type 2 diabetic humans and mechanisms leading to decreased muscle regeneration in obesity remain elusive, the initial findings point to the possibility that muscle satellite cell function is compromised under conditions of lipid overload. Elevated toxic lipid metabolites and increased pro-inflammatory cytokines as well as insulin and leptin resistance that occur in obese animals may contribute to decreased regenerative capacity of skeletal muscle. In addition, obesity-associated alterations in the metabolic state of skeletal muscle fibers and satellite cells may directly impair the potential for satellite cell-mediated repair. Here we discuss recent studies that expand our understanding of how obesity negatively impacts skeletal muscle maintenance and regeneration. PMID:24381559

  3. Dysregulation of SIRT-1 in aging mice increases skeletal muscle fatigue by a PARP-1-dependent mechanism

    PubMed Central

    Mohamed, Junaith S.; Wilson, Joseph C.; Myers, Matthew J.; Sisson, Kayla J.; Alway, Stephen E.

    2014-01-01

    Accumulation of reactive oxygen species (ROS) in skeletal muscles and the resulting decline in muscle performance are hallmarks of sarcopenia. However, the precise mechanism by which ROS results in a decline in muscle performance is unclear. We demonstrate that isometric-exercise concomitantly increases the activities of Silent information regulator 1 (SIRT-1) and Poly [ADP-ribose] polymerase (PARP-1), and that activated SIRT-1 physically binds with and inhibits PARP-1 activity by a deacetylation dependent mechanism in skeletal muscle from young mice. In contrast, skeletal muscle from aged mice displays higher PARP-1 activity and lower SIRT-1 activity due to decreased intracellular NAD+ content, and as a result reduced muscle performance in response to exercise. Interestingly, injection of PJ34, a PARP-1 inhibitor, in aged mice increased SIRT-1 activity by preserving intracellular NAD+ content, which resulted in higher skeletal muscle mitochondrial biogenesis and performance. We found that the higher activity of PARP-1 in H2O2-treated myotubes or in exercised-skeletal muscles from aged mice is due to an elevated level of PARP-1 acetylation by the histone acetyltransferase General control of amino acid synthesis protein 5-like 2 (GCN-5). These results suggest that activation of SIRT-1 and/or inhibition of PARP-1 may ameliorate skeletal muscle performance in pathophysiological conditions such as sarcopenia and disuse-induced atrophy in aging. PMID:25361036

  4. Dysregulation of SIRT-1 in aging mice increases skeletal muscle fatigue by a PARP-1-dependent mechanism.

    PubMed

    Mohamed, Junaith S; Wilson, Joseph C; Myers, Matthew J; Sisson, Kayla J; Alway, Stephen E

    2014-10-01

    Accumulation of reactive oxygen species (ROS) in skeletal muscles and the resulting decline in muscle performance are hallmarks of sarcopenia. However, the precise mechanism by which ROS results in a decline in muscle performance is unclear. We demonstrate that isometric-exercise concomitantly increases the activities of Silent information regulator 1 (SIRT-1) and Poly [ADP-ribose] polymerase (PARP-1), and that activated SIRT-1 physically binds with and inhibits PARP-1 activity by a deacetylation dependent mechanism in skeletal muscle from young mice. In contrast, skeletal muscle from aged mice displays higher PARP-1 activity and lower SIRT-1 activity due to decreased intracellular NAD+ content, and as a result reduced muscle performance in response to exercise. Interestingly, injection of PJ34, a PARP-1 inhibitor, in aged mice increased SIRT-1 activity by preserving intracellular NAD+ content, which resulted in higher skeletal muscle mitochondrial biogenesis and performance. We found that the higher activity of PARP-1 in H2O2-treated myotubes or in exercised-skeletal muscles from aged mice is due to an elevated level of PARP-1 acetylation by the histone acetyltransferase General control of amino acid synthesis protein 5-like 2 (GCN-5). These results suggest that activation of SIRT-1 and/or inhibition of PARP-1 may ameliorate skeletal muscle performance in pathophysiological conditions such as sarcopenia and disuse-induced atrophy in aging. PMID:25361036

  5. Maintaining skeletal muscle mass: lessons learned from hibernation.

    PubMed

    Ivakine, Evgueni A; Cohn, Ronald D

    2014-04-01

    Muscle disuse and starvation are often associated with a catabolic response leading to a dramatic loss of skeletal muscle mass. Hibernating animals represent a unique situation where muscle mass is maintained despite prolonged periods of immobilization and lack of nutrition. We analysed the molecular pathways upregulated during hibernation in an obligate hibernator, the 13-lined ground squirrel (Ictidomys tridecemlineatus). Although Akt has an established role in skeletal muscle maintenance, we found that activated Akt was decreased in skeletal muscle of hibernating squirrels. Another serine-threonine kinase, serum- and glucocorticoid-regulated kinase 1 (SGK1), was upregulated during hibernation and contributed to protection from loss of muscle mass via downregulation of proteolysis and autophagy and via an increase in protein synthesis. We extended our observations to non-hibernating animals and demonstrated that SGK1-null mice developed muscle atrophy. These mice displayed an exaggerated response to immobilization and starvation. Furthermore, SGK1 overexpression prevented immobilization-induced muscle atrophy. Taken together, our results identify SGK1 as a novel therapeutic target to combat skeletal muscle loss in acquired and inherited forms of muscle atrophy. PMID:24443348

  6. ACTIVATION OF CASPASE-3 IN THE SKELETAL MUSCLE DURING HEMODIALYSIS

    PubMed Central

    Boivin, Michel A; Battah, Shadi I; Dominic, Elizabeth A; Kalantar-Zadeh, Kamyar; Ferrando, Arny; Tzamaloukas, Antonios H; Dwivedi, Rama; Ma, Thomas A; Moseley, Pope; Raj, Dominic SC

    2010-01-01

    Background Muscle atrophy in end-stage renal disease (ESRD) may be due to the activation of apoptotic and proteolytic pathways. Objective We hypothesized that activation of caspase-3 in the skeletal muscle mediates apoptosis and proteolysis during hemodialysis (HD). Materials and Methods Eight ESRD patients were studied before (pre-HD) and during HD and the finding were compared with those from six healthy volunteers. Protein kinetics was determined by primed constant infusion of L-(ring 13C6) Phenylalanine. Results Caspase-3 activity in the skeletal muscle was higher in ESRD patients pre-HD than in controls (24966.0±4023.9 vs. 15293.3±2120.0 units, p<0.01) and increased further during HD (end-HD) (37666.6±4208.3 units) (p<0.001). 14 kDa actin fragments generated by caspase-3 mediated cleavage of actinomyosin was higher in the skeletal muscle pre-HD (68%) and during HD (164%) compared to controls. The abundance of ubiquitinized carboxy-terminal actin fragment was also significantly increased during HD. Skeletal muscle biopsies obtained at the end of HD exhibited augmented apoptosis, which was higher than that observed in pre-HD and control samples (p<0.001). IL-6 content in the soluble fraction of the muscle skeletal muscle was increased significantly during HD. Protein kinetic studies showed that catabolism was higher in ESRD patients during HD compared to pre-HD and control subjects. Muscle protein catabolism was positively associated with caspase-3 activity and skeletal muscle IL-6 content. Conclusion Muscle atrophy in ESRD may be due to IL-6 induced activation of caspase-3 resulting in apoptosis as well as muscle proteolysis during HD. PMID:20636378

  7. Adipokines in Healthy Skeletal Muscle and Metabolic Disease.

    PubMed

    Coles, C A

    2016-01-01

    Adipose tissue not only functions as a reserve to store energy but has become of major interest as an endocrine organ, releasing signalling molecules termed adipokines which impact on other tissues, such as skeletal muscle. Adipocytes, within skeletal muscle and adipose tissue, secrete adipokines to finely maintain the balance between feed intake and energy expenditure. This book chapter focuses on the three adipokines, adiponectin, leptin and IL-6, which have potent effects on skeletal muscle during rest and exercise. Similarly, adiponectin, leptin and IL-6 enhance glucose uptake and increase fatty acid oxidation in skeletal muscle. Fatty acid oxidation is increased through activation of AMPK (adenosine monophosphate-activated protein kinase signalling) causing phosphorylation and inhibition of ACC (acetyl-coenzyme A carboxylase), decreasing availability of malonyl CoA. Leptin and adiponectin also control feed intake via AMPK signalling in the hypothalamus. Adipokines function to maintain energy homeostasis, however, when feed intake exceeds energy expenditure adipokines can become dysregulated causing lipotoxicity in skeletal muscle and metabolic disease can prevail. Cross-talk between adipocytes and skeletal muscle via correct control by adipokines is important in controlling energy homeostasis during rest and exercise and can help prevent metabolic disease. PMID:27003399

  8. Renal function alterations during skeletal muscle disuse in simulated microgravity

    NASA Technical Reports Server (NTRS)

    Tucker, Bryan J.

    1992-01-01

    This project was to examine the alterations in renal functions during skeletal muscle disuse in simulated microgravity. Although this area could cover a wide range of investigative efforts, the limited funding resulted in the selection of two projects. These projects would result in data contributing to an area of research deemed high priority by NASA and would address issues of the alterations in renal response to vasoactive stimuli during conditions of skeletal muscle disuse as well as investigate the contribution of skeletal muscle disuse, conditions normally found in long term human exposure to microgravity, to the balance of fluid and macromolecules within the vasculature versus the interstitium. These two projects selected are as follows: investigate the role of angiotensin 2 on renal function during periods of simulated microgravity and skeletal muscle disuse to determine if the renal response is altered to changes in circulating concentrations of angiotensin 2 compared to appropriate controls; and determine if the shift of fluid balance from vasculature to the interstitium, the two components of extracellular fluid volume, that occur during prolonged exposure to microgravity and skeletal muscle disuse is a result, in part, to alterations in the fluid and macromolecular balance in the peripheral capillary beds, of which the skeletal muscle contains the majority of recruitment capillaries. A recruitment capillary bed would be most sensitive to alterations in Starling forces and fluid and macromolecular permeability.

  9. Circadian Rhythms, the Molecular Clock, and Skeletal Muscle

    PubMed Central

    Lefta, Mellani; Wolff, Gretchen; Esser, Karyn A.

    2015-01-01

    Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a molecular clock mechanism found in most, if not all, cell types including skeletal muscle. The mammalian molecular clock is a complex of multiple oscillating networks that are regulated through transcriptional mechanisms, timed protein turnover, and input from small molecules. At this time, very little is known about circadian aspects of skeletal muscle function/metabolism but some progress has been made on understanding the molecular clock in skeletal muscle. The goal of this chapter is to provide the basic terminology and concepts of circadian rhythms with a more detailed review of the current state of knowledge of the molecular clock, with reference to what is known in skeletal muscle. Research has demonstrated that the molecular clock is active in skeletal muscles and that the muscle-specific transcription factor, MyoD, is a direct target of the molecular clock. Skeletal muscle of clock-compromised mice, Bmal1−/− and ClockΔ19 mice, are weak and exhibit significant disruptions in expression of many genes required for adult muscle structure and metabolism. We suggest that the interaction between the molecular clock, MyoD, and metabolic factors, such as PGC-1, provide a potential system of feedback loops that may be critical for both maintenance and adaptation of skeletal muscle. PMID:21621073

  10. Macrophage Plasticity in Skeletal Muscle Repair

    PubMed Central

    Rigamonti, Elena; Sciorati, Clara; Rovere-Querini, Patrizia

    2014-01-01

    Macrophages are one of the first barriers of host defence against pathogens. Beyond their role in innate immunity, macrophages play increasingly defined roles in orchestrating the healing of various injured tissues. Perturbations of macrophage function and/or activation may result in impaired regeneration and fibrosis deposition as described in several chronic pathological diseases. Heterogeneity and plasticity have been demonstrated to be hallmarks of macrophages. In response to environmental cues they display a proinflammatory (M1) or an alternative anti-inflammatory (M2) phenotype. A lot of evidence demonstrated that after acute injury M1 macrophages infiltrate early to promote the clearance of necrotic debris, whereas M2 macrophages appear later to sustain tissue healing. Whether the sequential presence of two different macrophage populations results from a dynamic shift in macrophage polarization or from the recruitment of new circulating monocytes is a subject of ongoing debate. In this paper, we discuss the current available information about the role that different phenotypes of macrophages plays after injury and during the remodelling phase in different tissue types, with particular attention to the skeletal muscle. PMID:24860823

  11. Myogenic mechanisms in the skeletal muscle circulation.

    PubMed

    Grände, P O

    1989-09-01

    Experiments were carried out on cat skeletal muscle to investigate the myogenic control in local vascular regulation, using a technique which allowed registration of pure myogenic responses to transmural pressure changes. The amplitudes of the responses to standardized transmural pressure increases were used to test myogenic reactivity in various situations. The technique also permitted continuous recordings of vascular resistance in the whole vascular bed and in its three consecutive vascular segments, i.e. proximal arterial vessels (greater than 25 microns inner diameter), microvessels (less than 25 microns) and veins. The experiments confirmed the presence of a myogenic control system triggered by the transmural pressure distension and mainly located in the arterial microvessels. The myogenic control seems to contribute to the initiation and establishment of basal vascular tone and, in synergism with metabolic vasodilator influences, to autoregulation of blood flow. Consequently, factors that depress myogenic reactivity should induce vasodilation, as also shown in the present study for metabolic influence, beta-adrenergic activation and calcium antagonism. Both the humoral and the neurogenic beta-adrenergic effects depress myogenic reactivity and counter alpha-adrenergic constriction. PMID:2809807

  12. Skeletal muscle tissue in movement and health: positives and negatives.

    PubMed

    Lindstedt, Stan L

    2016-01-01

    The history of muscle physiology is a wonderful lesson in 'the scientific method'; our functional hypotheses have been limited by our ability to decipher (observe) muscle structure. The simplistic understanding of how muscles work made a large leap with the remarkable insights of A. V. Hill, who related muscle force and power to shortening velocity and energy use. However, Hill's perspective was largely limited to isometric and isotonic contractions founded on isolated muscle properties that do not always reflect how muscles function in vivo. Robert Josephson incorporated lengthening contractions into a work loop analysis that shifted the focus to dynamic muscle function, varying force, length and work done both by and on muscle during a single muscle work cycle. It became apparent that muscle is both a force generator and a spring. Titin, the missing filament in the sliding filament model, is a muscle spring, which functions very differently in cardiac versus skeletal muscle; its possible role in these two muscle types is discussed relative to their contrasting function. The good news for those of us who choose to work on skeletal muscle is that muscle has been reluctant to reveal all of its secrets. PMID:26792329

  13. Bex1 knock out mice show altered skeletal muscle regeneration

    SciTech Connect

    Koo, Jae Hyung Smiley, Mark A.; Lovering, Richard M.; Margolis, Frank L.

    2007-11-16

    Bex1 and Calmodulin (CaM) are upregulated during skeletal muscle regeneration. We confirm this finding and demonstrate the novel finding that they interact in a calcium-dependent manner. To study the role of Bex1 and its interaction with CaM in skeletal muscle regeneration, we generated Bex1 knock out (Bex1-KO) mice. These mice appeared to develop normally and are fertile, but displayed a functional deficit in exercise performance compared to wild type (WT) mice. After intramuscular injection of cardiotoxin, which causes extensive and reproducible myotrauma followed by recovery, regenerating muscles of Bex1-KO mice exhibited elevated and prolonged cell proliferation, as well as delayed cell differentiation, compared to WT mice. Thus, our results provide the first evidence that Bex1-KO mice show altered muscle regeneration, and allow us to propose that the interaction of Bex1 with Ca{sup 2+}/CaM may be involved in skeletal muscle regeneration.

  14. Skeletal muscle hypertrophy and structure and function of skeletal muscle fibres in male body builders

    PubMed Central

    D'Antona, Giuseppe; Lanfranconi, Francesca; Pellegrino, Maria Antonietta; Brocca, Lorenza; Adami, Raffaella; Rossi, Rosetta; Moro, Giorgio; Miotti, Danilo; Canepari, Monica; Bottinelli, Roberto

    2006-01-01

    Needle biopsy samples were taken from vastus lateralis muscle (VL) of five male body builders (BB, age 27.4 ± 0.93 years; mean ±s.e.m.), who had being performing hypertrophic heavy resistance exercise (HHRE) for at least 2 years, and from five male active, but untrained control subjects (CTRL, age 29.9 ± 2.01 years). The following determinations were performed: anatomical cross-sectional area and volume of the quadriceps and VL muscles in vivo by magnetic resonance imaging (MRI); myosin heavy chain isoform (MHC) distribution of the whole biopsy samples by SDS-PAGE; cross-sectional area (CSA), force (Po), specific force (Po/CSA) and maximum shortening velocity (Vo) of a large population (n= 524) of single skinned muscle fibres classified on the basis of MHC isoform composition by SDS-PAGE; actin sliding velocity (Vf) on pure myosin isoforms by in vitro motility assays. In BB a preferential hypertrophy of fast and especially type 2X fibres was observed. The very large hypertrophy of VL in vivo could not be fully accounted for by single muscle fibre hypertrophy. CSA of VL in vivo was, in fact, 54% larger in BB than in CTRL, whereas mean fibre area was only 14% larger in BB than in CTRL. MHC isoform distribution was shifted towards 2X fibres in BB. Po/CSA was significantly lower in type 1 fibres from BB than in type 1 fibres from CTRL whereas both type 2A and type 2X fibres were significantly stronger in BB than in CTRL. Vo of type 1 fibres and Vf of myosin 1 were significantly lower in BB than in CTRL, whereas no difference was observed among fast fibres and myosin 2A. The findings indicate that skeletal muscle of BB was markedly adapted to HHRE through extreme hypertrophy, a shift towards the stronger and more powerful fibre types and an increase in specific force of muscle fibres. Such adaptations could not be fully accounted for by well known mechanisms of muscle plasticity, i.e. by the hypertrophy of single muscle fibre (quantitative mechanism) and by a regulation of contractile properties of muscle fibres based on MHC isoform content (qualitative mechanism). Two BB subjects took anabolic steroids and three BB subjects did not. The former BB differed from the latter BB mostly for the size of their muscles and muscle fibres. PMID:16339176

  15. Estimation of skeletal muscle mass from body creatine content

    NASA Technical Reports Server (NTRS)

    Pace, N.; Rahlmann, D. F.

    1982-01-01

    Procedures have been developed for studying the effect of changes in gravitational loading on skeletal muscle mass through measurements of the body creatine content. These procedures were developed for studies of gravitational scale effects in a four-species model, comprising the hamster, rat, guinea pig, and rabbit, which provides a sufficient range of body size for assessment of allometric parameters. Since intracellular muscle creatine concentration varies among species, and with age within a given species, the concentration values for metabolically mature individuals of these four species were established. The creatine content of the carcass, skin, viscera, smooth muscle, and skeletal muscle was determined for each species. In addition, the skeletal muscle mass of the major body components was determined, as well as the total and fat-free masses of the body and carcass, and the percent skeletal muscle in each. It is concluded that these procedures are particularly useful for studying the effect of gravitational loading on the skeletal muscle content of the animal carcass, which is the principal weight-bearing organ of the body.

  16. Naturally derived and synthetic scaffolds for skeletal muscle reconstruction.

    PubMed

    Wolf, Matthew T; Dearth, Christopher L; Sonnenberg, Sonya B; Loboa, Elizabeth G; Badylak, Stephen F

    2015-04-01

    Skeletal muscle tissue has an inherent capacity for regeneration following injury. However, severe trauma, such as volumetric muscle loss, overwhelms these natural muscle repair mechanisms prompting the search for a tissue engineering/regenerative medicine approach to promote functional skeletal muscle restoration. A desirable approach involves a bioscaffold that simultaneously acts as an inductive microenvironment and as a cell/drug delivery vehicle to encourage muscle ingrowth. Both biologically active, naturally derived materials (such as extracellular matrix) and carefully engineered synthetic polymers have been developed to provide such a muscle regenerative environment. Next generation naturally derived/synthetic "hybrid materials" would combine the advantageous properties of these materials to create an optimal platform for cell/drug delivery and possess inherent bioactive properties. Advances in scaffolds using muscle tissue engineering are reviewed herein. PMID:25174309

  17. No-dependent signaling pathways in unloaded skeletal muscle

    PubMed Central

    Shenkman, Boris S.; Nemirovskaya, Tatiana L.; Lomonosova, Yulia N.

    2015-01-01

    The main focus of the current review is the nitric oxide (NO)-mediated signaling mechanism in unloaded skeletal. Review of the published data describing muscles during physical activity and inactivity demonstrates that NO is an essential trigger of signaling processes, which leads to structural and metabolic changes of the muscle fibers. The experiments with modulation of NO-synthase (NOS) activity during muscle unloading demonstrate the ability of an activated enzyme to stabilize degradation processes and prevent development of muscle atrophy. Various forms of muscle mechanical activity, i.e., plantar afferent stimulation, resistive exercise and passive chronic stretch increase the content of neural NOS (nNOS) and thus may facilitate an increase in NO production. Recent studies demonstrate that NO-synthase participates in the regulation of protein and energy metabolism in skeletal muscle by fine-tuning and stabilizing complex signaling systems which regulate protein synthesis and degradation in the fibers of inactive muscle. PMID:26582991

  18. Action of obestatin in skeletal muscle repair: stem cell expansion, muscle growth, and microenvironment remodeling.

    PubMed

    Gurriarán-Rodríguez, Uxía; Santos-Zas, Icía; González-Sánchez, Jessica; Beiroa, Daniel; Moresi, Viviana; Mosteiro, Carlos S; Lin, Wei; Viñuela, Juan E; Señarís, José; García-Caballero, Tomás; Casanueva, Felipe F; Nogueiras, Rubén; Gallego, Rosalía; Renaud, Jean-Marc; Adamo, Sergio; Pazos, Yolanda; Camiña, Jesús P

    2015-06-01

    The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Overall, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration. PMID:25762009

  19. Premature Aging in Skeletal Muscle Lacking Serum Response Factor

    PubMed Central

    Lahoute, Charlotte; Sotiropoulos, Athanassia; Favier, Marilyne; Guillet-Deniau, Isabelle; Charvet, Claude; Ferry, Arnaud; Butler-Browne, Gillian; Metzger, Daniel; Tuil, David; Daegelen, Dominique

    2008-01-01

    Aging is associated with a progressive loss of muscle mass, increased adiposity and fibrosis that leads to sarcopenia. At the molecular level, muscle aging is known to alter the expression of a variety of genes but very little is known about the molecular effectors involved. SRF (Serum Response Factor) is a crucial transcription factor for muscle-specific gene expression and for post-natal skeletal muscle growth. To assess its role in adult skeletal muscle physiology, we developed a post-mitotic myofiber-specific and tamoxifen-inducible SRF knockout model. Five months after SRF loss, no obvious muscle phenotype was observed suggesting that SRF is not crucial for myofiber maintenance. However, mutant mice progressively developed IIB myofiber-specific atrophy accompanied by a metabolic switch towards a more oxidative phenotype, muscular lipid accumulation, sarcomere disorganization and fibrosis. After injury, mutant muscles exhibited an altered regeneration process, showing smaller regenerated fibers and persistent fibrosis. All of these features are strongly reminiscent of abnormalities encountered in aging skeletal muscle. Interestingly, we also observed an important age associated decrease in SRF expression in mice and human muscles. Altogether, these results suggest that a naturally occurring SRF down-regulation precedes and contributes to the muscle aging process. Indeed, triggering SRF loss in the muscles of mutant mice results in an accelerated aging process. PMID:19079548

  20. Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle

    PubMed Central

    Rivas, Donato A.; Lessard, Sarah J.; Saito, Misato; Friedhuber, Anna M.; Koch, Lauren G.; Britton, Steven L.; Yaspelkis, Ben B.

    2011-01-01

    Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (?30%; P = 0.04), glucose oxidation (?50%; P = 0.04), and lipid oxidation (?40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR. PMID:21270346

  1. Enzyme alteration in skeletal muscle of mice with muscular dystrophy.

    PubMed

    Kitahara, A; Imai, F; Takaya, S; Sato, K

    1977-12-22

    1. Developmental enzyme alterations were investigated in skeletal muscle of the hereditary progressive muscular dystrophy (PMD) mice of C57BL/6J strain. 2. Enzymes examined were classified into three groups according to changes of activities in dystrophy muscle during ageing. Activities of creatine kinase (EC 2.7.3.2), pyruvate kinase (EC 2.7.1.40), glycogen phosphorylase (EC 2.4.1.1), and fructose-biphosphate aldolase (EC 4.1.2.13), each of which had the respective muscle specific isoenzyme of extremely high activity in normal adult skeletal muscle, decreased rapidly in dystrophy muscle from the early stage of the disease with ageing. Activities of glycogen synthase (EC 2.4.1.11) and hexokinase (EC 2.7.1.1) were higher in dystrophy muscle in the early stage but decreased gradually to lower levels than those in the control with ageing. Activities of glucose-6-phosphate dehydrogenase (EC 1.1.1.49) were always much higher in dystrophy muscle than in the control, with no relation to ageing. 3. Isoenzymes of creatine kinase, pyruvate kinase and phosphorylase in dystrophy muscle were mainly the muscle types, indicating that muscle differentiation was not blocked profoundly even in dystrophy muscle. In limited cases, especially in the early stage of the disease, very weak activities of the non-muscle fetal type isoenzymes of creatine kinase and phosphorylase were detected, apparently associated with partial muscle regeneration in dystrophy muscle. PMID:412523

  2. Hindlimb skeletal muscle function in myostatin-deficient mice.

    PubMed

    Gentry, Bettina A; Ferreira, J Andries; Phillips, Charlotte L; Brown, Marybeth

    2011-01-01

    Absence of functional myostatin (MSTN) during fetal development results in adult skeletal muscle hypertrophy and hyperplasia. To more fully characterize MSTN loss in hindlimb muscles, the morphology and contractile function of the soleus, plantaris, gastrocnemius, tibialis anterior, and quadriceps muscles in male and female null (Mstn(-/-)), heterozygous (Mstn(+/-)), and wild-type (Mstn(+/+)) mice were investigated. Muscle weights of Mstn(-/-) mice were greater than those of Mstn(+/+) and Mstn(+/-) mice. Fiber cross-sectional area (CSA) was increased in female Mstn(-/-) soleus and gastrocnemius muscles and in the quadriceps of male Mstn(-/-) mice; peak tetanic force in Mstn(-/-) mice did not parallel the increased muscle weight or CSA. Male Mstn(-/-) muscle exhibited moderate degeneration. Visible pathology in male mice and decreased contractile strength relative to increased muscle weight suggest MSTN loss results in muscle impairment, which is dose-, sex-, and muscle-dependent. PMID:21082689

  3. Physiologic and biochemical aspects of skeletal muscle denervation and reinnervation

    NASA Technical Reports Server (NTRS)

    Max, S. R.; Mayer, R. F.

    1984-01-01

    Some of the physiologic and biochemical changes that occur in mammalian skeletal muscle following denervation and reinnervation are considered and some comparisons are made with changes observed following altered motor function. The nature of the trophic influence by which nerves control muscle properties are discussed, including the effects of choline acetyltransferase and acetylcholinesterase and the role of the acetylcholine receptor.

  4. The impact of vitamin D on skeletal muscle function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review discusses the clinical and laboratory studies that have examined a role of vitamin D in skeletal muscle. Many observational studies, mainly in older populations, indicate that vitamin D status is positively associated with muscle strength and physical performance and inversely associated...

  5. Acylcarnitines: potential implications for skeletal muscle insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin resistance is linked to increased acylcarnitine species in a number of tissues including skeletal muscle, due to incomplete fatty acid oxidation (FAO). It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aim of this stud...

  6. Molecular responses to moderate endurance exercise in skeletal muscle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study examined alterations in skeletal-muscle growth and atrophy-related molecular events after a single bout of moderate-intensity endurance exercise. Muscle biopsies were obtained from 10 men (23 +/- 1 yr, body mass 80 +/- 2 kg, and VO(2peak) 45 +/- 1 ml x kg'¹ x min'¹) immediately (0 hr) and...

  7. Skeletal Muscle as a Peripheral Modifier of Behavior

    ERIC Educational Resources Information Center

    Jenkins, Robert R.

    1978-01-01

    Discusses how muscle can exert an influence on the behavioral potential of an organism and attempts to refute the "all or none law" by demonstrating that skeletal muscle is not merely a slave of the central nervous system. (Author/MA)

  8. Vitamin D and its role in skeletal muscle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review discusses the clinical and laboratory studies that have examined a role of vitamin D in skeletal muscle. Many observational studies, mainly in older populations, indicate that vitamin D status is positively associated with muscle strength and physical performance and inversely associated...

  9. Leucine-enriched essential amino acid supplementation during moderate steady state exercise enhances postexercise muscle protein synthesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: The effects of essential amino acid (EAA) supplementation during moderate steady state (ie, endurance) exercise on postexercise skeletal muscle metabolism are not well described, and the potential role of supplemental leucine on muscle protein synthesis (MPS) and associated molecular re...

  10. Oxidants, antioxidants and alcohol: implications for skeletal and cardiac muscle.

    PubMed

    Preedy, V R; Patel, V B; Reilly, M E; Richardson, P J; Falkous, G; Mantle, D

    1999-08-01

    The chronic form of alcoholic skeletal myopathy is characterized by selective atrophy of Type II fibers and affects up to two thirds of all alcohol misusers. Plasma selenium and alpha-tocopherol are reduced in myopathic alcoholics compared to alcoholic patients without myopathy. Plasma carnosinase is also reduced in myopathic alcoholics, implicating a mechanism related to reduced intramuscular carnosine, an imidazole dipeptide with putative antioxidant properties. Together with the observation that alcoholic patients have increased indices of lipid peroxidation, there is evidence suggestive of free radical (i.e., unpaired electrons or reactive oxygen species) mediated damage in the pathogenesis of alcohol-induced muscle disease. Protein synthesis is a multi-step process that encompasses amino acid transport, signal transduction, translation and transcription. Any defect in one or more of the innumerable components of each process will have an impact on protein synthesis, as determined by radiolabelling of constituent proteins. Both acute and chronic alcohol exposure are associated with a reduction in skeletal muscle protein synthesis. Paradoxically, alcohol-feeding studies in rats have shown that the imidazole dipeptide concentrations are increased in myopathic muscles though alpha-tocopherol contents are not significantly altered. In acutely dosed rats, where protein synthesis is reduced, protein carbonyl concentrations (an index of oxidative damage to muscle) also decline slightly or are unaltered, contrary to the expected increase. Alcoholic cardiomyopathy can ensue from heavy consumption of alcohol over a long period of time. The clinical features include poor myocardial contractility with reduced left ventricular ejection volume, raised tissue enzymes, dilation of the left ventricle, raised auto- antibodies and defects in mitochondrial function. Whilst oxidant damage occurs in experimental models, however this issues remains to be confirmed in the clinical setting. In the rat, circulating troponin-T release increases in the presence of ethanol, a mechanism ascribed to free radical mediated damage, as it is prevented with the xanthine oxidase inhibitor and beta-blocker, propranolol. However, whilst propranolol prevents the release of troponin-T, it does not prevent the fall in whole cardiac protein synthesis, suggestive of localized ischemic damage due to ethanol. PMID:10430553

  11. Natriuretic peptides enhance the oxidative capacity of human skeletal muscle.

    PubMed

    Engeli, Stefan; Birkenfeld, Andreas L; Badin, Pierre-Marie; Bourlier, Virginie; Louche, Katie; Viguerie, Nathalie; Thalamas, Claire; Montastier, Emilie; Larrouy, Dominique; Harant, Isabelle; de Glisezinski, Isabelle; Lieske, Stefanie; Reinke, Julia; Beckmann, Bibiana; Langin, Dominique; Jordan, Jens; Moro, Cedric

    2012-12-01

    Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP-dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training-induced improvement in skeletal muscle fat oxidative capacity in humans. PMID:23114600

  12. Natriuretic peptides enhance the oxidative capacity of human skeletal muscle

    PubMed Central

    Engeli, Stefan; Birkenfeld, Andreas L.; Badin, Pierre-Marie; Bourlier, Virginie; Louche, Katie; Viguerie, Nathalie; Thalamas, Claire; Montastier, Emilie; Larrouy, Dominique; Harant, Isabelle; de Glisezinski, Isabelle; Lieske, Stefanie; Reinke, Julia; Beckmann, Bibiana; Langin, Dominique; Jordan, Jens; Moro, Cedric

    2012-01-01

    Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP–dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training–induced improvement in skeletal muscle fat oxidative capacity in humans. PMID:23114600

  13. A method for preparing skeletal muscle fiber basal laminae

    SciTech Connect

    Carlson, E.C.; Carlson, B.M. )

    1991-07-01

    Previous attempts to prepare skeletal muscle basal laminae (BL) for ultrastructural analyses have been hampered by difficulties in successfully removing skeletal muscle proteins and cellular debris from BL tubes. In the present study the authors describe a two phase method which results in an acellular muscle preparation, the BL of which are examined by light, transmission electron, and scanning electron microscopy. In the first phase, excised rat extensor digitorum longus muscles are subjected to x-radiation and then soaked in Marcaine to inhibit muscle regeneration and to destroy peripheral muscle fibers. The muscles are then grafted back into their original sites and allowed to remain in place 7-14 days to allow for maximal removal of degenerating muscle tissue with minimal scar tissue formation. In the second phase, the muscle grafts are subjected sequentially to EDTA, triton X-100, DNAase, and sodium deoxycholate to remove phagocytizing cells and associated degenerating muscle tissue. These procedures result in translucent, acellular muscle grafts which show numerous empty tubes of BL backed by endomysial collagenous fibers. These preparations should be useful for morphological analyses of isolated muscle BL and for possible in vitro studies by which the biological activity of muscle BL can be examined.

  14. Polychlorobiphenyls inhibit skeletal muscle differentiation in culture.

    PubMed

    Coletti, D; Palleschi, S; Silvestroni, L; Cannavò, A; Vivarelli, E; Tomei, F; Molinaro, M; Adamo, S

    2001-09-15

    Polychlorinated biphenyls (PCBs) are ubiquitous and persistent pollutants whose role in developmental toxicity is of great concern. The observation that the offspring of PCB-exposed mothers (both in humans and rodents) display reduced body mass prompted us to investigate the effects of commercial mixtures of PCB congeners (Aroclor 1232, 1254, and 1262) on differentiation of both a myogenic cell line and primary myogenic cell cultures. The fusion of L6 myoblasts into multinucleated myotubes and the increase of creatine kinase (CK) activity were dose-dependently inhibited by Aroclor 1254 at concentrations (0.1-4 microg/ml) that caused no effect on cell density. Ultrastructural analysis demonstrated that Aroclor 1254 also prevented the accumulation of contractile filaments while inducing hypertrophy of the smooth endoplasmic reticulum and appearance of membrane-filled autophagosomes. Half-maximal inhibition (IC50) of CK activity accumulation occurred at 0.01 microg/ml for Aroclor 1262, 2 microg/ml for Aroclor 1254, and 8 microg/ml for Aroclor 1232. Aroclor-dependent inhibition of myogenic differentiation was also shown by the reduced expression and nuclear accumulation of beta-galactosidase in primary cultures of fetal myoblasts from transgenic mice expressing this reporter gene under the control of the myosin light chain promoter. These data show that skeletal muscle differentiation is specifically impaired by PCBs and may explain the reported depression of body mass growth in PCB-exposed offspring at birth. Furthermore, myogenic cell cultures are highly sensitive to PCBs and allow the detection of biological effects of environmental levels of these pollutants. PMID:11559021

  15. Impact of Conjugated Linoleic Acid (CLA) on Skeletal Muscle Metabolism.

    PubMed

    Kim, Yoo; Kim, Jonggun; Whang, Kwang-Youn; Park, Yeonhwa

    2016-02-01

    Conjugated linoleic acid (CLA) has garnered special attention as a food bioactive compound that prevents and attenuates obesity. Although most studies on the effects of CLA on obesity have focused on the reduction of body fat, a number of studies have demonstrated that CLA also increases lean body mass and enhances physical performances. It has been suggested that these effects may be due in part to physiological changes in the skeletal muscle, such as changes in the muscle fiber type transformation, alteration of the intracellular signaling pathways in muscle metabolism, or energy metabolism. However, the mode of action for CLA in muscle metabolism is not completely understood. The purpose of this review is to summarize the current knowledge of the effects of CLA on skeletal muscle metabolism. Given that CLA not only reduces body fat, but also improves lean mass, there is great potential for the use of CLA to improve muscle metabolism, which would have a significant health impact. PMID:26729488

  16. Autophagy in skeletal muscle homeostasis and in muscular dystrophies.

    PubMed

    Grumati, Paolo; Bonaldo, Paolo

    2012-01-01

    Skeletal muscles are the agent of motion and one of the most important tissues responsible for the control of metabolism. The maintenance of muscle homeostasis is finely regulated by the balance between catabolic and anabolic process. Macroautophagy (or autophagy) is a catabolic process that provides the degradation of protein aggregation and damaged organelles through the fusion between autophagosomes and lysosomes. Proper regulation of the autophagy flux is fundamental for the homeostasis of skeletal muscles during physiological situations and in response to stress. Defective as well as excessive autophagy is harmful for muscle health and has a pathogenic role in several forms of muscle diseases. This review will focus on the role of autophagy in muscle homeostasis and diseases. PMID:24710479

  17. Mechanically induced alterations in cultured skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H. H.; Hatfaludy, S.; Karlisch, P.; Shansky, J.

    1991-01-01

    Model systems are available for mechanically stimulating cultured skeletal muscle cells by passive tensile forces which simulate those found in vivo. When applied to embryonic muscle cells in vitro these forces induce tissue organogenesis, metabolic adaptations, and muscle cell growth. The mechanical stimulation of muscle cell growth correlates with stretch-induced increases in the efflux of prostaglandins PGE2 and PGF2(alpha) in a time and frequency dependent manner. These prostaglandins act as mechanical 'second messengers' regulating skeletal muscle protein turnover rates. Since they also effect bone remodelling in response to tissue loading and unloading, secreted prostaglandins may serve as paracrine growth factors, coordinating the growth rates of muscle and bone in response to external mechanical forces. Cell culture model systems will supplement other models in understanding mechanical transduction processes at the molecular level.

  18. In vitro stimulation of skeletal muscle protein synthesis by leucine and insulin

    SciTech Connect

    Hatlestad, C.L.; Layman, D.K.

    1986-03-01

    The objective of this study was to determine the potential of leu to stimulate skeletal muscle protein synthesis in the presence or absence of insulin or insulin plus a mixture of the other plasma amino acids. Male Sprague-Dawley rats weighing 75 g were fasted for 24 hrs, sacrificed, and the soleus muscle isolated from the hind limb. Protein synthesis was determined in isolated muscles incubated for 2 hrs at 37/sup 0/C in a Krebs-Ringer bicarbonate buffer containing 0.5 ..mu..Ci of /sup 14/C-tyrosine and supplemented with either 10 mM glucose (G), glucose plus 0.1 IU/m. insulin (I), or glucose, insulin and plasma levels of amino acids (IAA). Contralateral muscles were incubated in the respective media with the addition of 0.5 mM L-leucine. Insulin stimulated protein synthesis by 51% above the G group, and IAA produced a 110% stimulation. Leu stimulated protein synthesis by an additional 15-20% in each of the medias. These results confirm the ability of leu to stimulate skeletal muscle protein synthesis in vitro and establish that the effect is additive with stimulations by insulin and other amino acids.

  19. Epigenetic regulation of skeletal muscle development and differentiation.

    PubMed

    Bharathy, Narendra; Ling, Belinda Mei Tze; Taneja, Reshma

    2013-01-01

    Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. Formation of skeletal muscle involves a series of steps in which cells are committed towards the myogenic lineage, undergo expansion to give rise to myoblasts that differentiate into multinucleated myotubes, and mature to form adult muscle fibers. The commitment, proliferation, and differentiation of progenitor cells involve both genetic and epigenetic changes that culminate in alterations in gene expression. Members of the Myogenic regulatory factor (MRF), as well as the Myocyte Enhancer Factor (MEF2) families control distinct steps of skeletal muscle proliferation and differentiation. In addition, -growing evidence indicates that chromatin modifying enzymes and remodeling complexes epigenetically reprogram muscle promoters at various stages that preclude or promote MRF and MEF2 activites. Among these, histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs) and SWI/SNF complexes alter chromatin structure through post-translational modifications to impact MRF and MEF2 activities. With such new and emerging knowledge, we are beginning to develop a true molecular understanding of the mechanisms by which skeletal muscle development and differentiation is regulated. Elucidation of the mechanisms by which epigenetic regulators control myogenesis will likely provide a new foundation for the development of novel therapeutic drugs for muscle dystrophies, ageing-related regeneration defects that occur due to altered proliferation and differentiation, and other malignancies. PMID:23150250

  20. Decellularized Human Skeletal Muscle as Biologic Scaffold for Reconstructive Surgery

    PubMed Central

    Porzionato, Andrea; Sfriso, Maria Martina; Pontini, Alex; Macchi, Veronica; Petrelli, Lucia; Pavan, Piero G.; Natali, Arturo N.; Bassetto, Franco; Vindigni, Vincenzo; De Caro, Raffaele

    2015-01-01

    Engineered skeletal muscle tissues have been proposed as potential solutions for volumetric muscle losses, and biologic scaffolds have been obtained by decellularization of animal skeletal muscles. The aim of the present work was to analyse the characteristics of a biologic scaffold obtained by decellularization of human skeletal muscles (also through comparison with rats and rabbits) and to evaluate its integration capability in a rabbit model with an abdominal wall defect. Rat, rabbit and human muscle samples were alternatively decellularized with two protocols: n.1, involving sodium deoxycholate and DNase I; n.2, trypsin-EDTA and Triton X-NH4OH. Protocol 2 proved more effective, removing all cellular material and maintaining the three-dimensional networks of collagen and elastic fibers. Ultrastructural analyses with transmission and scanning electron microscopy confirmed the preservation of collagen, elastic fibres, glycosaminoglycans and proteoglycans. Implantation of human scaffolds in rabbits gave good results in terms of integration, although recellularization by muscle cells was not completely achieved. In conclusion, human skeletal muscles may be effectively decellularized to obtain scaffolds preserving the architecture of the extracellular matrix and showing mechanical properties suitable for implantation/integration. Further analyses will be necessary to verify the suitability of these scaffolds for in vitro recolonization by autologous cells before in vivo implantation. PMID:26140375

  1. Compensatory Hypertrophy of Skeletal Muscle: Contractile Characteristics

    ERIC Educational Resources Information Center

    Ianuzzo, C. D.; Chen, V.

    1977-01-01

    Describes an experiment using rats that demonstrates contractile characteristics of normal and hypertrophied muscle. Compensatory hypertrophy of the plantaris muscle is induced by surgical removal of the synergistic gastrocnemium muscle. Includes methods for determination of contractile properties of normal and hypertrophied muscle and…

  2. Hypodynamic and hypokinetic condition of skeletal muscles

    NASA Technical Reports Server (NTRS)

    Katinas, G. S.; Oganov, V. S.; Potapov, A. N.

    1980-01-01

    Data are presented in regard to the effect of unilateral brachial amputation on the physiological characteristics of two functionally different muscles, the brachial muscle (flexor of the brachium) and the medial head of the brachial triceps muscle (extensor of the brachium), which in rats represents a separate muscle. Hypokinesia and hypodynamia were studied.

  3. Quantitative force comparison of polyacrylonitrile fibers with skeletal muscle

    NASA Astrophysics Data System (ADS)

    Gonzalez, Roger V.; Lee, Christopher Y.

    1998-07-01

    The possibility of using certain polymer gels as artificial skeletal muscle was investigated due to its ability to shorten or contract when saturated in acidic or basic solutions, respectively. Polyacrylonitrile (PAN) fiber is such an example of a polymer gel. Mechanical performance characteristics of PAN fibers were studied and compared to voluntary muscle mechanical properties. The experimental methods used to determine the mechanical properties of the PAN fibers were modeled after A. V. Hill's classic experiments of the force-length and force-velocity properties of voluntary muscle. In addition, the force-molarity, length-molarity, and force-time characteristics were measured for the PAN fibers. These characteristics were quantitatively and qualitatively compared to voluntary muscle properties when relevant and used to determine the feasibility of implementing PAN fibers as artificial skeletal muscle in modeling movement across the human elbow joint. The results indicated qualitative similarities with the mechanical characteristics of voluntary muscle, especially force-velocity property. The force capabilities of the PAN fibers were at the lower end of voluntary muscle force generation. (i.e. 20 - 200 N/cm2) Activation- contraction time was also substantially larger than skeletal muscle. Based on these data, it was concluded that using PAN fibers as artificial muscles in modeling the human elbow joint is feasible only under certain conditions. Additional characterization studies are needed to determine if individual PAN fibers can generate higher forces using a different experimental protocol or a different architectural arrangement of the fibers.

  4. Antioxidants in skeletal muscle physiology, a radically different approach.

    PubMed

    Carmen Gomez-Cabrera, Mari

    2014-10-01

    Regular physical exercise has many health benefits (1). Paradoxically, it is also clear that contracting skeletal muscles generate reactive oxygen species (ROS) and that prolonged and intense exercise can result in oxidative damage to cellular constituents (2-4). Reactive oxygen species production is dependent on the intensity of the exercise with higher amount of ROS generated by strenuous exercise (5, 6). Antioxidants may reduce the adverse effects of exercise-induced ROS (2-4). However, ROS are not only toxic but rather play an important role in cell signalling and in the regulation of gene expression (7, 8) and force production in skeletal muscle (9). Thus, we have recently raised questions about the validity of using oral antioxidant supplementation during training by athletes (10, 11). We have found that redox sensitive signaling pathways are inolved in skeletal muscle atrophy due to disuse and aging (12). Loss of skeletal muscle mass and function is an important limiting factor in the maintenance of health and well-being both in the young and in the old population (13, 14). I will report experiments showing that both hormonal (15) and non-hormonal interventions (13) are effective in the maintenance of redox homeostasis and in the prevention of skeletal muscle atrophy. PMID:26461276

  5. Investigative study of radiopharmaceuticals useful for imaging skeletal muscle injury in experimental animals

    SciTech Connect

    Owunwanne, A.; Malki, A.; Sadek, S.; el-Gazzar, A.; Yacoub, T.; Abdel-Dayem, H.M.

    1989-01-01

    An experimental animal model for studying skeletal muscle injury is described. Tc-99m PYP is accumulated on the skeletal muscle injury, but its uptake on the adjacent bone obscures its usefulness in delineating the extent of the muscle injury. In-111 antimyosin accumulates and delineates the extent of the skeletal muscle injury and does not accumulate on the adjacent bone. Hence, In-111 antimyosin is a good radiopharmaceutical for studying the severity and prognosis of skeletal muscle injury.

  6. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    SciTech Connect

    Hamrick, Mark W.; Herberg, Samuel; Arounleut, Phonepasong; Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA ; He, Hong-Zhi; Department of Dermatology, Henry Ford Health System, Detroit, MI ; Shiver, Austin; Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA ; Qi, Rui-Qun; Department of Dermatology, Henry Ford Health System, Detroit, MI ; Zhou, Li; Department of Dermatology, Henry Ford Health System, Detroit, MI; Department of Internal Medicine, Henry Ford Health System, Detroit, MI ; Isales, Carlos M.; Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA ; and others

    2010-09-24

    Research highlights: {yields} Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. {yields} We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. {yields} Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. {yields} Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient-related hormones such as leptin may be able to reverse muscle atrophy and alter the expression of atrophy-related miRNAs in aging skeletal muscle.

  7. Effective fiber hypertrophy in satellite cell-depleted skeletal muscle

    PubMed Central

    McCarthy, John J.; Mula, Jyothi; Miyazaki, Mitsunori; Erfani, Rod; Garrison, Kelcye; Farooqui, Amreen B.; Srikuea, Ratchakrit; Lawson, Benjamin A.; Grimes, Barry; Keller, Charles; Van Zant, Gary; Campbell, Kenneth S.; Esser, Karyn A.; Dupont-Versteegden, Esther E.; Peterson, Charlotte A.

    2011-01-01

    An important unresolved question in skeletal muscle plasticity is whether satellite cells are necessary for muscle fiber hypertrophy. To address this issue, a novel mouse strain (Pax7-DTA) was created which enabled the conditional ablation of >90% of satellite cells in mature skeletal muscle following tamoxifen administration. To test the hypothesis that satellite cells are necessary for skeletal muscle hypertrophy, the plantaris muscle of adult Pax7-DTA mice was subjected to mechanical overload by surgical removal of the synergist muscle. Following two weeks of overload, satellite cell-depleted muscle showed the same increases in muscle mass (approximately twofold) and fiber cross-sectional area with hypertrophy as observed in the vehicle-treated group. The typical increase in myonuclei with hypertrophy was absent in satellite cell-depleted fibers, resulting in expansion of the myonuclear domain. Consistent with lack of nuclear addition to enlarged fibers, long-term BrdU labeling showed a significant reduction in the number of BrdU-positive myonuclei in satellite cell-depleted muscle compared with vehicle-treated muscle. Single fiber functional analyses showed no difference in specific force, Ca2+ sensitivity, rate of cross-bridge cycling and cooperativity between hypertrophied fibers from vehicle and tamoxifen-treated groups. Although a small component of the hypertrophic response, both fiber hyperplasia and regeneration were significantly blunted following satellite cell depletion, indicating a distinct requirement for satellite cells during these processes. These results provide convincing evidence that skeletal muscle fibers are capable of mounting a robust hypertrophic response to mechanical overload that is not dependent on satellite cells. PMID:21828094

  8. Assessment of Calcium Sparks in Intact Skeletal Muscle Fibers

    PubMed Central

    Park, Ki Ho; Weisleder, Noah; Zhou, Jingsong; Gumpper, Kristyn; Zhou, Xinyu; Duann, Pu; Ma, Jianjie; Lin, Pei-Hui

    2014-01-01

    Maintaining homeostatic Ca2+ signaling is a fundamental physiological process in living cells. Ca2+ sparks are the elementary units of Ca2+ signaling in the striated muscle fibers that appear as highly localized Ca2+ release events mediated by ryanodine receptor (RyR) Ca2+ release channels on the sarcoplasmic reticulum (SR) membrane. Proper assessment of muscle Ca2+ sparks could provide information on the intracellular Ca2+ handling properties of healthy and diseased striated muscles. Although Ca2+ sparks events are commonly seen in resting cardiomyocytes, they are rarely observed in resting skeletal muscle fibers; thus there is a need for methods to generate and analyze sparks in skeletal muscle fibers. Detailed here is an experimental protocol for measuring Ca2+ sparks in isolated flexor digitorm brevis (FDB) muscle fibers using fluorescent Ca2+ indictors and laser scanning confocal microscopy. In this approach, isolated FDB fibers are exposed to transient hypoosmotic stress followed by a return to isotonic physiological solution. Under these conditions, a robust Ca2+ sparks response is detected adjacent to the sarcolemmal membrane in young healthy FDB muscle fibers. Altered Ca2+ sparks response is detected in dystrophic or aged skeletal muscle fibers. This approach has recently demonstrated that membrane-delimited signaling involving cross-talk between inositol (1,4,5)-triphosphate receptor (IP3R) and RyR contributes to Ca2+ spark activation in skeletal muscle. In summary, our studies using osmotic stress induced Ca2+ sparks showed that this intracellular response reflects a muscle signaling mechanism in physiology and aging/disease states, including mouse models of muscle dystrophy (mdx mice) or amyotrophic lateral sclerosis (ALS model). PMID:24638093

  9. Growth Factors and Tension-Induced Skeletal Muscle Growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.

    1994-01-01

    The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we have performed experiments to determine whether mechanical stimulation of cultured avian muscle cells alters their response to anabolic steroids or glucocorticoids. In static cultures, testosterone had no effect on muscle cell growth, but 5alpha-dihydrotestosterone and the synthetic steroid stanozolol increased cell growth by up to 18% and 30%, respectively, after a three day exposure. We completed development of a new IBM-based mechanical cell stimulator system to provide greater flexibility in operating and monitoring our experiments. Our previous long term studies on myofiber growth were designed around a perfusion system of our own design. We have recently changed to performing these studies using a modified CELLCO cartridge bioreactor system Z since it has been certified as the ground-based model for the Shuttle's Space Tissue Loss (STL) F= Cell Culture Module. The current goals of this aspect of the project are three fold: 1) to design a Z cell culture system for studying avian skeletal myofiber atrophy on the Shuttle and Space Station; 0 2) to expand the use of bioreactors to cells which do not grow in either suspension or attached to the hollow fibers; and 3) to combine the bioreactor system with our computerized mechanical cell stimulator to have a better in vitro model to study tension/gravity/stretch regulation of skeletal muscle size. Preliminary studies also reported on involved : (1) how release of tension can induce rapid atrophy of tissues cultured avian skeletal muscle cells, and (2) a mechanism to transfer and maintain avian skeletal muscle organoids in modified cartridges in the Space Tissue Loss Module.

  10. Skeletal muscle as a regulator of the longevity protein, Klotho.

    PubMed

    Avin, Keith G; Coen, Paul M; Huang, Wan; Stolz, Donna B; Sowa, Gwendolyn A; Dubé, John J; Goodpaster, Bret H; O'Doherty, Robert M; Ambrosio, Fabrisia

    2014-01-01

    Klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Similar anti-aging effects have also been ascribed to exercise and physical activity. While an association between muscle function and Klotho expression has been previously suggested from longitudinal cohort studies, a direct relationship between circulating Klotho and skeletal muscle has not been investigated. In this paper, we present a review of the literature and preliminary evidence that, together, suggests Klotho expression may be modulated by skeletal muscle activity. Our pilot clinical findings performed in young and aged individuals suggest that circulating Klotho levels are upregulated in response to an acute exercise bout, but that the response may be dependent on fitness level. A similar upregulation of circulating Klotho is also observed in response to an acute exercise in young and old mice, suggesting that this may be a good model for mechanistically probing the role of physical activity on Klotho expression. Finally, we highlight overlapping signaling pathways that are modulated by both Klotho and skeletal muscle and propose potential mechanisms for cross-talk between the two. It is hoped that this review will stimulate further consideration of the relationship between skeletal muscle activity and Klotho expression, potentially leading to important insights into the well-documented systemic anti-aging effects of exercise. PMID:24987372

  11. Skeletal muscle as a regulator of the longevity protein, Klotho

    PubMed Central

    Avin, Keith G.; Coen, Paul M.; Huang, Wan; Stolz, Donna B.; Sowa, Gwendolyn A.; Dubé, John J.; Goodpaster, Bret H.; O'Doherty, Robert M.; Ambrosio, Fabrisia

    2014-01-01

    Klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Similar anti-aging effects have also been ascribed to exercise and physical activity. While an association between muscle function and Klotho expression has been previously suggested from longitudinal cohort studies, a direct relationship between circulating Klotho and skeletal muscle has not been investigated. In this paper, we present a review of the literature and preliminary evidence that, together, suggests Klotho expression may be modulated by skeletal muscle activity. Our pilot clinical findings performed in young and aged individuals suggest that circulating Klotho levels are upregulated in response to an acute exercise bout, but that the response may be dependent on fitness level. A similar upregulation of circulating Klotho is also observed in response to an acute exercise in young and old mice, suggesting that this may be a good model for mechanistically probing the role of physical activity on Klotho expression. Finally, we highlight overlapping signaling pathways that are modulated by both Klotho and skeletal muscle and propose potential mechanisms for cross-talk between the two. It is hoped that this review will stimulate further consideration of the relationship between skeletal muscle activity and Klotho expression, potentially leading to important insights into the well-documented systemic anti-aging effects of exercise. PMID:24987372

  12. Kelch proteins: emerging roles in skeletal muscle development and diseases

    PubMed Central

    2014-01-01

    Our understanding of genes that cause skeletal muscle disease has increased tremendously over the past three decades. Advances in approaches to genetics and genomics have aided in the identification of new pathogenic mechanisms in rare genetic disorders and have opened up new avenues for therapeutic interventions by identification of new molecular pathways in muscle disease. Recent studies have identified mutations of several Kelch proteins in skeletal muscle disorders. The Kelch superfamily is one of the largest evolutionary conserved gene families. The 66 known family members all possess a Kelch-repeat containing domain and are implicated in diverse biological functions. In skeletal muscle development, several Kelch family members regulate the processes of proliferation and/or differentiation resulting in normal functioning of mature muscles. Importantly, many Kelch proteins function as substrate-specific adaptors for Cullin E3 ubiquitin ligase (Cul3), a core component of the ubiquitin-proteasome system to regulate the protein turnover. This review discusses the emerging roles of Kelch proteins in skeletal muscle function and disease. PMID:24959344

  13. Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have previously reported that the expression of mitochondrial deacetylase SIRT3 is high in the slow oxidative muscle and that the expression of muscle SIRT3 level is increased by dietary restriction or exercise training. To explore the function of SIRT3 in skeletal muscle, we report here the esta...

  14. Changes in skeletal muscle gene expression following clenbuterol administration

    PubMed Central

    Spurlock, Diane M; McDaneld, Tara G; McIntyre, Lauren M

    2006-01-01

    Background Beta-adrenergic receptor agonists (BA) induce skeletal muscle hypertrophy, yet specific mechanisms that lead to this effect are not well understood. The objective of this research was to identify novel genes and physiological pathways that potentially facilitate BA induced skeletal muscle growth. The Affymetrix platform was utilized to identify gene expression changes in mouse skeletal muscle 24 hours and 10 days after administration of the BA clenbuterol. Results Administration of clenbuterol stimulated anabolic activity, as indicated by decreased blood urea nitrogen (BUN; P < 0.01) and increased body weight gain (P < 0.05) 24 hours or 10 days, respectively, after initiation of clenbuterol treatment. A total of 22,605 probesets were evaluated with 52 probesets defined as differentially expressed based on a false discovery rate of 10%. Differential mRNA abundance of four of these genes was validated in an independent experiment by quantitative PCR. Functional characterization of differentially expressed genes revealed several categories that participate in biological processes important to skeletal muscle growth, including regulators of transcription and translation, mediators of cell-signalling pathways, and genes involved in polyamine metabolism. Conclusion Global evaluation of gene expression after administration of clenbuterol identified changes in gene expression and overrepresented functional categories of genes that may regulate BA-induced muscle hypertrophy. Changes in mRNA abundance of multiple genes associated with myogenic differentiation may indicate an important effect of BA on proliferation, differentiation, and/or recruitment of satellite cells into muscle fibers to promote muscle hypertrophy. Increased mRNA abundance of genes involved in the initiation of translation suggests that increased levels of protein synthesis often associated with BA administration may result from a general up-regulation of translational initiators. Additionally, numerous other genes and physiological pathways were identified that will be important targets for further investigations of the hypertrophic effect of BA on skeletal muscle. PMID:17181869

  15. Skeletal Muscle Cell Behavior After Physical Agent Treatments.

    PubMed

    Battistelli, Michela; Salucci, Sara; Guescini, Michele; Curzi, Davide; Stocchi, Vilberto; Falcieri, Elisabetta

    2015-01-01

    Apoptosis is essential for skeletal muscle development and homeostasis. It has been frequently involved in several muscle myopathies and sarcopenia, as well as in denervation, in disuse and acute strenuous or eccentric physical exercise. In this work skeletal muscle cell death, induced in vitro by a variety of physical triggers, has been investigated. C2C12 myoblasts and myotubes were exposed to UVB for 30 min, hyperthermia for 1 h at 43 °C, low pH for 3 h, hypothermia for 4h at 0 - 6°C, all followed by 2 - 4 h recovery. Their effects have been analysed by means of morpho- functional and molecular approaches. After UVB radiation, hyperthermia and acidosis, morphological apoptotic features and in situ DNA fragmentation appeared, more evident in myoblasts. Interestingly, apoptotic, non apoptotic and necrotic nuclei could be occasionally observed within the same myotube. Low pH induced apoptosis and necrosis, both characterized by swollen nuclei. In all these experimental conditions, the molecular investigations revealed a caspase pathway involvement in inducing cell death. Differently, hypothermia showed a scant and initial chromatin margination, in the presence of a diffused autophagic component. In this case, in situ DNA fragmentation and caspase activation have not been detected. Myoblasts and myotubes appeared sensitive to physical agents, some of which, induced apoptotic cell death. Moreover, hypothermia exposure seemed to enhance autophagic response, thus representing a way to delay trauma-correlated muscle inflammation. This study permits to highlight skeletal muscle cell behavior in response to physical agents, by adding important information to muscle cell death knowledge. UVB radiation and hyperthermia, usually used in clinical therapy, have also adverse effects on skeletal muscle such as myonuclei loss and cell death, contributing to muscle mass decrease. Acidosis occurs physiologically in muscular fatigue, reducing not only the athlete performance, but causing muscle cell damage or death too. Finally, hypothermia, stimulating the autophagic response, could have a key role in muscle injury prevention. PMID:25613787

  16. Growth factor involvement in tension-induced skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.

    1993-01-01

    Long-term manned space travel will require a better understanding of skeletal muscle atrophy which results from microgravity. Astronaut strength and dexterity must be maintained for normal mission operations and for emergency situations. Although exercise in space slows the rate of muscle loss, it does not prevent it. A biochemical understanding of how gravity/tension/exercise help to maintain muscle size by altering protein synthesis and/or degradation rate should ultimately allow pharmacological intervention to prevent muscle atrophy in microgravity. The overall objective is to examine some of the basic biochemical processes involved in tension-induced muscle growth. With an experimental in vitro system, the role of exogenous and endogenous muscle growth factors in mechanically stimulated muscle growth are examined. Differentiated avian skeletal myofibers can be 'exercised' in tissue culture using a newly developed dynamic mechanical cell stimulator device which simulates different muscle activity patterns. Patterns of mechanical activity which significantly affect muscle growth and metabolic characteristics were found. Both exogenous and endogenous growth factors are essential for tension-induced muscle growth. Exogenous growth factors found in serum, such as insulin, insulin-like growth factors, and steroids, are important regulators of muscle protein turnover rates and mechanically-induced muscle growth. Endogenous growth factors are synthesized and released into the culture medium when muscle cells are mechanically stimulated. At least one family of mechanically induced endogenous factors, the prostaglandins, help to regulate the rates of protein turnover in muscle cells. Endogenously synthesized IGF-1 is another. The interaction of muscle mechanical activity and these growth factors in the regulation of muscle protein turnover rates with our in vitro model system is studied.

  17. Exercise-Induced Skeletal Muscle Damage.

    ERIC Educational Resources Information Center

    Evans, William J.

    1987-01-01

    Eccentric exercise, in which the muscles exert force by lengthening, is associated with delayed onset muscle soreness. How soreness occurs, how recovery proceeds, and what precautions athletes should take are described. (Author/MT)

  18. Establishment of bipotent progenitor cell clone from rat skeletal muscle.

    PubMed

    Murakami, Yousuke; Yada, Erica; Nakano, Shin-ichi; Miyagoe-Suzuki, Yuko; Hosoyama, Tohru; Matsuwaki, Takashi; Yamanouchi, Keitaro; Nishihara, Masugi

    2011-12-01

    The present study describes the isolation, cloning and characterization of adipogenic progenitor cells from rat skeletal muscle. Among the obtained 10 clones, the most highly adipogenic progenitor, 2G11 cells, were further characterized. In addition to their adipogenicity, 2G11 cells retain myogenic potential as revealed by formation of multinucleated myotubes when co-cultured with myoblasts. 2G11 cells were resistant to an inhibitory effect of basic fibroblast growth factor on adipogenesis, while adipogenesis of widely used preadipogenic cell line, 3T3-L1 cells, was suppressed almost completely by the same treatment. In vivo transplantation experiments revealed that 2G11 cells are able to possess both adipogenicity and myogenicity in vivo. These results indicate the presence of bipotent progenitor cells in rat skeletal muscle, and suggest that such cells may contribute to ectopic fat formation in skeletal muscle. PMID:22111633

  19. Bone and skeletal muscle: neighbors with close ties.

    PubMed

    DiGirolamo, Douglas J; Kiel, Douglas P; Esser, Karyn A

    2013-07-01

    The musculoskeletal system evolved in mammals to perform diverse functions that include locomotion, facilitating breathing, protecting internal organs, and coordinating global energy expenditure. Bone and skeletal muscles involved with locomotion are both derived from somitic mesoderm and accumulate peak tissue mass synchronously, according to genetic information and environmental stimuli. Aging results in the progressive and parallel loss of bone (osteopenia) and skeletal muscle (sarcopenia) with profound consequences for quality of life. Age-associated sarcopenia results in reduced endurance, poor balance, and reduced mobility that predispose elderly individuals to falls, which more frequently result in fracture because of concomitant osteoporosis. Thus, a better understanding of the mechanisms underlying the parallel development and involution of these tissues is critical to developing new and more effective means to combat osteoporosis and sarcopenia in our increasingly aged population. This perspective highlights recent advances in our understanding of mechanisms coupling bone and skeletal muscle mass, and identify critical areas where further work is needed. PMID:23630111

  20. Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy*

    PubMed Central

    Ebert, Scott M.; Dyle, Michael C.; Kunkel, Steven D.; Bullard, Steven A.; Bongers, Kale S.; Fox, Daniel K.; Dierdorff, Jason M.; Foster, Eric D.; Adams, Christopher M.

    2012-01-01

    Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy. PMID:22692209

  1. A comparative histochemical and morphometric study of canine skeletal muscle.

    PubMed Central

    Kuzon, W M; Rosenblatt, J D; Pynn, B R; Marchetti, P J; Plyley, M J; McKee, N H

    1989-01-01

    The purpose of this study was to determine whether there were differences in skeletal muscle properties in the hindlimb muscles of different types of dogs. Muscle samples were obtained from the gracilis, sartorius cranial head, sartorius caudal head and tibialis anterior muscles of mixed-breed and hound-type dogs and Beagles. Fiber type, fiber size and capillary morphometry determinations of each muscle from each dog were made from sections stained for myofibrillar ATPase activity. Individual animals were bilaterally symmetric for all measured variables. Fiber type, fiber size and capillary geometry varied between dogs of a given type and muscles within a given dog. There were no differences between dog types for fiber type or fiber size; significant variation in log(muscle)/log(body) mass ratios between dog types was observed for all muscles. The results indicate that for a given muscle, significant variation can occur in skeletal muscle characteristics between different types of dogs and that these differences can be independent of differences in exercise history. Images Fig. 1. PMID:2523755

  2. Functional heterogeneity of side population cells in skeletal muscle

    SciTech Connect

    Uezumi, Akiyoshi; Ojima, Koichi; Fukada, So-ichiro; Ikemoto, Madoka; Masuda, Satoru; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi . E-mail: takeda@ncnp.go.jp

    2006-03-17

    Skeletal muscle regeneration has been exclusively attributed to myogenic precursors, satellite cells. A stem cell-rich fraction referred to as side population (SP) cells also resides in skeletal muscle, but its roles in muscle regeneration remain unclear. We found that muscle SP cells could be subdivided into three sub-fractions using CD31 and CD45 markers. The majority of SP cells in normal non-regenerating muscle expressed CD31 and had endothelial characteristics. However, CD31{sup -}CD45{sup -} SP cells, which are a minor subpopulation in normal muscle, actively proliferated upon muscle injury and expressed not only several regulatory genes for muscle regeneration but also some mesenchymal lineage markers. CD31{sup -}CD45{sup -} SP cells showed the greatest myogenic potential among three SP sub-fractions, but indeed revealed mesenchymal potentials in vitro. These SP cells preferentially differentiated into myofibers after intramuscular transplantation in vivo. Our results revealed the heterogeneity of muscle SP cells and suggest that CD31{sup -}CD45{sup -} SP cells participate in muscle regeneration.

  3. Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways.

    PubMed

    Rodriguez, J; Vernus, B; Chelh, I; Cassar-Malek, I; Gabillard, J C; Hadj Sassi, A; Seiliez, I; Picard, B; Bonnieu, A

    2014-11-01

    Myostatin, a member of the transforming growth factor-β superfamily, is a potent negative regulator of skeletal muscle growth and is conserved in many species, from rodents to humans. Myostatin inactivation can induce skeletal muscle hypertrophy, while its overexpression or systemic administration causes muscle atrophy. As it represents a potential target for stimulating muscle growth and/or preventing muscle wasting, myostatin regulation and functions in the control of muscle mass have been extensively studied. A wealth of data strongly suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression. Moreover, myostatin plays a central role in integrating/mediating anabolic and catabolic responses. Myostatin negatively regulates the activity of the Akt pathway, which promotes protein synthesis, and increases the activity of the ubiquitin-proteasome system to induce atrophy. Several new studies have brought new information on how myostatin may affect both ribosomal biogenesis and translation efficiency of specific mRNA subclasses. In addition, although myostatin has been identified as a modulator of the major catabolic pathways, including the ubiquitin-proteasome and the autophagy-lysosome systems, the underlying mechanisms are only partially understood. The goal of this review is to highlight outstanding questions about myostatin-mediated regulation of the anabolic and catabolic signaling pathways in skeletal muscle. Particular emphasis has been placed on (1) the cross-regulation between myostatin, the growth-promoting pathways and the proteolytic systems; (2) how myostatin inhibition leads to muscle hypertrophy; and (3) the regulation of translation by myostatin. PMID:25080109

  4. Therapeutic Approaches to Skeletal Muscle Repair and Healing

    PubMed Central

    Danna, Natalie R.; Beutel, Bryan G.; Campbell, Kirk A.; Bosco, Joseph A.

    2014-01-01

    Context: Skeletal muscle is comprised of a highly organized network of cells, neurovascular structures, and connective tissue. Muscle injury is typically followed by a well-orchestrated healing response that consists of the following phases: inflammation, regeneration, and fibrosis. This review presents the mechanisms of action and evidence supporting the effectiveness of various traditional and novel therapies at each phase of the skeletal muscle healing process. Evidence Acquisition: Relevant published articles were identified using MEDLINE (1978-2013). Study Design: Clinical review. Level of Evidence: Level 3. Results: To facilitate muscle healing, surgical techniques involving direct suture repair, as well as the implantation of innovative biologic scaffolds, have been developed. Nonsteroidal anti-inflammatory drugs may be potentially supplanted by nitric oxide and curcumin in modulating the inflammatory pathway. Studies in muscle regeneration have identified stem cells, myogenic factors, and β-agonists capable of enhancing the regenerative capabilities of injured tissue. Furthermore, transforming growth factor-β1 (TGF-β1) and, more recently, myostatin and the rennin-angiotensin system have been implicated in fibrous tissue formation; several antifibrotic agents have demonstrated the ability to disrupt these systems. Conclusion: Effective repair of skeletal muscle after severe injury is unlikely to be achieved with a single intervention. For full functional recovery of muscle there is a need to control inflammation, stimulate regeneration, and limit fibrosis. Strength-of-Recommendation Taxonomy (SORT): B PMID:24982709

  5. Maternal nutrient restriction affects properties of skeletal muscle in offspring

    PubMed Central

    Zhu, Mei J; Ford, Stephen P; Means, Warrie J; Hess, Bret W; Nathanielsz, Peter W; Du, Min

    2006-01-01

    Maternal nutrient restriction (NR) affects fetal development with long-term consequences on postnatal health of offspring, including predisposition to obesity and diabetes. Most studies have been conducted in fetuses in late gestation, and little information is available on the persistent impact of NR from early to mid-gestation on properties of offspring skeletal muscle, which was the aim of this study. Pregnant ewes were subjected to 50% NR from day 28–78 of gestation and allowed to deliver. The longissimus dorsi muscle was sampled from 8-month-old offspring. Maternal NR during early to mid-gestation decreased the number of myofibres in the offspring and increased the ratio of myosin IIb to other isoforms by 17.6 ± 4.9% (P < 0.05) compared with offspring of ad libitum fed ewes. Activity of carnitine palmitoyltransferase-1, a key enzyme controlling fatty acid oxidation, was reduced by 24.7 ± 4.5% (P < 0.05) in skeletal muscle of offspring of NR ewes and would contribute to increased fat accumulation observed in offspring of NR ewes. Intramuscular triglyceride content (IMTG) was increased in skeletal muscle of NR lambs, a finding which may be linked to predisposition to diabetes in offspring of NR mothers, since enhanced IMTG predisposes to insulin resistance in skeletal muscle. Proteomic analysis by two-dimensional gel electrophoresis demonstrated downregulation of several catabolic enzymes in 8-month-old offspring of NR ewes. These data demonstrate that the early to mid-gestation period is important for skeletal muscle development. Impaired muscle development during this stage of gestation affects the number and composition of fibres in offspring which may lead to long-term physiological consequences, including predisposition to obesity and diabetes. PMID:16763001

  6. Road to Exercise Mimetics: Targeting Nuclear Receptors in Skeletal Muscle

    PubMed Central

    Fan, Weiwei; Atkins, Annette R; Yu, Ruth T.; Downes, Michael; Evans, Ronald M.

    2014-01-01

    Skeletal muscle comprises the largest organ in the human body and is the major site for energy expenditure. It exhibits remarkable plasticity in response to physiological stimuli such as exercise. Physical exercise remodels skeletal muscle and enhances its capability to burn calories, which has been shown to be beneficial for many clinical conditions including metabolic syndrome and cancer. Nuclear receptors (NRs) comprise a class of transcription factors found only in metazoans that regulate major biological processes such as reproduction, development, and metabolism. Recent studies have demonstrated crucial roles for NRs and their co-regulators in regulating skeletal muscle energy metabolism and exercise-induced muscle remodeling. While nothing can fully replace exercise, development of exercise mimetics that enhance or even substitute for the beneficial effects of physical exercise would be of great benefit. The unique property of NRs that allows modulation by endogenous or synthetic ligands makes them bona fide therapeutic targets. In this review, we present an overview of the current understanding of NRs and their co-regulators in skeletal muscle oxidative metabolism and summarize recent progress in the development of exercise mimetics that target NRs and their co-regulators. PMID:24280961

  7. Functional classification of skeletal muscle networks. II. Applications to pathophysiology

    PubMed Central

    Wang, Yu; Winters, Jack

    2012-01-01

    In our preceding companion paper (Wang Y, Winters J, Subramaniam S. J Appl Physiol. doi: 10.1152/japplphysiol.01514.2011), we used extensive expression profile data on normal human subjects, in combination with legacy knowledge to classify skeletal muscle function into four models, namely excitation-activation, mechanical, metabolic, and signaling-production model families. In this paper, we demonstrate how this classification can be applied to study two well-characterized myopathies: amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Using skeletal muscle profile data from ALS and DMD patients compared with that from normal subjects, normal young in the case of DMD, we delineate molecular mechanisms that are causative and consequential to skeletal muscle dysfunction. In ALS, our analysis establishes the metabolic role and specifically identifies the mechanisms of calcium dysregulation and defects in mitochondrial transport of materials as important for muscle dysfunction. In DMD, we illustrate how impaired mechanical function is strongly coordinated with other three functional networks, resulting in transformation of the skeletal muscle into hybrid forms as a compensatory mechanism. Our functional models also provide, in exquisite detail, the mechanistic role of myriad proteins in these four families in normal and disease function. PMID:23085957

  8. Prospective heterotopic ossification progenitors in adult human skeletal muscle.

    PubMed

    Downey, Jennifer; Lauzier, Dominique; Kloen, Peter; Klarskov, Klaus; Richter, Martin; Hamdy, Reggie; Faucheux, Nathalie; Scimè, Anthony; Balg, Frédéric; Grenier, Guillaume

    2015-02-01

    Skeletal muscle has strong regenerative capabilities. However, failed regeneration can lead to complications where aberrant tissue forms as is the case with heterotopic ossification (HO), in which chondrocytes, osteoblasts and white and brown adipocytes can arise following severe trauma. In humans, the various HO cell types likely originate from multipotent mesenchymal stromal cells (MSCs) in skeletal muscle, which have not been identified in humans until now. In the present study, adherent cells from freshly digested skeletal muscle tissue were expanded in defined culture medium and were FACS-enriched for the CD73(+)CD105(+)CD90(-) population, which displayed robust multilineage potential. Clonal differentiation assays confirmed that all three lineages originated from a single multipotent progenitor. In addition to differentiating into typical HO lineages, human muscle resident MSCs (hmrMSCs) also differentiated into brown adipocytes expressing uncoupling protein 1 (UCP1). Characterizing this novel multipotent hmrMSC population with a brown adipocyte differentiation capacity has enhanced our understanding of the contribution of non-myogenic progenitor cells to regeneration and aberrant tissue formation in human skeletal muscle. PMID:25445454

  9. Diffusion-Tensor MRI Based Skeletal Muscle Fiber Tracking

    PubMed Central

    Damon, Bruce M.; Buck, Amanda K. W.; Ding, Zhaohua

    2014-01-01

    A skeletal muscle's function is strongly influenced by the internal organization and geometric properties of its fibers, a property known as muscle architecture. Diffusion-tensor magnetic resonance imaging-based fiber tracking provides a powerful tool for non-invasive muscle architecture studies, has three-dimensional sensitivity, and uses a fixed frame of reference. Significant advances have been made in muscle fiber tracking technology, including defining seed points for fiber tracking, quantitatively characterizing muscle architecture, implementing denoising procedures, and testing validity and repeatability. Some examples exist of how these data can be integrated with those from other advanced MRI and computational methods to provide novel insights into muscle function. Perspectives are offered regarding future directions in muscle diffusion-tensor imaging, including needs to develop an improved understanding for the microstructural basis for reduced and anisotropic diffusion, establish the best practices for data acquisition and analysis, and integrate fiber tracking with other physiological data. PMID:25429308

  10. Human skeletal muscle responses to spaceflight and possible countermeasures

    NASA Technical Reports Server (NTRS)

    Gollnick, Philip D.; Edgerton, V. Reggie; Saltin, Bengt

    1990-01-01

    The current status of knowledge concerning the effects of unweighting skeletal muscle is summarized. The results of both ground-based and space-based animal studies are reviewed which show that there is rapid loss in muscle mass, primarily in slow-twitch muscle, of the rat during unweighting of muscle. There is also a shift in the myosin isoforms with muscles such that slow-twitch muscles take on many of the characteristics of fast-twitch muscles. Ground-based studies in human suggest that programs of electrical stimulation can be developed to simulate normal muscular contractions. Attempts to develop countermeasures to the adverse effects of space travel on muscular functions in humans have not been successful to date.

  11. Systems-based Discovery of Tomatidine as a Natural Small Molecule Inhibitor of Skeletal Muscle Atrophy*

    PubMed Central

    Dyle, Michael C.; Ebert, Scott M.; Cook, Daniel P.; Kunkel, Steven D.; Fox, Daniel K.; Bongers, Kale S.; Bullard, Steven A.; Dierdorff, Jason M.; Adams, Christopher M.

    2014-01-01

    Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy. PMID:24719321

  12. Protein synthesis in skeletal muscle of neonatal pigs is enhanced by administration of beta-hydroxy-beta-methylbutyrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many low-birth-weight infants experience failure to thrive. The amino acid leucine stimulates protein synthesis in skeletal muscle of the neonate, but less is known about the effects of the leucine metabolite ß-hydroxy-ß-methylbutyrate (HMB). To determine the effects of HMB on protein synthesis and ...

  13. Protein synthesis in skeletal muscle of neonatal pigs is enhanced by administration of Beta-hydroxy-Beta-methylbutyrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many low-birth-weight infants experience failure to thrive. The amino acid leucine stimulates protein synthesis in skeletal muscle of the neonate, but less is known about the effects of the leucine metabolite Beta-hydroxy-Beta-methylbutyrate (HMB). To determine the effects of HMB on protein synthesi...

  14. Skeletal muscle molecular alterations precede whole-muscle dysfunction in NYHA Class II heart failure patients

    PubMed Central

    Godard, Michael P; Whitman, Samantha A; Song, Yao-Hua; Delafontaine, Patrice

    2012-01-01

    Background Heart failure (HF), a debilitating disease in a growing number of adults, exerts structural and neurohormonal changes in both cardiac and skeletal muscles. However, these alterations and their affected molecular pathways remain uncharacterized. Disease progression is known to transform skeletal muscle fiber composition by unknown mechanisms. In addition, perturbation of specific hormonal pathways, including those involving skeletal muscle insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-5 (IGFB-5) appears to occur, likely affecting muscle metabolism and regeneration. We hypothesized that changes in IGF-1 and IGFB-5 mRNA levels correlate with the transformation of single–skeletal muscle fiber myosin heavy chain isoforms early in disease progression, making these molecules valuable markers of skeletal muscle changes in heart failure. Materials and methods To investigate these molecules during “early” events in HF patients, we obtained skeletal muscle biopsies from New York Heart Association (NYHA) Class II HF patients and controls for molecular analyses of single fibers, and we also quantified isometric strength and muscle size. Results There were more (P < 0.05) single muscle fibers coexpressing two or more myosin heavy chains in the HF patients (30% ± 7%) compared to the control subjects (13% ± 2%). IGF-1 and IGFBP-5 expression was fivefold and 15-fold lower in patients with in HF compared to control subjects (P < 0.05), respectively. Strikingly, there was a correlation in IGF-1 expression and muscle cross-sectional area (P < 0.05) resulting in a decrease in whole-muscle quality (P < 0.05) in the HF patients, despite no significant decrease in isometric strength or whole-muscle size. Conclusion These data indicate that molecular alterations in myosin heavy chain isoforms, IGF-1, and IGFB-5 levels precede the gross morphological and functional deficits that have previously been associated with HF, and may be used as a predictor of functional outcome in patients. PMID:23204842

  15. Glucocorticoid-induced skeletal muscle atrophy.

    PubMed

    Schakman, O; Kalista, S; Barbé, C; Loumaye, A; Thissen, J P

    2013-10-01

    Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23806868

  16. Parvalbumin gene transfer impairs skeletal muscle contractility in old mice.

    PubMed

    Murphy, Kate T; Ham, Daniel J; Church, Jarrod E; Naim, Timur; Trieu, Jennifer; Williams, David A; Lynch, Gordon S

    2012-08-01

    Sarcopenia is the progressive age-related loss of skeletal muscle mass associated with functional impairments that reduce mobility and quality of life. Overt muscle wasting with sarcopenia is usually preceded by a slowing of the rate of relaxation and a reduction in maximum force production. Parvalbumin (PV) is a cytosolic Ca(2+) buffer thought to facilitate relaxation in muscle. We tested the hypothesis that restoration of PV levels in muscles of old mice would increase the magnitude and hasten relaxation of submaximal and maximal force responses. The tibialis anterior (TA) muscles of young (6 month), adult (13 month), and old (26 month) C57BL/6 mice received electroporation-assisted gene transfer of plasmid encoding PV or empty plasmid (pcDNA3.1). Contractile properties of TA muscles were assessed in situ 14 days after transfer. In old mice, muscles with increased PV expression had a 40% slower rate of tetanic force development (p<0.01), and maximum twitch and tetanic force were 22% and 16% lower than control values, respectively (p<0.05). Muscles with increased PV expression from old mice had an 18% lower maximum specific (normalized) force than controls, and absolute force was `26% lower at higher stimulation frequencies (150-300 Hz, p<0.05). In contrast, there was no effect of increased PV expression on TA muscle contractile properties in young and adult mice. The impairments in skeletal muscle function in old mice argue against PV overexpression as a therapeutic strategy for ameliorating aspects of contractile dysfunction with sarcopenia and help clarify directions for therapeutic interventions for age-related changes in skeletal muscle structure and function. PMID:22455364

  17. The Skeletal Muscle Anabolic Response to Plant- versus Animal-Based Protein Consumption.

    PubMed

    van Vliet, Stephan; Burd, Nicholas A; van Loon, Luc J C

    2015-09-01

    Clinical and consumer market interest is increasingly directed toward the use of plant-based proteins as dietary components aimed at preserving or increasing skeletal muscle mass. However, recent evidence suggests that the ingestion of the plant-based proteins in soy and wheat results in a lower muscle protein synthetic response when compared with several animal-based proteins. The possible lower anabolic properties of plant-based protein sources may be attributed to the lower digestibility of plant-based sources, in addition to greater splanchnic extraction and subsequent urea synthesis of plant protein-derived amino acids compared with animal-based proteins. The latter may be related to the relative lack of specific essential amino acids in plant- as opposed to animal-based proteins. Furthermore, most plant proteins have a relatively low leucine content, which may further reduce their anabolic properties when compared with animal proteins. However, few studies have actually assessed the postprandial muscle protein synthetic response to the ingestion of plant proteins, with soy and wheat protein being the primary sources studied. Despite the proposed lower anabolic properties of plant vs. animal proteins, various strategies may be applied to augment the anabolic properties of plant proteins. These may include the following: 1) fortification of plant-based protein sources with the amino acids methionine, lysine, and/or leucine; 2) selective breeding of plant sources to improve amino acid profiles; 3) consumption of greater amounts of plant-based protein sources; or 4) ingesting multiple protein sources to provide a more balanced amino acid profile. However, the efficacy of such dietary strategies on postprandial muscle protein synthesis remains to be studied. Future research comparing the anabolic properties of a variety of plant-based proteins should define the preferred protein sources to be used in nutritional interventions to support skeletal muscle mass gain or maintenance in both healthy and clinical populations. PMID:26224750

  18. Mathematically modeling the effects of electrically stimulating skeletal muscle.

    PubMed

    Davidson, J B; Kim, J; Cheng, L K; Röhrle, O; Shorten, P R; Soboleva, T K; Clarke, R D; Pullan, A J

    2006-01-01

    A framework for modeling the activation of skeletal muscle is presented for studying functional electrical stimulation. A mathematical model of the cellular responses of skeletal muscle, created at AgResearch (Ruakura, New Zealand www.agresearch.co.nz), has been integrated with an anatomical, finite element model of the semitendinosus muscle, which was constructed from CT scans of the hind limb of a sheep. The tibial nerve was also constructed from digitized CT scans, and has been modeled using the Hodgkin Huxley neural model. The relevant cellular equations have been solved over these geometries. The results obtained, i.e speed of action potential propagation through the nerve and muscle, and the duration of twitch force, agree with published values. PMID:17946255

  19. Transcriptional regulation of decreased protein synthesis during skeletal muscle unloading

    NASA Technical Reports Server (NTRS)

    Howard, G.; Steffen, J. M.; Geoghegan, T. E.

    1989-01-01

    The regulatory role of transcriptional alterations in unloaded skeletal muscles was investigated by determining levels of total muscle RNA and mRNA fractions in soleus, gastrocnemius, and extensor digitorum longus (EDL) of rats subjected to whole-body suspension for up to 7 days. After 7 days, total RNA and mRNA contents were lower in soleus and gastrocnemius, compared with controls, but the concentrations of both RNAs per g muscle were unaltered. Alpha-actin mRNA (assessed by dot hybridization) was significantly reduced in soleus after 1, 3, and 7 days of suspension and in gastrocnemius after 3 and 7 days, but was unchanged in EDL. Protein synthesis directed by RNA extracted from soleus and EDL indicated marked alteration in mRNAs coding for several small proteins. Results suggest that altered transcription and availability of specific mRNAs contribute significantly to the regulation of protein synthesis during skeletal muscle unloading.

  20. The antioxidant requirement for plasma membrane repair in skeletal muscle.

    PubMed

    Labazi, Mohamed; McNeil, Anna K; Kurtz, Timothy; Lee, Taylor C; Pegg, Ronald B; Angeli, José Pedro Friedmann; Conrad, Marcus; McNeil, Paul L

    2015-07-01

    Vitamin E (VE) deficiency results in pronounced muscle weakness and atrophy but the cell biological mechanism of the pathology is unknown. We previously showed that VE supplementation promotes membrane repair in cultured cells and that oxidants potently inhibit repair. Here we provide three independent lines of evidence that VE is required for skeletal muscle myocyte plasma membrane repair in vivo. We also show that when another lipid-directed antioxidant, glutathione peroxidase 4 (Gpx4), is genetically deleted in mouse embryonic fibroblasts, repair fails catastrophically, unless cells are supplemented with VE. We conclude that lipid-directed antioxidant activity provided by VE, and possibly also Gpx4, is an essential component of the membrane repair mechanism in skeletal muscle. This work explains why VE is essential to muscle health and identifies VE as a requisite component of the plasma membrane repair mechanism in vivo. PMID:25843658

  1. Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.

    PubMed

    Li, Lei O; Grevengoed, Trisha J; Paul, David S; Ilkayeva, Olga; Koves, Timothy R; Pascual, Florencia; Newgard, Christopher B; Muoio, Deborah M; Coleman, Rosalind A

    2015-01-01

    The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-specific deficiency of long-chain acyl-CoA synthetase (ACSL)1. ACSL1 deficiency caused a 91% loss of ACSL-specific activity and a 60-85% decrease in muscle FA oxidation. Acsl1(M-/-) mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1(M-/-) mice ran only 48% as far as controls. At the time that Acsl1(M-/-) mice were exhausted but control mice continued to run, liver and muscle glycogen and triacylglycerol stores were similar in both genotypes; however, plasma glucose concentrations in Acsl1(M-/-) mice were ∼40 mg/dL, whereas glucose concentrations in controls were ∼90 mg/dL. Excess use of glucose and the likely use of amino acids for fuel within muscle depleted glucose reserves and diminished substrate availability for hepatic gluconeogenesis. Surprisingly, the content of muscle acyl-CoA at exhaustion was markedly elevated, indicating that acyl-CoAs synthesized by other ACSL isoforms were not available for β-oxidation. This compartmentalization of acyl-CoAs resulted in both an excessive glucose requirement and severely compromised systemic glucose homeostasis. PMID:25071025

  2. Leucine supplementation improves regeneration of skeletal muscles from old rats.

    PubMed

    Pereira, Marcelo G; Silva, Meiricris T; da Cunha, Fernanda M; Moriscot, Anselmo S; Aoki, Marcelo S; Miyabara, Elen H

    2015-12-01

    The decreased regenerative capacity of old skeletal muscles involves disrupted turnover of proteins. This study investigated whether leucine supplementation in old rats could improve muscle regenerative capacity. Young and old male Wistar rats were supplemented with leucine; then, the muscles were cryolesioned and examined after 3 and 10 days. Leucine supplementation attenuated the decrease in the expression of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and eukaryotic translation initiation factor 4E (eIF4E) in young and old muscles on day 3 post-injury and promoted an increase in the cross-sectional area of regenerating myofibers from both young and old soleus muscles on day 10 post-injury. This supplementation decreased the levels of ubiquitinated proteins and increased the proteasome activity in young regenerating muscles, but the opposite effect was observed in old regenerating muscles. Moreover, leucine decreased the inflammation area and induced an increase in the number of proliferating satellite cells in both young and old muscles. Our results suggest that leucine supplementation improves the regeneration of skeletal muscles from old rats, through the preservation of certain biological responses upon leucine supplementation. Such responses comprise the decrease in the inflammation area, increase in the number of proliferating satellite cells and size of regenerating myofibers, combined with the modulation of components of the phosphoinositide 3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and ubiquitin-proteasome system. PMID:26481769

  3. Role of muscle stem cells during skeletal regeneration.

    PubMed

    Abou-Khalil, Rana; Yang, Frank; Lieu, Shirley; Julien, Anais; Perry, Jaselle; Pereira, Catia; Relaix, Frédéric; Miclau, Theodore; Marcucio, Ralph; Colnot, Céline

    2015-05-01

    Although the importance of muscle in skeletal regeneration is well recognized clinically, the mechanisms by which muscle supports bone repair have remained elusive. Muscle flaps are often used to cover the damaged bone after traumatic injury yet their contribution to bone healing is not known. Here, we show that direct bone-muscle interactions are required for periosteum activation and callus formation, and that muscle grafts provide a source of stem cells for skeletal regeneration. We investigated the role of satellite cells, the muscle stem cells. Satellite cells loss in Pax7(-/-) mice and satellite cell ablation in Pax7(Cre) (ERT) (2/) (+) ;DTA(f/f) mice impaired bone regeneration. Although satellite cells did not contribute as a large source of cells endogenously, they exhibited a potential to contribute to bone repair after transplantation. The fracture healing phenotype in Pax7(Cre) (ERT) (2/) (+) ;DTA(f/f) mice was associated with decreased bone morphogenetic proteins (BMPs), insulin-like growth factor 1, and fibroblast growth factor 2 expression that are normally upregulated in response to fracture in satellite cells. Exogenous rhBMP2 improved bone healing in Pax7(Cre) (ERT) (2/) (+) ;DTA(f/f) mice further supporting the role of satellite cells as a source of growth factors. These results provide the first functional evidence for a direct contribution of muscle to bone regeneration with important clinical implications as it may impact the use of muscle flaps, muscle stem cells, and growth factors in orthopedic applications. PMID:25594525

  4. Genetic and epigenetic control of skeletal muscle development.

    PubMed

    Brand-Saberi, Beate

    2005-07-01

    In recent years our understanding of the molecular processes underlying skeletal myogenesis has improved considerably. Overt myogenesis is preceded by a number of steps leading to the specification of muscle precursor cells. During this period, myogenic precursors express mRNAs for Muscle Regulatory Factors (MRFs) of the bHLH-family of transcription factors: MyoD, Myf5, Myogenin and MRF4. These factors are specific for developing skeletal muscle and their identification belongs to the great achievements in muscle research. Other transcriptional regulators involved in myogenesis are Pax3 and Pax7, as well as the myocyte enhancer factors (MEFs), especially MEF2. Other inhibitory transcription factors may interact with histones to render muscle-specific genes inacessible. More recently, signaling events involving the Wnt-glycoproteins and Sonic Hedgehog have been identified that lead to the induction or expansion of muscle-specific genes during embryogenesis. Sources of these signals were identified to be the neural tube, ectoderm and notochord. Interestingly, a bias towards muscle differentiation already resides in cells of the epiblast. Thus, it can be reasoned that muscle differentiation does not have to be induced, but maybe just derepressed. Apart from inductive or permissive signals involved in differentiation control, other signalling events have been described leading to the definite arrangement of muscle groups in the body. These processes involve the changes in the cytoskeleton, delay of differentiation, cell migration and target recognition. PMID:16130819

  5. Progression of inflammation during immunodeficient mouse skeletal muscle regeneration.

    PubMed

    Grabowska, Iwona; Mazur, Magdalena A; Kowalski, K; Helinska, A; Moraczewski, Jerzy; Stremi?ska, W?adys?awa; Hoser, Gra?yna; Kawiak, Jerzy; Ciemerych, Maria A; Brzoska, Edyta

    2015-12-01

    The skeletal muscle injury triggers the inflammatory response which is crucial for damaged muscle fiber degradation and satellite cell activation. Immunodeficient mice are often used as a model to study the myogenic potential of transplanted human stem cells. Therefore, it is crucial to elucidate whether such model truly reflects processes occurring under physiological conditions. To answer this question we compared skeletal muscle regeneration of BALB/c, i.e. animals producing all types of inflammatory cells, and SCID mice. Results of our study documented that initial stages of muscles regeneration in both strains of mice were comparable. However, lower number of mononucleated cells was noticed in regenerating SCID mouse muscles. Significant differences in the number of CD14-/CD45+and CD14+/CD45+cells between BALB/c and SCID muscles were also observed. In addition, we found important differences in M1 and M2 macrophage levels of BALB/c and SCID mouse muscles identified by CD68 and CD163 markers. Thus, our data show that differences in inflammatory response during muscle regeneration, were not translated into significant modifications in muscle regeneration. PMID:26613733

  6. Metformin Protects Skeletal Muscle from Cardiotoxin Induced Degeneration

    PubMed Central

    Langone, Francesca; Cannata, Stefano; Fuoco, Claudia; Lettieri Barbato, Daniele; Testa, Stefano; Nardozza, Aurelio Pio; Ciriolo, Maria Rosa; Castagnoli, Luisa; Gargioli, Cesare; Cesareni, Gianni

    2014-01-01

    The skeletal muscle tissue has a remarkable capacity to regenerate upon injury. Recent studies have suggested that this regenerative process is improved when AMPK is activated. In the muscle of young and old mice a low calorie diet, which activates AMPK, markedly enhances muscle regeneration. Remarkably, intraperitoneal injection of AICAR, an AMPK agonist, improves the structural integrity of muscles of dystrophin-deficient mdx mice. Building on these observations we asked whether metformin, a powerful anti-hyperglycemic drug, which indirectly activates AMPK, affects the response of skeletal muscle to damage. In our conditions, metformin treatment did not significantly influence muscle regeneration. On the other hand we observed that the muscles of metformin treated mice are more resilient to cardiotoxin injury displaying lesser muscle damage. Accordingly myotubes, originated in vitro from differentiated C2C12 myoblast cell line, become more resistant to cardiotoxin damage after pre-incubation with metformin. Our results indicate that metformin limits cardiotoxin damage by protecting myotubes from necrosis. Although the details of the molecular mechanisms underlying the protective effect remain to be elucidated, we report a correlation between the ability of metformin to promote resistance to damage and its capacity to counteract the increment of intracellular calcium levels induced by cardiotoxin treatment. Since increased cytoplasmic calcium concentrations characterize additional muscle pathological conditions, including dystrophies, metformin treatment could prove a valuable strategy to ameliorate the conditions of patients affected by dystrophies. PMID:25461598

  7. Potential of laryngeal muscle regeneration using induced pluripotent stem cell-derived skeletal muscle cells.

    PubMed

    Dirja, Bayu Tirta; Yoshie, Susumu; Ikeda, Masakazu; Imaizumi, Mitsuyoshi; Nakamura, Ryosuke; Otsuki, Koshi; Nomoto, Yukio; Wada, Ikuo; Hazama, Akihiro; Omori, Koichi

    2016-04-01

    Conclusion Induced pluripotent stem (iPS) cells may be a new potential cell source for laryngeal muscle regeneration in the treatment of vocal fold atrophy after recurrent laryngeal nerve paralysis. Objectives Unilateral vocal fold paralysis can lead to degeneration, atrophy, and loss of force of the thyroarytenoid muscle. At present, there are some treatments such as thyroplasty, arytenoid adduction, and vocal fold injection. However, such treatments cannot restore reduced mass of the thyroarytenoid muscle. iPS cells have been recognized as supplying a potential resource for cell transplantation. The aim of this study was to assess the effectiveness of the use of iPS cells for the regeneration of laryngeal muscle through the evaluation of both in vitro and in vivo experiments. Methods Skeletal muscle cells were generated from tdTomato-labeled iPS cells using embryoid body formation. Differentiation into skeletal muscle cells was analyzed by gene expression and immunocytochemistry. The tdTomato-labeled iPS cell-derived skeletal muscle cells were transplanted into the left atrophied thyroarytenoid muscle. To evaluate the engraftment of these cells after transplantation, immunohistochemistry was performed. Results The tdTomato-labeled iPS cells were successfully differentiated into skeletal muscle cells through an in vitro experiment. These cells survived in the atrophied thyroarytenoid muscle after transplantation. PMID:26824385

  8. Suppression of muscle protein turnover and amino acid degradation by dietary protein deficiency

    NASA Technical Reports Server (NTRS)

    Tawa, N. E. Jr; Goldberg, A. L.

    1992-01-01

    To define the adaptations that conserve amino acids and muscle protein when dietary protein intake is inadequate, rats (60-70 g final wt) were fed a normal or protein-deficient (PD) diet (18 or 1% lactalbumin), and their muscles were studied in vitro. After 7 days on the PD diet, both protein degradation and synthesis fell 30-40% in skeletal muscles and atria. This fall in proteolysis did not result from reduced amino acid supply to the muscle and preceded any clear decrease in plasma amino acids. Oxidation of branched-chain amino acids, glutamine and alanine synthesis, and uptake of alpha-aminoisobutyrate also fell by 30-50% in muscles and adipose tissue of PD rats. After 1 day on the PD diet, muscle protein synthesis and amino acid uptake decreased by 25-40%, and after 3 days proteolysis and leucine oxidation fell 30-45%. Upon refeeding with the normal diet, protein synthesis also rose more rapidly (+30% by 1 day) than proteolysis, which increased significantly after 3 days (+60%). These different time courses suggest distinct endocrine signals for these responses. The high rate of protein synthesis and low rate of proteolysis during the first 3 days of refeeding a normal diet to PD rats contributes to the rapid weight gain ("catch-up growth") of such animals.

  9. Ultrastructural alterations in skeletal muscle fibers of rats after exercise

    NASA Technical Reports Server (NTRS)

    Akuzawa, M.; Hataya, M.

    1982-01-01

    Ultrastructural alterations in skeletal muscle fibers were electron microscopically studied in rats forced to run on the treadmill until all-out. When they were mild and limited to relatively small areas, the reconstruction of filaments ensued within 10 days without infiltration of cells. When they were severe and extensive, phagocytes infiltrated in the lesions and removed degenerative sacroplasmic debris from muscle fibers. A little later, myoblasts appeared and regeneration was accomplished in 30 days in much the same manner as in myogenesis.

  10. The Emerging Biomolecular Role of Vitamin D in Skeletal Muscle

    PubMed Central

    Pojednic, Rachele M.; Ceglia, Lisa

    2015-01-01

    In this review, we summarize current evidence for a direct effect of vitamin D on skeletal muscle. A number of studies identify the receptor for 1,25-dihydroxyvitamin-D3 (vitamin D receptor (VDR)) and the enzyme CYP27B1 (1-α-hydroxylase) in muscle. We hypothesize that vitamin D acts on myocytes via the VDR, and we examine proposed effects on myocyte proliferation, differentiation, growth, and inflammation. PMID:24508736

  11. Maternal Obesity, Inflammation, and Fetal Skeletal Muscle Development1

    PubMed Central

    Du, Min; Yan, Xu; Tong, Jun F.; Zhao, Junxing; Zhu, Mei J.

    2009-01-01

    Maternal obesity coupled with Western-style high-energy diets represents a special problem that can result in poor fetal development, leading to harmful, persistent effects on offspring, including predisposition to obesity and type 2 diabetes. Mechanisms linking maternal obesity to the increased incidence of obesity and other metabolic diseases in offspring remain poorly defined. Because skeletal muscle is the principal site for glucose and fatty acid utilization and composes 40%50% of total body mass, changes in the properties of offspring skeletal muscle and its mass resulting from maternal obesity may be responsible for the increase in type 2 diabetes and obesity. Fetal stage is crucial for skeletal muscle development because there is no net increase in the muscle fiber number after birth. Fetal skeletal muscle development involves myogenesis, adipogenesis, and fibrogenesis, which are all derived from mesenchymal stem cells (MSCs). Shifting commitment of MSCs from myogenesis to adipogenesis and fibrogenesis will result in increased intramuscular fat and connective tissue, as well as reduced numbers of muscle fiber and/or diameter, all of which have lasting negative effects on offspring muscle function and properties. Maternal obesity leads to low-grade inflammation, which changes the commitment of MSCs in fetal muscle through several possible mechanisms: 1) inflammation downregulates wingless and int (WNT) signaling, which attenuates myogenesis; 2) inflammation inhibits AMP-activated protein kinase, which promotes adipogenesis; and 3) inflammation may induce epigenetic modification through polycomb group proteins. More studies are needed to further explore the underlying mechanisms associated with maternal obesity, inflammation, and the commitment of MSCs. PMID:19516021

  12. The emerging biomolecular role of vitamin D in skeletal muscle.

    PubMed

    Pojednic, Rachele M; Ceglia, Lisa

    2014-04-01

    In this review, we summarize current evidence for a direct effect of vitamin D on skeletal muscle. A number of studies identify the receptor for 1,25-dihydroxyvitamin-D3 (vitamin D receptor (VDR)) and the enzyme CYP27B1 (1-α-hydroxylase) in muscle. We hypothesize that vitamin D acts on myocytes via the VDR, and we examine proposed effects on myocyte proliferation, differentiation, growth, and inflammation. PMID:24508736

  13. Store-Operated Ca2+ Entry (SOCE) Contributes to Normal Skeletal Muscle Contractility in young but not in aged skeletal muscle

    PubMed Central

    Brotto, Leticia S.; Bougoin, Sylvain; Nosek, Thomas M.; Reid, Michael; Hardin, Brian; Pan, Zui; Ma, Jianjie; Parness, Jerome

    2011-01-01

    Muscle atrophy alone is insufficient to explain the significant decline in contractile force of skeletal muscle during normal aging. One contributing factor to decreased contractile force in aging skeletal muscle could be compromised excitation-contraction (E-C) coupling, without sufficient available Ca2+ to allow for repetitive muscle contractility, skeletal muscles naturally become weaker. Using biophysical approaches, we previously showed that store-operated Ca2+ entry (SOCE) is compromised in aged skeletal muscle but not in young ones. While important, a missing component from previous studies is whether or not SOCE function correlates with contractile function during aging. Here we test the contribution of extracellular Ca2+ to contractile function of skeletal muscle during aging. First, we demonstrate graded coupling between SR Ca2+ release channel-mediated Ca2+ release and activation of SOCE. Inhibition of SOCE produced significant reduction of contractile force in young skeletal muscle, particularly at high frequency stimulation, and such effects were completely absent in aged skeletal muscle. Our data indicate that SOCE contributes to the normal physiological contractile response of young healthy skeletal muscle and that defective extracellular Ca2+ entry through SOCE contributes to the reduced contractile force characteristic of aged skeletal muscle. PMID:21666285

  14. Exosomes from differentiating human skeletal muscle cells trigger myogenesis of stem cells and provide biochemical cues for skeletal muscle regeneration.

    PubMed

    Choi, Ji Suk; Yoon, Hwa In; Lee, Kyoung Soo; Choi, Young Chan; Yang, Seong Hyun; Kim, In-San; Cho, Yong Woo

    2016-01-28

    Exosomes released from skeletal muscle cells play important roles in myogenesis and muscle development via the transfer of specific signal molecules. In this study, we investigated whether exosomes secreted during myotube differentiation from human skeletal myoblasts (HSkM) could induce a cellular response from human adipose-derived stem cells (HASCs) and enhance muscle regeneration in a muscle laceration mouse model. The exosomes contained various signal molecules including myogenic growth factors related to muscle development, such as insulin-like growth factors (IGFs), hepatocyte growth factor (HGF), fibroblast growth factor-2 (FGF2), and platelet-derived growth factor-AA (PDGF-AA). Interestingly, exosome-treated HASCs fused with neighboring cells at early time points and exhibited a myotube-like phenotype with increased expression of myogenic proteins (myosin heavy chain and desmin). On day 21, mRNAs of terminal myogenic genes were also up-regulated in exosome-treated HASCs. Moreover, in vivo studies demonstrated that exosomes from differentiating HSkM reduced the fibrotic area and increased the number of regenerated myofibers in the injury site, resulting in significant improvement of skeletal muscle regeneration. Our findings suggest that exosomes act as a biochemical cue directing stem cell differentiation and provide a cell-free therapeutic approach for muscle regeneration. PMID:26699421

  15. Calsequestrins in skeletal and cardiac muscle from adult Danio rerio.

    PubMed

    Furlan, Sandra; Mosole, Simone; Murgia, Marta; Nagaraj, Nagarjuna; Argenton, Francesco; Volpe, Pompeo; Nori, Alessandra

    2016-04-01

    Calsequestrin (Casq) is a high capacity, low affinity Ca(2+)-binding protein, critical for Ca(2+)-buffering in cardiac and skeletal muscle sarcoplasmic reticulum. All vertebrates have multiple genes encoding for different Casq isoforms. Increasing interest has been focused on mammalian and human Casq genes since mutations of both cardiac (Casq2) and skeletal muscle (Casq1) isoforms cause different, and sometime severe, human pathologies. Danio rerio (zebrafish) is a powerful model for studying function and mutations of human proteins. In this work, expression, biochemical properties cellular and sub-cellular localization of D. rerio native Casq isoforms are investigated. By quantitative PCR, three mRNAs were detected in skeletal muscle and heart with different abundances. Three zebrafish Casqs: Casq1a, Casq1b and Casq2 were identified by mass spectrometry (Data are available via ProteomeXchange with identifier PXD002455). Skeletal and cardiac zebrafish calsequestrins share properties with mammalian Casq1 and Casq2. Skeletal Casqs were found primarily, but not exclusively, at the sarcomere Z-line level where terminal cisternae of sarcoplasmic reticulum are located. PMID:26585961

  16. Myopathic changes in murine skeletal muscle lacking synemin

    PubMed Central

    García-Pelagio, Karla P.; Muriel, Joaquin; O'Neill, Andrea; Desmond, Patrick F.; Lovering, Richard M.; Lund, Linda; Bond, Meredith

    2015-01-01

    Diseases of striated muscle linked to intermediate filament (IF) proteins are associated with defects in the organization of the contractile apparatus and its links to costameres, which connect the sarcomeres to the cell membrane. Here we study the role in skeletal muscle of synemin, a type IV IF protein, by examining mice null for synemin (synm-null). Synm-null mice have a mild skeletal muscle phenotype. Tibialis anterior (TA) muscles show a significant decrease in mean fiber diameter, a decrease in twitch and tetanic force, and an increase in susceptibility to injury caused by lengthening contractions. Organization of proteins associated with the contractile apparatus and costameres is not significantly altered in the synm-null. Elastimetry of the sarcolemma and associated contractile apparatus in extensor digitorum longus myofibers reveals a reduction in tension consistent with an increase in sarcolemmal deformability. Although fatigue after repeated isometric contractions is more marked in TA muscles of synm-null mice, the ability of the mice to run uphill on a treadmill is similar to controls. Our results suggest that synemin contributes to linkage between costameres and the contractile apparatus and that the absence of synemin results in decreased fiber size and increased sarcolemmal deformability and susceptibility to injury. Thus synemin plays a moderate but distinct role in fast twitch skeletal muscle. PMID:25567810

  17. Skeletal muscle respiratory capacity, endurance, and glycogen utilization.

    PubMed

    Fitts, R H; Booth, F W; Winder, W W; Holloszy, J O

    1975-04-01

    This study was undertaken to evaluate the relationship between physical performance capacity and the mitochondrial content of skeletal muscle. Four groups of rats were trained by means of treadmill running 5 days/wk for 13 wk. One group ran 10 min/day, a second group ran 30 min/day, a third group ran 60 min/day, and a fourth group ran 120 min/day. The magnitude of the exercise-induced adaptive increase in gastrocnemius muscle respiratory capacity varied over a twofold range in the four groups. There were significant correlations between the levels of three mitochondrial markers (cytochrome c, citrate synthase, respiratory capacity) in the animals' gastrocnemius muscles and the duration of a run to exhaustion. There was also a significant correlation between the amounts of glycogen remaining in liver and skeletal muscle after a 30-min-long exercise test and the respiratory capacity of the animal's leg muscles. These findings are compatible with the interpretation that a close relationshiop exists between skeletal muscle mitochondrial content and the capacity to perform endurance exercise. PMID:165725

  18. Vitamin D Deficiency Promotes Skeletal Muscle Hypersensitivity and Sensory Hyperinnervation

    PubMed Central

    Tague, Sarah E.; Clarke, Gwenaëlle L.; Winter, Michelle K.; McCarson, Kenneth E.; Wright, Douglas E.; Smith, Peter G.

    2012-01-01

    Musculoskeletal pain affects nearly half of all adults, most of whom are vitamin D deficient. Previous findings demonstrated that putative nociceptors (“pain-sensing” nerves) express vitamin D receptors (VDRs), suggesting responsiveness to 1,25-dihydroxyvitamin D. In the present study, rats receiving vitamin D-deficient diets for 2– 4 weeks showed mechanical deep muscle hypersensitivity, but not cutaneous hypersensitivity. Muscle hypersensitivity was accompanied by balance deficits and occurred before onset of overt muscle or bone pathology. Hypersensitivity was not due to hypocalcemia and was actually accelerated by increased dietary calcium. Morphometry of skeletal muscle innervation showed increased numbers of presumptive nociceptor axons (peripherin-positive axons containing calcitonin gene-related peptide), without changes in sympathetic or skeletal muscle motor innervation. Similarly, there was no change in epidermal innervation. In culture, sensory neurons displayed enriched VDR expression in growth cones, and sprouting was regulated by VDR-mediated rapid response signaling pathways, while sympathetic outgrowth was not affected by different concentrations of 1,25-dihydroxyvitamin D. These findings indicate that vitamin D deficiency can lead to selective alterations in target innervation, resulting in presumptive nociceptor hyperinnervation of skeletal muscle, which in turn is likely to contribute to muscular hypersensitivity and pain. PMID:21957236

  19. Structural and mechanical alterations in spastic skeletal muscle.

    PubMed

    Foran, Jared R H; Steinman, Suzanne; Barash, Ilona; Chambers, Henry G; Lieber, Richard L

    2005-10-01

    Spasticity, a neurological problem secondary to an upper motor neuron lesion, has a significant effect on skeletal muscle. The upper motor neuron lesions may be secondary to a cerebral vascular accident, head injury, spinal cord injury, or degenerative diseases such as multiple sclerosis, or perinatal brain injuries such as cerebral palsy. Functional ability in these patients can be severely compromised but the basic mechanisms underlying these deficits are not clearly understood. In this review we evaluate the current evidence in the literature that suggests that skeletal muscle tissue itself is altered in spastic conditions. Experimental studies were evaluated that included a variety of methods encompassing joint mechanics, tissue mechanics, and muscle morphology. Taken together, the literature strongly supports the assertion that 'spastic muscles' are altered in a way that is unique among muscle plasticity models and inconsistent with simple transformation due to chronic stimulation or disuse. Further studies are required to detail the intra- and extracellular modifications of skeletal muscle that occur secondary to spasticity so that novel therapeutic treatments can be developed for this impairment. PMID:16174321

  20. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghreli...

  1. Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease

    PubMed Central

    Kim, Ho Cheol; Mofarrahi, Mahroo; Hussain, Sabah NA

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) is a debilitating disease characterized by inflammation-induced airflow limitation and parenchymal destruction. In addition to pulmonary manifestations, patients with COPD develop systemic problems, including skeletal muscle and other organ-specific dysfunctions, nutritional abnormalities, weight loss, and adverse psychological responses. Patients with COPD often complain of dyspnea on exertion, reduced exercise capacity, and develop a progressive decline in lung function with increasing age. These symptoms have been attributed to increases in the work of breathing and in impairments in gas exchange that result from airflow limitation and dynamic hyperinflation. However, there is mounting evidence to suggest that skeletal muscle dysfunction, independent of lung function, contributes significantly to reduced exercise capacity and poor quality of life in these patients. Limb and ventilatory skeletal muscle dysfunction in COPD patients has been attributed to a myriad of factors, including the presence of low grade systemic inflammatory processes, nutritional depletion, corticosteroid medications, chronic inactivity, age, hypoxemia, smoking, oxidative and nitrosative stresses, protein degradation and changes in vascular density. This review briefly summarizes the contribution of these factors to overall skeletal muscle dysfunction in patients with COPD, with particular attention paid to the latest advances in the field. PMID:19281080

  2. MicroRNA Transcriptome Profiles During Swine Skeletal Muscle Development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    MicroRNA (miR) are a class of small RNAs that regulate gene expression by inhibiting translation of protein encoding transcripts. To evaluate the role of miR in skeletal muscle of swine, global microRNA abundance was measured at specific developmental stages including proliferating satellite cells,...

  3. Redox Signaling in Skeletal Muscle: Role of Aging and Exercise

    ERIC Educational Resources Information Center

    Ji, Li Li

    2015-01-01

    Skeletal muscle contraction is associated with the production of ROS due to altered O[subscript 2] distribution and flux in the cell. Despite a highly efficient antioxidant defense, a small surplus of ROS, such as hydrogen peroxide and nitric oxide, may serve as signaling molecules to stimulate cellular adaptation to reach new homeostasis largely…

  4. 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

  5. Functional Overload Enhances Satellite Cell Properties in Skeletal Muscle

    PubMed Central

    Fujimaki, Shin; Machida, Masanao; Wakabayashi, Tamami; Asashima, Makoto; Takemasa, Tohru; Kuwabara, Tomoko

    2016-01-01

    Skeletal muscle represents a plentiful and accessible source of adult stem cells. Skeletal-muscle-derived stem cells, termed satellite cells, play essential roles in postnatal growth, maintenance, repair, and regeneration of skeletal muscle. Although it is well known that the number of satellite cells increases following physical exercise, functional alterations in satellite cells such as proliferative capacity and differentiation efficiency following exercise and their molecular mechanisms remain unclear. Here, we found that functional overload, which is widely used to model resistance exercise, causes skeletal muscle hypertrophy and converts satellite cells from quiescent state to activated state. Our analysis showed that functional overload induces the expression of MyoD in satellite cells and enhances the proliferative capacity and differentiation potential of these cells. The changes in satellite cell properties coincided with the inactivation of Notch signaling and the activation of Wnt signaling and likely involve modulation by transcription factors of the Sox family. These results indicate the effects of resistance exercise on the regulation of satellite cells and provide insight into the molecular mechanism of satellite cell activation following physical exercise. PMID:26779264

  6. Adipose tissue and skeletal muscle blood flow during mental stress

    SciTech Connect

    Linde, B.; Hjemdahl, P.; Freyschuss, U.; Juhlin-Dannfelt, A.

    1989-01-01

    Mental stress (a modified Stroop color word conflict test (CWT)) increased adipose tissue blood flow (ATBF; 133Xe clearance) by 70% and reduced adipose tissue vascular resistance (ATR) by 25% in healthy male volunteers. The vasculatures of adipose tissue (abdomen as well as thigh), skeletal muscle of the calf (133Xe clearance), and the entire calf (venous occlusion plethysmography) responded similarly. Arterial epinephrine (Epi) and glycerol levels were approximately doubled by stress. Beta-Blockade by metoprolol (beta 1-selective) or propranolol (nonselective) attenuated CWT-induced tachycardia similarly. Metoprolol attenuated stress-induced vasodilation in the calf and tended to do so in adipose tissue. Propranolol abolished vasodilation in the calf and resulted in vasoconstriction during CWT in adipose tissue. Decreases in ATR, but not in skeletal muscle or calf vascular resistances, were correlated to increases in arterial plasma glycerol (r = -0.42, P less than 0.05), whereas decreases in skeletal muscle and calf vascular resistances, but not in ATR, were correlated to increases in arterial Epi levels (r = -0.69, P less than 0.01; and r = -0.43, P less than 0.05, respectively). The results suggest that mental stress increases nutritive blood flow in adipose tissue and skeletal muscle considerably, both through the elevation of perfusion pressure and via vasodilatation. Withdrawal of vasoconstrictor nerve activity, vascular beta 2-adrenoceptor stimulation by circulating Epi, and metabolic mechanisms (in adipose tissue) may contribute to the vasodilatation.

  7. Redox Signaling in Skeletal Muscle: Role of Aging and Exercise

    ERIC Educational Resources Information Center

    Ji, Li Li

    2015-01-01

    Skeletal muscle contraction is associated with the production of ROS due to altered O[subscript 2] distribution and flux in the cell. Despite a highly efficient antioxidant defense, a small surplus of ROS, such as hydrogen peroxide and nitric oxide, may serve as signaling molecules to stimulate cellular adaptation to reach new homeostasis largely

  8. Imatinib attenuates skeletal muscle dystrophy in mdx mice

    PubMed Central

    Huang, Ping; Zhao, Xinyu S.; Fields, Matthew; Ransohoff, Richard M.; Zhou, Lan

    2009-01-01

    Duchenne-Meryon muscular dystrophy (DMD) is the most common and lethal genetic muscle disease. Ameliorating muscle necrosis, inflammation, and fibrosis represents an important therapeutic approach for DMD. Imatinib, an antineoplastic agent, demonstrated antiinflammatory and antifibrotic effects in liver, kidney, lung, and skin of various animal models. This study tested antiinflammatory and antifibrotic effects of imatinib in mdx mice, a DMD mouse model. We treated mdx mice with intraperitoneal injections of imatinib at the peak of limb muscle inflammation and the onset of diaphragm fibrosis. Controls received PBS vehicle or were left untreated. Muscle necrosis, inflammation, fibrosis, and function were evaluated by measuring serum CK activity, endomysial CD45 immunoreactive inflammation area, endomysial collagen III deposition, and hind limb grip strength. Phosphorylation of the tyrosine kinase targets of imatinib was assessed by Western blot in diaphragm tissue and in primary cultures of peritoneal macrophages and skeletal muscle fibroblasts. Imatinib markedly reduced muscle necrosis, inflammation, and fibrosis, and significantly improved hind limb grip strength in mdx mice. Reduced clinical disease was accompanied by inhibition of c-abl and PDGFR phosphorylation and suppression of TNF-α and IL-1β expression. Imatinib therapy for DMD may hold promise for ameliorating muscle necrosis, inflammation, and fibrosis by inhibiting c-abl and PDGFR signaling pathways and downstream inflammatory cytokine and fibrotic gene expression.—Huang, P., Zhao, X. S., Fields, M., Ransohoff, R. M., Zhou, L. Imatinib attenuates skeletal muscle dystrophy in mdx mice. PMID:19289603

  9. Differential global gene expression in red and white skeletal muscle

    NASA Technical Reports Server (NTRS)

    Campbell, W. G.; Gordon, S. E.; Carlson, C. J.; Pattison, J. S.; Hamilton, M. T.; Booth, F. W.

    2001-01-01

    The differences in gene expression among the fiber types of skeletal muscle have long fascinated scientists, but for the most part, previous experiments have only reported differences of one or two genes at a time. The evolving technology of global mRNA expression analysis was employed to determine the potential differential expression of approximately 3,000 mRNAs between the white quad (white muscle) and the red soleus muscle (mixed red muscle) of female ICR mice (30-35 g). Microarray analysis identified 49 mRNA sequences that were differentially expressed between white and mixed red skeletal muscle, including newly identified differential expressions between muscle types. For example, the current findings increase the number of known, differentially expressed mRNAs for transcription factors/coregulators by nine and signaling proteins by three. The expanding knowledge of the diversity of mRNA expression between white and mixed red muscle suggests that there could be quite a complex regulation of phenotype between muscles of different fiber types.

  10. Role of PKCδ in Insulin Sensitivity and Skeletal Muscle Metabolism.

    PubMed

    Li, Mengyao; Vienberg, Sara G; Bezy, Olivier; O'Neill, Brian T; Kahn, C Ronald

    2015-12-01

    Protein kinase C (PKC)δ has been shown to be increased in liver in obesity and plays an important role in the development of hepatic insulin resistance in both mice and humans. In the current study, we explored the role of PKCδ in skeletal muscle in the control of insulin sensitivity and glucose metabolism by generating mice in which PKCδ was deleted specifically in muscle using Cre-lox recombination. Deletion of PKCδ in muscle improved insulin signaling in young mice, especially at low insulin doses; however, this did not change glucose tolerance or insulin tolerance tests done with pharmacological levels of insulin. Likewise, in young mice, muscle-specific deletion of PKCδ did not rescue high-fat diet-induced insulin resistance or glucose intolerance. However, with an increase in age, PKCδ levels in muscle increased, and by 6 to 7 months of age, muscle-specific deletion of PKCδ improved whole-body insulin sensitivity and muscle insulin resistance and by 15 months of age improved the age-related decline in whole-body glucose tolerance. At 15 months of age, M-PKCδKO mice also exhibited decreased metabolic rate and lower levels of some proteins of the OXPHOS complex suggesting a role for PKCδ in the regulation of mitochondrial mass at older age. These data indicate an important role of PKCδ in the regulation of insulin sensitivity and mitochondrial homeostasis in skeletal muscle with aging. PMID:26307588

  11. Advancements in stem cells treatment of skeletal muscle wasting

    PubMed Central

    Meregalli, Mirella; Farini, Andrea; Sitzia, Clementina; Torrente, Yvan

    2014-01-01

    Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders, in which progressive muscle wasting and weakness is often associated with exhaustion of muscle regeneration potential. Although physiological properties of skeletal muscle tissue are now well known, no treatments are effective for these diseases. Muscle regeneration was attempted by means transplantation of myogenic cells (from myoblast to embryonic stem cells) and also by interfering with the malignant processes that originate in pathological tissues, such as uncontrolled fibrosis and inflammation. Taking into account the advances in the isolation of new subpopulation of stem cells and in the creation of artificial stem cell niches, we discuss how these emerging technologies offer great promises for therapeutic approaches to muscle diseases and muscle wasting associated with aging. PMID:24575052

  12. Androgens Regulate Gene Expression in Avian Skeletal Muscles

    PubMed Central

    Fuxjager, Matthew J.; Barske, Julia; Du, Sienmi; Day, Lainy B.; Schlinger, Barney A.

    2012-01-01

    Circulating androgens in adult reproductively active male vertebrates influence a diversity of organ systems and thus are considered costly. Recently, we obtained evidence that androgen receptors (AR) are expressed in several skeletal muscles of three passeriform birds, the golden-collared manakin (Manacus vitellinus), zebra finch (Taenopygia guttata), and ochre-bellied flycatcher (Mionectes oleagieus). Because skeletal muscles that control wing movement make up the bulk of a bird’s body mass, evidence for widespread effects of androgen action on these muscles would greatly expand the functional impact of androgens beyond their well-characterized effects on relatively discrete targets throughout the avian body. To investigate this issue, we use quantitative PCR (qPCR) to determine if androgens alter gene mRNA expression patterns in wing musculature of wild golden-collared manakins and captive zebra finches. In manakins, the androgen testosterone (T) up-regulated expression of parvalbumin (PV) and insulin-like growth factor I (IGF-I), two genes whose products enhance cellular Ca2+ cycling and hypertrophy of skeletal muscle fibers. In T-treated zebra finches, the anti-androgen flutamide blunted PV and IGF-I expression. These results suggest that certain transcriptional effects of androgen action via AR are conserved in passerine skeletal muscle tissue. When we examined wing muscles of manakins, zebra finches and ochre-bellied flycatchers, we found that expression of PV and IGF-I varied across species and in a manner consistent with a function for AR-dependent gene regulation. Together, these findings imply that androgens have the potential to act on avian muscle in a way that may enhance the physicality required for successful reproduction. PMID:23284699

  13. Functional classification of skeletal muscle networks. I. Normal physiology

    PubMed Central

    Wang, Yu; Winters, Jack

    2012-01-01

    Extensive measurements of the parts list of human skeletal muscle through transcriptomics and other phenotypic assays offer the opportunity to reconstruct detailed functional models. Through integration of vast amounts of data present in databases and extant knowledge of muscle function combined with robust analyses that include a clustering approach, we present both a protein parts list and network models for skeletal muscle function. The model comprises the four key functional family networks that coexist within a functional space; namely, excitation-activation family (forward pathways that transmit a motoneuronal command signal into the spatial volume of the cell and then use Ca2+ fluxes to bind Ca2+ to troponin C sites on F-actin filaments, plus transmembrane pumps that maintain transmission capacity); mechanical transmission family (a sophisticated three-dimensional mechanical apparatus that bidirectionally couples the millions of actin-myosin nanomotors with external axial tensile forces at insertion sites); metabolic and bioenergetics family (pathways that supply energy for the skeletal muscle function under widely varying demands and provide for other cellular processes); and signaling-production family (which represents various sensing, signal transduction, and nuclear infrastructure that controls the turn over and structural integrity and regulates the maintenance, regeneration, and remodeling of the muscle). Within each family, we identify subfamilies that function as a unit through analysis of large-scale transcription profiles of muscle and other tissues. This comprehensive network model provides a framework for exploring functional mechanisms of the skeletal muscle in normal and pathophysiology, as well as for quantitative modeling. PMID:23085959

  14. Regulation of protein synthesis by amino acids in muscle of neonates.

    PubMed

    Suryawan, Agus; Davis, Teresa A

    2011-01-01

    The marked increase in skeletal muscle mass during the neonatal period is largely due to a high rate of postprandial protein synthesis that is modulated by an enhanced sensitivity to insulin and amino acids. The amino acid signaling pathway leading to the stimulation of protein synthesis has not been fully elucidated. Among the amino acids, leucine is considered to be a principal anabolic agent that regulates protein synthesis. mTORC1, which controls protein synthesis, has been implicated as a target for leucine. Until recently, there have been few studies exploring the role of amino acids in enhancing muscle protein synthesis in vivo. In this review, we discuss amino acid-induced protein synthesis in muscle in the neonate, focusing on current knowledge of the role of amino acids in the activation of mTORC1 leading to mRNA translation. The role of the amino acid transporters, SNAT2, LAT1, and PAT, in the modulation of mTORC1 activation and the role of amino acids in the activation of putative regulators of mTORC1, i.e., raptor, Rheb, MAP4K3, Vps34, and Rag GTPases, are discussed. PMID:21196241

  15. The effect of heat stress on skeletal muscle contractile properties.

    PubMed

    Locke, Marius; Celotti, Carlo

    2014-07-01

    An elevated heat-shock protein (HSP) content protects cells and tissues, including skeletal muscles, from certain stressors. We determined if heat stress and the elevated HSP content that results is correlated with protection of contractile characteristics of isolated fast and slow skeletal muscles when contracting at elevated temperatures. To elevate muscle HSP content, one hindlimb of Sprague-Dawley rats (21-28 days old, 70-90 g) was subjected to a 15 min 42 °C heat-stress. Twenty-four hours later, both extensor digitorum longus (EDL) and soleus muscles were removed, mounted in either 20 °C or 42 °C Krebs-Ringer solution, and electrically stimulated. Controls consisted of the same muscles from the contra-lateral (non-stressed) hindlimbs as well as muscles from other (unstressed) animals. Isolated muscles were twitched and brought to tetanus every 5 min for 30 min. As expected, HSP content was elevated in muscles from the heat-stressed limbs when compared with controls. Regardless of prior treatment, both EDL and soleus twitch tensions were lower at 42 °C when compared with 20 °C. In addition, when incubated at 42 °C, both muscles showed a drop in twitch tension between 5 and 30 min. For tetanic tension, both muscles also showed an increase in tension between 5 and 30 min when stimulated at 20 °C regardless of treatment but when stimulated at 42 °C no change was observed. No protective effect of an elevated HSP content was observed for either muscle. In conclusion, although heat stress caused an elevation in HSP content, no protective effects were conferred to isolated contracting muscles. PMID:24264930

  16. Vitamin D and its role in skeletal muscle.

    PubMed

    Ceglia, Lisa; Harris, Susan S

    2013-02-01

    This review discusses the clinical and laboratory studies that have examined a role of vitamin D in skeletal muscle. Many observational studies, mainly in older populations, indicate that vitamin D status is positively associated with muscle strength and physical performance and inversely associated with risk of falling. Clinical trials of vitamin D supplementation in older adults with low vitamin D status mostly report improvements in muscle performance and reductions in falls. The underlying mechanisms are probably both indirect via calcium and phosphate and direct via activation of the vitamin D receptor (VDR) on muscle cells by 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. VDR activation at the genomic level regulates transcription of genes involved in calcium handling and muscle cell differentiation and proliferation. A putative membrane-associated VDR activates intracellular signaling pathways also involved in calcium handling and signaling and myogenesis. Additional evidence comes from VDR knockout mouse models with abnormal muscle morphology and physical function, and VDR polymorphisms which are associated with differences in muscle strength. Recent identification of CYP27B1 bioactivity in skeletal muscle cells and in regenerating adult mouse muscle lends support to the direct action of both 25-hydroxyvitamin D and 1,25(OH)(2)D in muscle. Despite these research advances, many questions remain. Further research is needed to fully characterize molecular mechanisms of vitamin D action on muscle cells downstream of the VDR, describe the effects on muscle morphology and contractility, and determine whether these molecular and cellular effects translate into clinical improvements in physical function. PMID:22968766

  17. Post-exercise carbohydrate plus whey protein hydrolysates supplementation increases skeletal muscle glycogen level in rats.

    PubMed

    Morifuji, Masashi; Kanda, Atsushi; Koga, Jinichiro; Kawanaka, Kentaro; Higuchi, Mitsuru

    2010-04-01

    Recent studies showed that a combination of carbohydrate and protein was more effective than carbohydrate alone for replenishing muscle glycogen after exercise. However, it remains to be unclear whether the source or degree of hydrolysis of dietary protein influences post-exercise glycogen accumulation. The aim of this study was to compare the effect of dietary protein type on glycogen levels in the post-exercise phase, and to investigate the effects of post-exercise carbohydrate and protein supplementation on phosphorylated enzymes of Akt/PKB and atypical PKCs. Male Sprague-Dawley rats, trained for 3 days, swam with a 2% load of body weight for 4 h to deplete skeletal muscle glycogen. Immediately after the glycogen-depleting exercise, one group was killed, whereas the other groups were given either glucose or glucose plus protein (whey protein, whey protein hydrolysates (WPH), casein hydrolysates or branched-chain amino acid (BCAA) solutions. After 2 h, the rats were killed, and the triceps muscles quickly excised. WPH caused significant increases in skeletal muscle glycogen level (5.01 +/- 0.24 mg/g), compared with whey protein (4.23 +/- 0.24 mg/g), BCAA (3.92 +/- 0.18 mg/g) or casein hydrolysates (2.73 +/- 0.22 mg/g). Post-exercise ingestion of glucose plus WPH significantly increased both phosphorylated Akt/PKB (131%) and phosphorylated PKCzeta (154%) levels compared with glucose only. There was a significant positive correlation between skeletal muscle glycogen content and phosphorylated Akt/PKB (r = 0.674, P < 0.001) and PKCzeta (r = 0.481, P = 0.017). Post-exercise supplementation with carbohydrate and WPH increases skeletal muscle glycogen recovery by activating key enzymes such as Akt/PKB and atypical PKCs. PMID:19593593

  18. Myotube formation in skeletal muscle regeneration.

    PubMed Central

    Ali, M A

    1979-01-01

    Muscle fibre regeneration in the latissimus dorsi of adult rats has been studied by light and electron microscopy. Both 'continuous' and 'discontinuous' modes of regeneration occur. In 'continuous' regeneration sarcoplasmic buds grow from the damaged muscle fibres, their nuclei apparently originating from the healthy portion of the muscle fibre. In 'discontinuous' regeneration mononucleated cells accumulate inside intact but vacated, sarcolemmal tubes. They differentiate into myofibril-containing myoblasts which later fuse. 'Continuous' regeneration occurs when the sarcolemmal sheaths are disrupted; 'discontinuous' regeneration when the sarcolemmal sheaths remain intact. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:468707

  19. Mitochondrial Involvement and Impact in Aging Skeletal Muscle

    PubMed Central

    Hepple, Russell T.

    2014-01-01

    Atrophy is a defining feature of aging skeletal muscle that contributes to progressive weakness and an increased risk of mobility impairment, falls, and physical frailty in very advanced age. Amongst the most frequently implicated mechanisms of aging muscle atrophy is mitochondrial dysfunction. Recent studies employing methods that are well-suited to interrogating intrinsic mitochondrial function find that mitochondrial respiration and reactive oxygen species emission changes are inconsistent between aging rat muscles undergoing atrophy and appear normal in human skeletal muscle from septuagenarian physically active subjects. On the other hand, a sensitization to permeability transition seems to be a general property of atrophying muscle with aging and this effect is even seen in atrophying muscle from physically active septuagenarian subjects. In addition to this intrinsic alteration in mitochondrial function, factors extrinsic to the mitochondria may also modulate mitochondrial function in aging muscle. In particular, recent evidence implicates oxidative stress in the aging milieu as a factor that depresses respiratory function in vivo (an effect that is not present ex vivo). Furthermore, in very advanced age, not only does muscle atrophy become more severe and clinically relevant in terms of its impact, but also there is evidence that this is driven by an accumulation of severely atrophied denervated myofibers. As denervation can itself modulate mitochondrial function and recruit mitochondrial-mediated atrophy pathways, future investigations need to address the degree to which skeletal muscle mitochondrial alterations in very advanced age are a consequence of denervation, rather than a primary organelle defect, to refine our understanding of the relevance of mitochondria as a therapeutic target at this more advanced age. PMID:25309422

  20. Influence of spaceflight on rat skeletal muscle

    NASA Technical Reports Server (NTRS)

    Martin, Thomas P.; Edgerton, V. Reggie; Grindeland, Richard E.

    1988-01-01

    The effect of a 7-day spaceflight (aboard NASA's SL-3) on the size and the metabolism of single fibers from several rat muscles was investigated along with the specificity of these responses as related to the muscle type and the size of fibers. It was found that the loss of mass after flight was varied from 36 percent in the soleus to 15 percent in the extensor digitorum longus. Results of histochemical analyses showed that the succinate dehydrogenase (SDH) activity in muscles of flight-exposed rats was maintained at the control levels, whereas the alpha-glycerol phosphate dehydrogenase (GPD) activity was either maintained or increased. The analyses of the metabolic profiles of ATPase, SDH, and GPD indicated that, in some muscles, there was an increase in the poportion of fast oxidative-glycolytic fibers.

  1. Imaging 2D optical diffuse reflectance in skeletal muscle

    NASA Astrophysics Data System (ADS)

    Ranasinghesagara, Janaka; Yao, Gang

    2007-04-01

    We discovered a unique pattern of optical reflectance from fresh prerigor skeletal muscles, which can not be described using existing theories. A numerical fitting function was developed to quantify the equiintensity contours of acquired reflectance images. Using this model, we studied the changes of reflectance profile during stretching and rigor process. We found that the prominent anisotropic features diminished after rigor completion. These results suggested that muscle sarcomere structures played important roles in modulating light propagation in whole muscle. When incorporating the sarcomere diffraction in a Monte Carlo model, we showed that the resulting reflectance profiles quantitatively resembled the experimental observation.

  2. Metabolic benefits of resistance training and fast glycolytic skeletal muscle

    PubMed Central

    Walsh, Kenneth; Arany, Zoltan

    2011-01-01

    Skeletal muscle exhibits remarkable plasticity with respect to its metabolic properties. Recent work has shown that interventions such as resistance training, genetic alterations and pharmacological strategies that increase muscle mass and glycolytic capacity, and not necessarily oxidative competence, can improve body composition and systemic metabolism. We review here recent advances in our understanding of the signaling and transcriptional regulatory pathways of this strategy and review new evidence obtained from mice and humans that supports the notion that increasing muscle mass and glycolytic capacity may effectively counter insulin resistance and type 2 diabetes mellitus. PMID:21045171

  3. Passive in vivo elastography from skeletal muscle noise

    SciTech Connect

    Sabra, Karim G.; Conti, Stephane; Roux, Philippe; Kuperman, W. A.

    2007-05-07

    Measuring the in vivo elastic properties of muscles (e.g., stiffness) provides a means for diagnosing and monitoring muscular activity. The authors demonstrated a passive in vivo elastography technique without an active external radiation source. This technique instead uses cross correlations of contracting skeletal muscle noise recorded with skin-mounted sensors. Each passive sensor becomes a virtual in vivo shear wave source. The results point to a low-cost, noninvasive technique for monitoring biomechanical in vivo muscle properties. The efficacy of the passive elastography technique originates from the high density of cross paths between all sensor pairs, potentially achieving the same sensitivity obtained from active elastography methods.

  4. Postmortem calpain changes in ostrich skeletal muscle.

    PubMed

    Chang, Ya-Shiou; Hsu, Dun-Hui; Stromer, Mavin H; Chou, Rong-Ghi R

    2016-07-01

    The objective of this study was to study the postmortem calpain change in ostrich muscle. Iliotibialis cranialis and Obturatorius medialis muscles were removed from the both sides of carcasses (n=8). The muscles from the left side were sampled after 0, 1, 2, 3, and 7days of storage at 5°C, while the right-side muscles were taken at 1-, 3-, and 7-day postmortem for shear force measurements. The results showed that the calpain-1 activity was not detected in ostrich muscle during the entire 7-day postmortem storage period, while the calpain-11 was. The unautolyzed calpain-11 activity decreased and the autolyzed calpain-11 activity increased with time postmortem. Desmin content and shear force did not change during postmortem storage although a minor degradation of desmin was observed. Therefore, our results suggest that limited postmortem proteolysis (as suggested by the limited degradation of desmin) and tenderization might be due to the lack of calpain-1 and/or insufficient calpain-11 activity present in ostrich muscle. PMID:26971307

  5. Immunomodulatory effects of massage on nonperturbed skeletal muscle in rats

    PubMed Central

    Waters-Banker, Christine; Dupont-Versteegden, Esther E.

    2013-01-01

    Massage is an ancient manual therapy widely utilized by individuals seeking relief from various musculoskeletal maladies. Despite its popularity, the majority of evidence associated with massage benefits is anecdotal. Recent investigations have uncovered physiological evidence supporting its beneficial use following muscle injury; however, the effects of massage on healthy, unperturbed skeletal muscle are unknown. Utilizing a custom-fabricated massage mimetic device, the purpose of this investigation was to elucidate the effects of various loading magnitudes on healthy skeletal muscle with particular interest in the gene expression profile and modulation of key immune cells involved in the inflammatory response. Twenty-four male Wistar rats (200 g) were subjected to cyclic compressive loading (CCL) over the right tibialis anterior muscle for 30 min, once a day, for 4 consecutive days using four loading conditions: control (0N), low load (1.4N), moderate load (4.5N), and high load (11N). Microarray analysis showed that genes involved with the immune response were the most significantly affected by application of CCL. Load-dependent changes in cellular abundance were seen in the CCL limb for CD68+ cells, CD163+ cells, and CD43+cells. Surprisingly, load-independent changes were also discovered in the non-CCL contralateral limb, suggesting a systemic response. These results show that massage in the form of CCL exerts an immunomodulatory response to uninjured skeletal muscle, which is dependent upon the applied load. PMID:24201707

  6. Noncoding RNAs, Emerging Regulators of Skeletal Muscle Development and Diseases

    PubMed Central

    Nie, Mao; Deng, Zhong-Liang; Liu, Jianming; Wang, Da-Zhi

    2015-01-01

    A healthy and independent life requires skeletal muscles to maintain optimal function throughout the lifespan, which is in turn dependent on efficient activation of processes that regulate muscle development, homeostasis, and metabolism. Thus, identifying mechanisms that modulate these processes is of crucial priority. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), have emerged as a class of previously unrecognized transcripts whose importance in a wide range of biological processes and human disease is only starting to be appreciated. In this review, we summarize the roles of recently identified miRNAs and lncRNAs during skeletal muscle development and pathophysiology. We also discuss several molecular mechanisms of these noncoding RNAs. Undoubtedly, further systematic understanding of these noncoding RNAs' functions and mechanisms will not only greatly expand our knowledge of basic skeletal muscle biology, but also significantly facilitate the development of therapies for various muscle diseases, such as muscular dystrophies, cachexia, and sarcopenia. PMID:26258142

  7. Skeletal muscle responses to lower limb suspension in humans

    NASA Technical Reports Server (NTRS)

    Hather, Bruce M.; Adams, Gregory R.; Tesch, Per A.; Dudley, Gary A.

    1992-01-01

    The morphological responses of human skeletal muscle to unweighting were assessed by analyzing multiple transaxial magnetic resonance (MR) images of both lower limbs and skeletal muscle biopsies of the unweighted lower limb before and after six weeks of unilaterial (left) lower limb suspension (ULLS). Results indicated that, as a results of 6 weeks of unweighting (by the subjects walking on crutches using only one limb), the cross sectional area (CSA) of the thigh muscle of the unweighted left limb decreased 12 percent, while the CSA of the right thigh muscle did not change. The decrease was due to a twofold greater response of the knee extensors than the knee flexors. The pre- and post-ULLS biopsies of the left vastus lateralis showed a 14 percent decrease in average fiber CSA due to unweighting. The number of capillaries surrounding the different fiber types was unchanged after ULLS. Results showed that the adaptive responses of human skeletal muscle to unweighting are qualitatively, but not quantitatively, similar to those of lower mammals and not necessarily dependent on the fiber-type composition.

  8. Compartmentalization of NO signaling cascade in skeletal muscles

    SciTech Connect

    Buchwalow, Igor B. . E-mail: buchwalo@uni-muenster.de; Minin, Evgeny A.; Samoilova, Vera E.; Boecker, Werner; Wellner, Maren; Schmitz, Wilhelm; Neumann, Joachim

    2005-05-06

    Skeletal muscle functions regulated by NO are now firmly established. However, the literature on the compartmentalization of NO signaling in myocytes is highly controversial. To address this issue, we examined localization of enzymes engaged in L-arginine-NO-cGMP signaling in the rat quadriceps muscle. Employing immunocytochemical labeling complemented with tyramide signal amplification and electron microscopy, we found NO synthase expressed not only in the sarcolemma, but also along contractile fibers, in the sarcoplasmic reticulum and mitochondria. The expression pattern of NO synthase in myocytes showed striking parallels with the enzymes engaged in L-arginine-NO-cGMP signaling (arginase, phosphodiesterase, and soluble guanylyl cyclase). Our findings are indicative of an autocrine fashion of NO signaling in skeletal muscles at both cellular and subcellular levels, and challenge the notion that the NO generation is restricted to the sarcolemma.

  9. Improved Cell Culture Method for Growing Contracting Skeletal Muscle Models

    NASA Technical Reports Server (NTRS)

    Marquette, Michele L.; Sognier, Marguerite A.

    2013-01-01

    An improved method for culturing immature muscle cells (myoblasts) into a mature skeletal muscle overcomes some of the notable limitations of prior culture methods. The development of the method is a major advance in tissue engineering in that, for the first time, a cell-based model spontaneously fuses and differentiates into masses of highly aligned, contracting myotubes. This method enables (1) the construction of improved two-dimensional (monolayer) skeletal muscle test beds; (2) development of contracting three-dimensional tissue models; and (3) improved transplantable tissues for biomedical and regenerative medicine applications. With adaptation, this method also offers potential application for production of other tissue types (i.e., bone and cardiac) from corresponding precursor cells.

  10. Skeletal muscle activity and the fate of myonuclei.

    PubMed

    Shenkman, B S; Turtikova, O V; Nemirovskaya, T L; Grigoriev, A I

    2010-07-01

    Adult skeletal muscle fiber is a symplast multinuclear structure developed in ontogenesis by the fusion of the myoblasts (muscle progenitor cells). The nuclei of a muscle fiber (myonuclei) are those located at the periphery of fiber in the space between myofibrils and sarcolemma. In theory, a mass change in skeletal muscle during exercise or unloading may be associated with the altered myonuclear number, ratio of the transcription, and translation and proteolysis rates. Here we review the literature data related to the phenomenology and hypothetical mechanisms of the myonuclear number alterations during enhanced or reduced muscle contractile activity. In many cases (during severe muscle and systemic diseases and gravitational unloading), muscle atrophy is accompanied by a reduction in the amount of myonuclei. Such reduction is usually explained by the development of myonuclear apoptosis. A myonuclear number increase may be provided only by the satellite cell nuclei incorporation via cell fusion with the adjacent myofiber. It is believed that it is these cells which supply fiber with additional nuclei, providing postnatal growth, work hypertrophy, and repair processes. Here we discuss the possible mechanisms controlling satellite cell proliferation during exercise, functional unloading, and passive stretch. PMID:22649641

  11. Myostatin: a modulator of skeletal-muscle stem cells.

    PubMed

    Walsh, F S; Celeste, A J

    2005-12-01

    Myostatin, or GDF-8 (growth and differentiation factor-8), was first identified through sequence identity with members of the BMP (bone morphogenetic protein)/TGF-beta (transforming growth factor-beta) superfamily. The skeletal-muscle-specific expression pattern of myostatin suggested a role in muscle development. Mice with a targeted deletion of the myostatin gene exhibit a hypermuscular phenotype. In addition, inactivating mutations in the myostatin gene have been identified in 'double muscled' cattle breeds, such as the Belgian Blue and Piedmontese, as well as in a hypermuscular child. These findings define myostatin as a negative regulator of skeletal-muscle development. Myostatin binds with high affinity to the receptor serine threonine kinase ActRIIB (activin type IIB receptor), which initiates signalling through a smad2/3-dependent pathway. In an effort to validate myostatin as a therapeutic target in a post-embryonic setting, a neutralizing antibody was developed by screening for inhibition of myostatin binding to ActRIIB. Administration of this antimyostatin antibody to adult mice resulted in a significant increase in both muscle mass and functional strength. Importantly, similar results were obtained in a murine model of muscular dystrophy, the mdx mouse. Unlike the myostatin-deficient animals, which exhibit both muscle hypertrophy and hyperplasia, the antibody-treated mice demonstrate increased musculature through a hypertrophic mechanism. These results validate myostatin inhibition as a therapeutic approach to muscle wasting diseases such as muscular dystrophy, sarcopenic frailty of the elderly and amylotrophic lateral sclerosis. PMID:16246158

  12. Closed-loop control of movement of skeletal muscle.

    PubMed

    Petrofsky, J S; Phillips, C A

    1985-01-01

    Closed-loop (feedback) control of skeletal muscle is critically reviewed. The introductory section examines the advantages and disadvantages of open-loop as compared to closed-loop control in general, defines the problem, and outlines our approach. In the biological systems section, muscle structure and function are defined at the level of the motor nerve, neuromuscular junction, and sarcomere. Time delays, power and efficiency, fatigue, and other effects are also discussed in relation to the development of closed-loop control. This section then proceeds to review biological sensors and finally integrates this information by reviewing the body's own closed-loop control system. The third section critically reviews various approaches to the mathematical modeling of muscle. The control problem (in general) is reviewed with particular emphasis on contemporary control systems engineering. Essential to closed-loop control of paralyzed skeletal muscle is sensor technology. Therefore, the fourth section reviews external mechanical sensors. Specifically, potentiometers and Hall effect sensors, capacitive force transducers, inductive displacement transducers (LVDTs), and various position resolvers are discussed. Finally, the fifth section reviews the application of closed-loop control of skeletal muscle to the human being. The focus of this section is the paralyzed individual: past progress and future directions. An extensive bibliography of cited references is then provided so that the interested reader may pursue his/her particular area of interest in more detail. The authors acknowledge that such an extensive review of so many relevant areas is necessarily not complete and often overly simplistic, but our goal is a "first approach" to a comprehensive understanding of the closed-loop (feedback) control problem for achieving movement in paralyzed skeletal muscle. PMID:3902360

  13. The formation of skeletal muscle: from somite to limb.

    PubMed

    Buckingham, Margaret; Bajard, Lola; Chang, Ted; Daubas, Philippe; Hadchouel, Juliette; Meilhac, Sigolène; Montarras, Didier; Rocancourt, Didier; Relaix, Frédéric

    2003-01-01

    During embryogenesis, skeletal muscle forms in the vertebrate limb from progenitor cells originating in the somites. These cells delaminate from the hypaxial edge of the dorsal part of the somite, the dermomyotome, and migrate into the limb bud, where they proliferate, express myogenic determination factors and subsequently differentiate into skeletal muscle. A number of regulatory factors involved in these different steps have been identified. These include Pax3 with its target c-met, Lbx1 and Mox2 as well as the myogenic determination factors Myf5 and MyoD and factors required for differentiation such as Myogenin, Mrf4 and Mef2 isoforms. Mutants for genes such as Lbx1 and Mox2, expressed uniformly in limb muscle progenitors, reveal unexpected differences between fore and hind limb muscles, also indicated by the differential expression of Tbx genes. As development proceeds, a secondary wave of myogenesis takes place, and, postnatally, satellite cells become located under the basal lamina of adult muscle fibres. Satellite cells are thought to be the progenitor cells for adult muscle regeneration, during which similar genes to those which regulate myogenesis in the embryo also play a role. In particular, Pax3 as well as its orthologue Pax7 are important. The origin of secondary/fetal myoblasts and of adult satellite cells is unclear, as is the relation of the latter to so-called SP or stem cell populations, or indeed to potential mesangioblast progenitors, present in blood vessels. The oligoclonal origin of postnatal muscles points to a small number of founder cells, whether or not these have additional origins to the progenitor cells of the somite which form the first skeletal muscles, as discussed here for the embryonic limb. PMID:12587921

  14. Atomoxetine prevents dexamethasone-induced skeletal muscle atrophy in mice.

    PubMed

    Jesinkey, Sean R; Korrapati, Midhun C; Rasbach, Kyle A; Beeson, Craig C; Schnellmann, Rick G

    2014-12-01

    Skeletal muscle atrophy remains a clinical problem in numerous pathologic conditions. β2-Adrenergic receptor agonists, such as formoterol, can induce mitochondrial biogenesis (MB) to prevent such atrophy. Additionally, atomoxetine, an FDA-approved norepinephrine reuptake inhibitor, was positive in a cellular assay for MB. We used a mouse model of dexamethasone-induced skeletal muscle atrophy to investigate the potential role of atomoxetine and formoterol to prevent muscle mass loss. Mice were administered dexamethasone once daily in the presence or absence of formoterol (0.3 mg/kg), atomoxetine (0.1 mg/kg), or sterile saline. Animals were euthanized at 8, 16, and 24 hours or 8 days later. Gastrocnemius muscle weights, changes in mRNA and protein expression of peroxisome proliferator-activated receptor-γ coactivator-1 α (PGC-1α) isoforms, ATP synthase β, cytochrome c oxidase subunit I, NADH dehydrogenase (ubiquinone) 1 β subcomplex, 8, ND1, insulin-like growth factor 1 (IGF-1), myostatin, muscle Ring-finger protein-1 (muscle atrophy), phosphorylated forkhead box protein O 3a (p-FoxO3a), Akt, mammalian target of rapamycin (mTOR), and ribosomal protein S6 (rp-S6; muscle hypertrophy) in naive and muscle-atrophied mice were measured. Atomoxetine increased p-mTOR 24 hours after treatment in naïve mice, but did not change any other biomarkers. Formoterol robustly activated the PGC-1α-4-IGF1-Akt-mTOR-rp-S6 pathway and increased p-FoxO3a as early as 8 hours and repressed myostatin at 16 hours. In contrast to what was observed with acute treatment, chronic treatment (7 days) with atomoxetine increased p-Akt and p-FoxO3a, and sustained PGC-1α expression and skeletal muscle mass in dexamethasone-treated mice, in a manner comparable to formoterol. In conclusion, chronic treatment with a low dose of atomoxetine prevented dexamethasone-induced skeletal muscle wasting and supports a potential role in preventing muscle atrophy. PMID:25292181

  15. Leucine supplementation of a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent translation initiation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Protein synthesis and eukaryotic initiation factor (eIF) activation are increased in skeletal muscle of neonatal pigs parenterally infused with amino acids. Leucine appears to be the most effective single amino acid to trigger these effects. To examine the response to enteral leucine supplementation...

  16. Neuromuscular Electrical Stimulation for Skeletal Muscle Function

    PubMed Central

    Doucet, Barbara M.; Lam, Amy; Griffin, Lisa

    2012-01-01

    Lack of neural innervation due to neurological damage renders muscle unable to produce force. Use of electrical stimulation is a medium in which investigators have tried to find a way to restore movement and the ability to perform activities of daily living. Different methods of applying electrical current to modify neuromuscular activity are electrical stimulation (ES), neuromuscular electrical stimulation (NMES), transcutaneous electrical nerve stimulation (TENS), and functional electrical stimulation (FES). This review covers the aspects of electrical stimulation used for rehabilitation and functional purposes. Discussed are the various parameters of electrical stimulation, including frequency, pulse width/duration, duty cycle, intensity/amplitude, ramp time, pulse pattern, program duration, program frequency, and muscle group activated, and how they affect fatigue in the stimulated muscle. PMID:22737049

  17. Rapidly aggravated skeletal muscle metastases from an intrahepatic cholangiocarcinoma

    PubMed Central

    Lee, Jiyoung; Lee, Sung Wook; Han, Sang Young; Baek, Yang Hyun; Kim, Su Young; Rhyou, Hyo In

    2015-01-01

    We present a rare case of intrahepatic cholangiocarcinoma (ICC) with multiple skeletal muscle metastases. The patient was a 55-year-old Asian woman presenting with abdominal pain; abdominal and pelvic computed tomography and magnetic resonance cholangiopancreatography revealed an unresectable ICC with hepatic metastasis and metastastatic lymphadenopathy in the porto-caval area. After 3 mo of treatment with palliative radiotherapy and chemotherapy, magnetic resonance imaging of the thoracolumbar spine detected right psoas muscle and paraspinous muscle metastases. We performed an ultrasound-guided percutaneous fine-needle biopsy that confirmed a similar pattern of poorly differentiated adenocarcinoma. The patient treated with palliative chemotherapy and achieved 10 mo of survival. Here we report the first case quickly spread to multiple sites of muscle even though the three-month treatment, compare to the other cases reported muscle metastases at diagnosis. PMID:25684968

  18. Optimizing IGF-I for skeletal muscle therapeutics

    PubMed Central

    Philippou, Anastassios; Barton, Elisabeth R.

    2015-01-01

    It is virtually undisputed that IGF-I promotes cell growth and survival. However, the presence of several IGF-I isoforms, vast numbers of intracellular signaling components, and multiple receptors results in a complex and highly regulated system by which IGF-I actions are mediated. IGF-I has long been recognized as one of the critical factors for coordinating muscle growth, enhancing muscle repair, and increasing muscle mass and strength. How to optimize this panoply of pathways to drive anabolic processes in muscle as opposed to aberrant growth in other tissues is an area that deserves focus. This review will address how advances in the bioavailability, potency, and tissue response of IGF-I can provide new potential directions for skeletal muscle therapeutics. PMID:25002025

  19. The genetics of skeletal muscle disorders in horses.

    PubMed

    Mickelson, James R; Valberg, Stephanie J

    2015-01-01

    Horses are remarkable athletes and a fascinating species in which to study the genetic bases of athletic performance, skeletal muscle biology, and neuromuscular disease. Genetic selection in horses has resulted in many breeds that possess anatomical, physiological, and metabolic variations linked to speed, power, and endurance that are beginning to be defined at the molecular level. Along with the concentration of positive traits, equine breeding programs have also inadvertently concentrated heritable muscle diseases for which mutations impacting electrical conduction, muscle contraction, and energy metabolism within and across breeds have been characterized. The study of heritable muscle diseases in horses has provided exciting insights into the normal structure and function of muscle and important diagnostic tools for veterinarians. Results empower breeders and breed associations to make difficult decisions about how to use this information to improve the overall health and well-being of horses. PMID:25387114

  20. Enhanced Myogenesis in adult skeletal muscle by transgenic expression of Myostatin Propeptide

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle growth and maintenance are essential for human health. One of the muscle regulatory genes, namely myostatin, a member of transforming growth factor-ß, plays a dominant role in the genetic control of muscle mass. Transgenic expression of myostatin propeptide in skeletal muscle showed ...

  1. Activity Dependent Signal Transduction in Skeletal Muscle

    NASA Technical Reports Server (NTRS)

    Hamilton, Susan L.

    1999-01-01

    The overall goals of this project are: 1) to define the initial signal transduction events whereby the removal of gravitational load from antigravity muscles, such as the soleus, triggers muscle atrophy, and 2) to develop countermeasures to prevent this from happening. Our rationale for this approach is that, if countermeasures can be developed to regulate these early events, we could avoid having to deal with the multiple cascades of events that occur downstream from the initial event. One of our major findings is that hind limb suspension causes an early and sustained increase in intracellular Ca(2+) concentration ([Ca (2+)](sub i)). In most cells the consequences of changes in ([Ca (2+)](sub i))depend on the amplitude, frequency and duration of the Ca(2+) signal and on other factors in the intracellular environment. We propose that muscle remodeling in microgravity represents a change in the balance among several CA(2+) regulated signal transduction pathways, in particular those involving the transcription factors NFAT and NFkB and the pro-apoptotic protein BAD. Other Ca(2+) sensitive pathways involving PKC, ras, rac, and CaM kinase II may also contribute to muscle remodeling.

  2. Carnosine Content in Skeletal Muscle Is Dependent on Vitamin B6 Status in Rats

    PubMed Central

    Suidasari, Sofya; Stautemas, Jan; Uragami, Shinji; Yanaka, Noriyuki; Derave, Wim; Kato, Norihisa

    2016-01-01

    Carnosine, a histidine-containing dipeptide, is well known to be associated with skeletal muscle performance. However, there is limited information on the effect of dietary micronutrients on muscle carnosine level. Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, is involved in amino acid metabolisms in the body as a cofactor. We hypothesized that enzymes involved in β-alanine biosynthesis, the rate-limiting precursor of carnosine, may also be PLP dependent. Thus, we examined the effects of dietary vitamin B6 on the muscle carnosine content of rats. Male and female rats were fed a diet containing 1, 7, or 35 mg pyridoxine (PN) HCl/kg for 6 weeks. Carnosine in skeletal muscles was quantified by ultra-performance liquid chromatography coupled with tandem mass spectrometry. In the gastrocnemius muscle of male rats, carnosine concentration was significantly higher in the 7 and 35 mg groups (+70 and +61%, respectively) than in the 1 mg PN HCl/kg group, whereas that in the soleus muscle of male rats was significantly higher only in the 7 mg group (+43%) than in the 1 mg PN HCl/kg group (P < 0.05). In both muscles of female rats, carnosine concentration was significantly higher in the 7 and 35 mg groups (+32 to +226%) than in the 1 mg PN HCl/kg group (P < 0.05). We also found that, compared to the 1 mg group, β-alanine concentrations in the 7 and 35 mg groups were markedly elevated in gastrocnemius muscles of male (+153 and +148%, respectively, P < 0.05) and female (+381 and +437%, respectively, P < 0.05) rats. Noteworthy, the concentrations of ornithine in the 7 and 35 mg groups were decreased in gastrocnemius muscles of male rats (−46 and −54%, respectively, P < 0.05), which strongly inversely correlated with β-alanine concentration (r = −0.84, P < 0.01). In humans, 19% lower muscle carnosine content was found in soleus muscle of women of the lower plasma PLP tertile, but this was not observed in gastrocnemius muscle or in men. We conclude that adequate dietary vitamin B6 is essential for maintaining carnosine in skeletal muscles of rats. Significantly lower soleus carnosine content among women close to PLP deficiency suggests that a similar phenomenon exists in the humans. PMID:26835452

  3. Perfused skeletal muscle -- an experimental preparation for many questions!

    PubMed

    Barclay, Jack K; Stainsby, Wendell N

    2004-04-01

    Perfused mammalian skeletal muscle preparations either in vitro or in situ are one of the options to be considered when planning a physiological research program or project. Such preparations have been and continue to be used to investigate research questions as diverse as skeletal muscle function and metabolism, peripheral vascular function, and an approximation of exercise. When selecting a perfused muscle preparation, both anatomical and physiological organization must be evaluated in the context of the planned experiment. In any experiment, a number of physiologically significant variables can be manipulated, such as the level of flow and the arterial or inflow concentration of a gas or substance to control substrate supply and metabolite removal as well as the stimulation parameters to alter metabolic rate. The choice of blood or an artificial perfusate is of paramount importance because, when compared to blood-perfused preparations, those receiving artificial perfusates show depressed vascular autoregulation among other changes, indicating a decrease in physiological quality. Overall, perfused skeletal muscle preparations can be used to examine many and varied research questions with close to in-vivo quality and a high degree of accuracy and control if blood-perfused. PMID:15064422

  4. Sarcocystis fayeri in skeletal muscle of horses with neuromuscular disease.

    PubMed

    Aleman, Monica; Shapiro, Karen; Sis, Silvia; Williams, Diane C; Rejmanek, Daniel; Aguilar, Beatriz; Conrad, Patricia A

    2016-01-01

    Recent reports of Sarcocystis fayeri-induced toxicity in people consuming horse meat warrant investigation on the prevalence and molecular characterization of Sarcocystis spp. infection in horses. Sarcocysts in skeletal muscle of horses have been commonly regarded as an incidental finding. In this study, we investigated the prevalence of sarcocysts in skeletal muscle of horses with neuromuscular disease. Our findings indicated that S.?fayeri infection was common in young mature horses with neuromuscular disease and could be associated with myopathic and neurogenic processes. The number of infected muscles and number of sarcocysts per muscle were significantly higher in diseased than in control horses. S.?fayeri was predominantly found in low oxidative highly glycolytic myofibers. This pathogen had a high glycolytic metabolism. Common clinical signs of disease included muscle atrophy, weakness with or without apparent muscle pain, gait deficits, and dysphagia in horses with involvement of the tongue and esophagus. Horses with myositis were lethargic, apparently painful, stiff, and reluctant to move. Similar to humans, sarcocystosis and cardiomyopathy can occur in horses. This study did not establish causality but supported a possible association (8.9% of cases) with disease. The assumption of Sarcocysts spp. being an incidental finding in every case might be inaccurate. PMID:26522989

  5. Biochemical and mechanical environment cooperatively regulate skeletal muscle regeneration

    PubMed Central

    Calve, Sarah; Simon, Hans-Georg

    2012-01-01

    During forelimb regeneration in the newt Notophthalmus viridescens, the dynamic expression of a transitional matrix rich in hyaluronic acid, tenascin-C, and fibronectin controls muscle cell behavior in vivo and in vitro. However, the influence of extracellular matrix (ECM) remodeling on tissue stiffness and the cellular response to mechanical variations during regeneration was unknown. By measuring the transverse stiffness of tissues in situ, we found undifferentiated regenerative blastemas were less stiff than differentiated stump muscle (13.31.6 vs. 16.61.2 kPa). To directly determine how ECM and stiffness combine to affect skeletal muscle fragmentation, migration, and fusion, we coated silicone-based substrates ranging from 2 to 100 kPa with matrices representative of transitional (tenascin-C and fibronectin) and differentiated environments (laminin and Matrigel). Using live-cell imaging, we found softer tenascin-C-coated substrates significantly enhanced migration and fragmentation of primary newt muscle cells. In contrast, stiffer substrates coated with laminin, Matrigel, or fibronectin increased differentiation while suppressing migration and fragmentation. These data support our in vivo observations that a transitional matrix of reduced stiffness regulates muscle plasticity and progenitor cell recruitment into the regenerative blastema. These new findings will enable the determination of how biochemical and mechanical cues from the ECM control genetic pathways that drive regeneration.Calve, S., Simon, H.-G. Biochemical and mechanical environment cooperatively regulate skeletal muscle regeneration. PMID:22415307

  6. Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model.

    PubMed

    Tzika, A Aria; Fontes-Oliveira, Cibely Cristine; Shestov, Alexander A; Constantinou, Caterina; Psychogios, Nikolaos; Righi, Valeria; Mintzopoulos, Dionyssios; Busquets, Silvia; Lopez-Soriano, Francisco J; Milot, Sylvain; Lepine, Francois; Mindrinos, Michael N; Rahme, Laurence G; Argiles, Josep M

    2013-09-01

    Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochondrial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (31P NMR) spectroscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS). The mice used in both experiments were Lewis lung carcinoma models of cancer cachexia. A novel 'fragmented mass isotopomer' approach was used in our dynamic analysis of 13C mass isotopomer data. Our 31P NMR and GC/MS results indicated that the adenosine triphosphate (ATP) synthesis rate and tricarboxylic acid (TCA) cycle flux were reduced by 49% and 22%, respectively, in the cancer-bearing mice (p<0.008; t-test vs. controls). The ratio of ATP synthesis rate to the TCA cycle flux (an index of mitochondrial coupling) was reduced by 32% in the cancer-bearing mice (p=0.036; t-test vs. controls). Genomic analysis revealed aberrant expression levels for key regulatory genes and transmission electron microscopy (TEM) revealed ultrastructural abnormalities in the muscle fiber, consistent with the presence of abnormal, giant mitochondria. Taken together, these data suggest that mitochondrial uncoupling occurs in cancer cachexia and thus point to the mitochondria as a potential pharmaceutical target for the treatment of cachexia. These findings may prove relevant to elucidating the mechanisms underlying skeletal muscle wasting observed in other chronic diseases, as well as in aging. PMID:23817738

  7. Leucine supplementation improves skeletal muscle regeneration after cryolesion in rats.

    PubMed

    Pereira, Marcelo G; Baptista, Igor L; Carlassara, Eduardo O C; Moriscot, Anselmo S; Aoki, Marcelo S; Miyabara, Elen H

    2014-01-01

    This study was undertaken in order to provide further insight into the role of leucine supplementation in the skeletal muscle regeneration process, focusing on myofiber size and strength recovery. Young (2-month-old) rats were subjected or not to leucine supplementation (1.35 g/kg per day) started 3 days prior to cryolesion. Then, soleus muscles were cryolesioned and continued receiving leucine supplementation until 1, 3 and 10 days later. Soleus muscles from leucine-supplemented animals displayed an increase in myofiber size and a reduction in collagen type III expression on post-cryolesion day 10. Leucine was also effective in reducing FOXO3a activation and ubiquitinated protein accumulation in muscles at post-cryolesion days 3 and 10. In addition, leucine supplementation minimized the cryolesion-induced decrease in tetanic strength and increase in fatigue in regenerating muscles at post-cryolesion day 10. These beneficial effects of leucine were not accompanied by activation of any elements of the phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin signalling pathway in the regenerating muscles. Our results show that leucine improves myofiber size gain and strength recovery in regenerating soleus muscles through attenuation of protein ubiquitination. In addition, leucine might have therapeutic effects for muscle recovery following injury and in some muscle diseases. PMID:24416379

  8. The Effect of Statins on Skeletal Muscle Function

    PubMed Central

    Parker, Beth A.; Capizzi, Jeffrey A.; Grimaldi, Adam S.; Clarkson, Priscilla M.; Cole, Stephanie M.; Keadle, Justin; Chipkin, Stuart; Pescatello, Linda S.; Simpson, Kathleen; White, C. Michael; Thompson, Paul D.

    2015-01-01

    Background Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials and the effect of statins on muscle performance has not been carefully studied. Methods and Results The Effect of STatins On Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase (CK), exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo were administered for 6 months to 420 healthy, statin-naive subjects. No individual CK value exceeded 10 times normal, but average CK increased 20.8 ± 141.1 U/L (p<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 vs 10; p = 0.05). Myalgic subjects on atorvastatin or placebo decreased muscle strength in 5 of 14 and 4 of 14 variables respectively (p = 0.69). Conclusions These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average CK suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in CK should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. Clinical Trial Registration Information: www.clinicaltrials.gov; Identifier: NCT00609063. PMID:23183941

  9. Skeletal muscle calcineurin: influence of phenotype adaptation and atrophy

    NASA Technical Reports Server (NTRS)

    Spangenburg, E. E.; Williams, J. H.; Roy, R. R.; Talmadge, R. J.; Spangenberg, E. E. (Principal Investigator)

    2001-01-01

    Calcineurin (CaN) has been implicated as a signaling molecule that can transduce physiological stimuli (e.g., contractile activity) into molecular signals that initiate slow-fiber phenotypic gene expression and muscle growth. To determine the influence of muscle phenotype and atrophy on CaN levels in muscle, the levels of soluble CaN in rat muscles of varying phenotype, as assessed by myosin heavy chain (MHC)-isoform proportions, were determined by Western blotting. CaN levels were significantly greater in the plantaris muscle containing predominantly fast (IIx and IIb) MHC isoforms, compared with the soleus (predominantly type I MHC) or vastus intermedius (VI, contains all 4 adult MHC isoforms). Three months after a complete spinal cord transection (ST), the CaN levels in the VI muscle were significantly reduced, despite a significant increase in fast MHC isoforms. Surprisingly, the levels of CaN in the VI were highly correlated with muscle mass but not MHC isoform proportions in ST and control rats. These data demonstrate that CaN levels in skeletal muscle are highly correlated to muscle mass and that the normal relationship with phenotype is lost after ST.

  10. Seven skeletal muscles rich in slow muscle fibers may function to sustain neutral position in the rodent hindlimb.

    PubMed

    Hitomi, Yoshiaki; Kizaki, Takako; Watanabe, Sumiko; Matsumura, George; Fujioka, Yasunori; Haga, Shukoh; Izawa, Tetsuya; Taniguchi, Naoyuki; Ohno, Hideki

    2005-01-01

    Skeletal muscles consist of slow-twitch and fast-twitch muscle fibers, which have distinct physiological and biochemical properties. The muscle fiber composition determines the contractile velocity and fatigability of a particular skeletal muscle. We analyzed the systemic distribution of slow muscle fibers in all rodent skeletal muscles by myosin ATPase staining and found that only seven hindlimb skeletal muscles were extremely rich in slow muscle fibers. These included the mouse piriformis (56.5%), gluteus minimus (35.7%), vastus intermedius (24.7%), quadratus femoris (69.9%), adductor brevis (44.3%), gracilis (24.6%), and soleus muscles (35.1%). In mice, the relative proportion of slow muscle fibers did not exceed 15% in skeletal muscles in other regions. The distribution of slow muscle fibers was well conserved in rats and rabbits. The soleus muscle is an important antigravity muscle in both rodents and humans; therefore, these skeletal muscles rich in slow muscle fibers might play an important role in sustaining neutral alignment of the lower extremity. PMID:15621508

  11. Diffraction Ellipsometry Studies of Skeletal Muscle Structure

    NASA Astrophysics Data System (ADS)

    Kerr, William Lloyd

    Many of the techniques used to study the structure and contraction mechanism of muscle rely on the interaction of light or other electromagnetic radiation with the muscle. Some of the most important of these techniques are light and electron microscopy, x-ray diffraction, spectroscopy of muscle fibers "labelled" with spin or fluorescent probes, visible spectrum diffraction, and transmission birefringence. Chapter I of this dissertation reviews these techniques, focussing on what they have to tell us about muscle structure. In Chapter II, we discuss experiments in which the microstructural features of relaxed, skinned fibers compressed with polyvinylpyrollidone were examined by optical diffraction ellipsometry. The change in polarization state of light after interacting with the muscle is described by the differential field ratio (DFR) and birefringence (Deltan). Compression of single fibers with 0%-21% PVP caused an increase in up to 23% and 31% for DFR and Deltan, respectively. Theoretical modelling suggests that the average S-1 tilt angle may be reduced upon compression of the filament lattice. This is supported by experiments in which S-1 was cleaved with alpha-chymotrypsin. Experiments comparing fibers with intact membranes and skinned fibers compressed to an equivalent lattice spacing showed little difference in DFR or Deltan. Chapter III deals with experiments on contracting, intact fibers. The differential field ratio (DFR) was monitored for tetanically contracting muscle fibers subject to rapid (<0.4 msec) release or stretch. Upon stimulation, DFR decreases 14% from its resting value; the half-time for the decrease leads that of tension rise by 10 msecs. This suggests that the movement of cross -bridges precedes tension development and that the average cross-bridge angle is more perpendicular in the contracting state. Upon rapid release of 0.5% of the fiber length, DFR decreases 9.5% further simultaneous with the length step. Rapid and slow recovery phases were observed. A smaller decrease in DFR was seen upon 0.5% rapid stretch, but a rapid recovery phase was not observed. Our discussion of these results suggests that a crossbridge has internal flexibility, and that an undamped elastic element may reside somewhere in the crossbridge itself.

  12. In vivo muscle amino acid transport involves two distinct processes.

    PubMed

    Miller, Sharon; Chinkes, David; MacLean, David A; Gore, Dennis; Wolfe, Robert R

    2004-07-01

    We have tested the hypothesis that transit through the interstitial fluid, rather than across cell membranes, is rate limiting for amino acid uptake from blood into muscle in human subjects. To quantify muscle transmembrane transport of naturally occurring amino acids, we developed a novel 4-pool model that distinguishes between the interstitial and intracellular fluid compartments. Transport kinetics of phenylalanine, leucine, lysine, and alanine were quantified using tracers labeled with stable isotopes. The results indicate that interstitial fluid is a functional compartment insofar as amino acid kinetics are concerned. In the case of leucine and alanine, transit between blood and interstitial fluid was potentially rate limiting for muscle amino acid uptake and release in the postabsorptive state. For example, in the case of leucine, the rate of transport between blood and interstitial fluid compared with the corresponding rate between interstitial fluid and muscle was 247 +/- 36 vs. 610 +/- 95 nmol.min(-1).100 ml leg(-1), respectively (P < 0.05). Our results are consistent with the process of diffusion governing transit from blood to interstitial fluid without selectivity, and of specific amino acid transport systems with varying degrees of efficiency governing transit from interstitial fluid to muscle. These results imply that changes in factors that affect the transit of amino acids from blood through interstitial fluid, such as muscle blood flow or edema, could play a major role in controlling the rate of muscle amino acid uptake. PMID:15191883

  13. Prolonged bed rest decreases skeletal muscle and whole body protein synthesis

    NASA Technical Reports Server (NTRS)

    Ferrando, A. A.; Lane, H. W.; Stuart, C. A.; Davis-Street, J.; Wolfe, R. R.

    1996-01-01

    We sought to determine the extent to which the loss of lean body mass and nitrogen during inactivity was due to alterations in skeletal muscle protein metabolism. Six male subjects were studied during 7 days of diet stabilization and after 14 days of stimulated microgravity (-6 degrees bed rest). Nitrogen balance became more negative (P < 0.03) during the 2nd wk of bed rest. Leg and whole body lean mass decreased after bed rest (P < 0.05). Serum cortisol, insulin, insulin-like growth factor I, and testosterone values did not change. Arteriovenous model calculations based on the infusion of L-[ring-13C6]-phenylalanine in five subjects revealed a 50% decrease in muscle protein synthesis (PS; P < 0.03). Fractional PS by tracer incorporation into muscle protein also decreased by 46% (P < 0.05). The decrease in PS was related to a corresponding decrease in the sum of intracellular amino acid appearance from protein breakdown and inward transport. Whole body protein synthesis determined by [15N]alanine ingestion on six subjects also revealed a 14% decrease (P < 0.01). Neither model-derived nor whole body values for protein breakdown change significantly. These results indicate that the loss of body protein with inactivity is predominantly due to a decrease in muscle PS and that this decrease is reflected in both whole body and skeletal muscle measures.

  14. Abnormal skeletal muscle bioenergetics in familial hypertrophic cardiomyopathy.

    PubMed Central

    Thompson, C. H.; Kemp, G. J.; Taylor, D. J.; Conway, M.; Rajagopalan, B.; O'Donoghue, A.; Styles, P.; McKenna, W. J.; Radda, G. K.

    1997-01-01

    OBJECTIVE: To determine the skeletal muscle metabolic manifestations of familial hypertrophic cardiomyopathy. DESIGN: A case-control study. SETTING: 31P magnetic resonance spectroscopy of the calf muscle was performed on volunteers from a centre specialising in familial hypertrophic cardiomyopathy. PATIENTS: Five patients with abnormal beta myosin heavy chain protein in cardiac and skeletal muscle and five patients with a troponin T abnormality in cardiac muscle were compared with healthy controls. RESULTS: High energy phosphate metabolism in vivo was examined in a non-invasive manner. In resting muscle, the beta myosin heavy chain group had a higher ratio of phosphocreatine to ATP concentration (4.51 (SD 0.17)) than either the troponin T group (3.88 (0.42)) or controls (n = 16; 4.04 (0.40)). Exercise duration was reduced compared to controls, and during the fourth minute of exercise phosphocreatine depletion and muscle acidification were greater in both patient groups. After exercise, the recovery of phosphocreatine-an index of oxidative metabolic capacity of the muscle-was slower in the beta myosin heavy chain group (mean half time 0.65 (0.08) minutes) than in the troponin T group (0.60 (0.17) minutes) or controls (0.48 (0.14) minutes). CONCLUSIONS: Exercise metabolism was abnormal in both groups of subjects, and the affected contractile protein determined the metabolic changes in muscle at rest and during recovery. In patients with abnormal beta myosin heavy chain protein, there was a decrease in oxidative capacity consistent with the reduction in mitochondria reported in muscle biopsy studies of similar patients. PMID:9326994

  15. Fragility fracture risk and skeletal muscle function.

    PubMed

    Pérez-López, F R; Ara, I

    2016-02-01

    Low-intensity fractures are closely related with age-related musculoskeletal disorders, including osteoporosis, muscle dysfunction and sarcopenia, age-related chronic diseases, and pharmacological treatments. During the last years, a huge amount of information and recommendations has been released in relation to bone metabolism and mineral content. Muscle dysfunction and sarcopenia are highly prevalent during the second half of life, especially in older subjects. The development of sarcopenia may be slowed through healthy lifestyle changes, which include adequate dietary protein, vitamin D and mineral intakes, and regular physical activity. Prevention of falls should be integral, including correction in major involved factors in order to reduce fragility fracture, improve quality of life and appropriately focus clinical and economic resources. Therefore, to obtain better results a global approach is needed to prevent age-related fractures in frail patients that is not only centered on bone metabolism and antiresorptive drugs. PMID:26588486

  16. Insulin action in denervated skeletal muscle

    SciTech Connect

    Smith, R.L.

    1987-01-01

    The goal of this study was to determine the mechanisms responsible for reduced insulin response in denervated muscle. Denervation for 3 days of rat muscles consisting of very different compositions of fiber types decreased insulin stimulated (U-/sup 14/C)glucose incorporation into glycogen by 80%. Associated with the reduction in glycogen synthesis was a decreased activation of glycogen synthase. Denervation of hemidiaphragms for 1 day decreased both the basal and insulin stimulated activity ratios of glycogen synthase and the rate of insulin stimulated (U-/sup 14/C(glucose incorporation into glycogen by 50%. Insulin stimulation of 2-deoxy(/sup 3/H)glucose uptake was not decreased until 3 days after denervation. Consistent with the effects on glucose transport,insulin did not increase the intracellular concentration of glucose-6-P in muscles 3 days after denervation. Furthermore, since the Ka for glucose-6-P activation of glycogen synthase was not decreased by insulin in denervated hemidiaphragms, the effects of denervation on glycogen synthase and glucose transport were synergistic resulting in the 80% decrease in glycogen synthesis rates.

  17. Sarcoglycans in human skeletal muscle and human cardiac muscle: a confocal laser scanning microscope study.

    PubMed

    Anastasi, G; Cutroneo, G; Trimarchi, F; Rizzo, G; Bramanti, P; Bruschetta, D; Fugazzotto, D; Cinelli, M P; Soscia, A; Santoro, G; Favaloro, A

    2003-01-01

    Sarcoglycans are a subcomplex of transmembrane proteins which are part of the dystrophin-glycoprotein complex. They are expressed in the skeletal, cardiac and smooth muscle. Although numerous studies have been conducted on the sarcoglycan subcomplex in skeletal and cardiac muscle, the manner of the distribution and localization of these proteins along the nonjunctional sarcolemma is not clear. We therefore carried out an indirect immunofluorescence study on surgical biopsies of normal human skeletal muscle and of healthy human atrial myocardium biopsies of patients affected by valvulopathy. Our results indicate that, in skeletal muscle, sarcoglycans have a costameric distribution and all colocalize with each other. Only in a few cases did the alpha-sarcoglycan not colocalize with other sarcoglycans. In addition, these glycoproteins can be localized in different fibers either in the regions of the sarcolemma over band I or band A. In cardiac muscle, our results show a costameric distribution of all proteins examined and, unlike in skeletal muscle, they show a constant colocalization of all sarcoglycans with each other, along with a consistent localization of these proteins in the region of the sarcolemma over band I. In our opinion, this situation seems to confirm the hypothesis of a correlation between the region of the sarcolemma occupied by costameric proteins and the metabolic type, fast or slow, of the muscular fibers. These data, besides opening a new line of research in understanding interactions between the sarcoglycans and other transmembrane proteins, could also be extended to skeletal and cardiac muscles affected by neuromuscular and cardiovascular pathologies to understand possible structural alterations. PMID:12566627

  18. Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy

    PubMed Central

    Bongers, Kale S.; Fox, Daniel K.; Kunkel, Steven D.; Stebounova, Larissa V.; Murry, Daryl J.; Pufall, Miles A.; Ebert, Scott M.; Dyle, Michael C.; Bullard, Steven A.; Dierdorff, Jason M.

    2014-01-01

    Skeletal muscle atrophy is a common and debilitating condition that remains poorly understood at the molecular level. To better understand the mechanisms of muscle atrophy, we used mouse models to search for a skeletal muscle protein that helps to maintain muscle mass and is specifically lost during muscle atrophy. We discovered that diverse causes of muscle atrophy (limb immobilization, fasting, muscle denervation, and aging) strongly reduced expression of the enzyme spermine oxidase. Importantly, a reduction in spermine oxidase was sufficient to induce muscle fiber atrophy. Conversely, forced expression of spermine oxidase increased muscle fiber size in multiple models of muscle atrophy (immobilization, fasting, and denervation). Interestingly, the reduction of spermine oxidase during muscle atrophy was mediated by p21, a protein that is highly induced during muscle atrophy and actively promotes muscle atrophy. In addition, we found that spermine oxidase decreased skeletal muscle mRNAs that promote muscle atrophy (e.g., myogenin) and increased mRNAs that help to maintain muscle mass (e.g., mitofusin-2). Thus, in healthy skeletal muscle, a relatively low level of p21 permits expression of spermine oxidase, which helps to maintain basal muscle gene expression and fiber size; conversely, during conditions that cause muscle atrophy, p21 expression rises, leading to reduced spermine oxidase expression, disruption of basal muscle gene expression, and muscle fiber atrophy. Collectively, these results identify spermine oxidase as an important positive regulator of muscle gene expression and fiber size, and elucidate p21-mediated repression of spermine oxidase as a key step in the pathogenesis of skeletal muscle atrophy. PMID:25406264

  19. Spermine oxidase maintains basal skeletal muscle gene expression and fiber size and is strongly repressed by conditions that cause skeletal muscle atrophy.

    PubMed

    Bongers, Kale S; Fox, Daniel K; Kunkel, Steven D; Stebounova, Larissa V; Murry, Daryl J; Pufall, Miles A; Ebert, Scott M; Dyle, Michael C; Bullard, Steven A; Dierdorff, Jason M; Adams, Christopher M

    2015-01-15

    Skeletal muscle atrophy is a common and debilitating condition that remains poorly understood at the molecular level. To better understand the mechanisms of muscle atrophy, we used mouse models to search for a skeletal muscle protein that helps to maintain muscle mass and is specifically lost during muscle atrophy. We discovered that diverse causes of muscle atrophy (limb immobilization, fasting, muscle denervation, and aging) strongly reduced expression of the enzyme spermine oxidase. Importantly, a reduction in spermine oxidase was sufficient to induce muscle fiber atrophy. Conversely, forced expression of spermine oxidase increased muscle fiber size in multiple models of muscle atrophy (immobilization, fasting, and denervation). Interestingly, the reduction of spermine oxidase during muscle atrophy was mediated by p21, a protein that is highly induced during muscle atrophy and actively promotes muscle atrophy. In addition, we found that spermine oxidase decreased skeletal muscle mRNAs that promote muscle atrophy (e.g., myogenin) and increased mRNAs that help to maintain muscle mass (e.g., mitofusin-2). Thus, in healthy skeletal muscle, a relatively low level of p21 permits expression of spermine oxidase, which helps to maintain basal muscle gene expression and fiber size; conversely, during conditions that cause muscle atrophy, p21 expression rises, leading to reduced spermine oxidase expression, disruption of basal muscle gene expression, and muscle fiber atrophy. Collectively, these results identify spermine oxidase as an important positive regulator of muscle gene expression and fiber size, and elucidate p21-mediated repression of spermine oxidase as a key step in the pathogenesis of skeletal muscle atrophy. PMID:25406264

  20. Skeletal Muscle Catabolism in TNBS-Induced Murine Colitis

    PubMed Central

    Puleo, Frances; Meirelles, Katia; Navaratnarajah, Maithili; Fitzpatrick, Leo; Shumate, Margaret L.; Cooney, Robert N.; Lang, Charles H.

    2010-01-01

    The present study determined whether the muscle atrophy produced by colitis is associated with altered rates of muscle protein synthesis or degradation, as well as the potential role of the local (e.g., muscle) insulin-like growth factor (IGF) system and muscle-specific ubiquitin E3 ligases atrogin-1 and MuRF1 in mediating altered muscle protein balance. Colitis was induced in C57BL/6 mice by intra-rectal administration of trinitrobenzne sulfonic acid (TNBS), and blood and tissues collected on day 10. Mice with inflammatory bowel disease (IBD) demonstrated reduced skeletal muscle mass and protein content, whereas colonic segment weight and gross damage score were both increased in mice with colitis, compared to time-matched control values. There was no change in muscle protein synthesis in mice with IBD, but there was an increased protein breakdown (45%), proteasome activity (85%), and mRNA expression for atrogin-1 and MuRF1 (200–300%) in muscle. These changes were associated with a reduction in liver (but not muscle) IGF-I mRNA as well as a reduction in both total and free IGF-I in the blood. Colitis decreased the hepatic content of IGF binding protein (IGFBP)-3 mRNA by 40% and increased IGFBP-1 mRNA by 100%. In contrast, colitis did alter IGFBP mRNAs in muscle. The TNFα, IL-6 and NOS2 mRNA content of both liver and skeletal muscle was increased in TNBS-treated mice, and plasma TNFα and IL-6 concentrations were also elevated. These data suggest TNBS-induced colitis is independent of a change in muscle protein synthesis but dependent on stimulation of protein degradation via increased expression of muscle-specific atrogenes, which may be mediated in part by the reduction in circulating concentration of IGF-I and the concomitant increase in inflammatory mediators observed in the blood and muscle per se. PMID:20546811

  1. Direct optical activation of skeletal muscle fibres efficiently controls muscle contraction and attenuates denervation atrophy

    PubMed Central

    Magown, Philippe; Shettar, Basavaraj; Zhang, Ying; Rafuse, Victor F.

    2015-01-01

    Neural prostheses can restore meaningful function to paralysed muscles by electrically stimulating innervating motor axons, but fail when muscles are completely denervated, as seen in amyotrophic lateral sclerosis, or after a peripheral nerve or spinal cord injury. Here we show that channelrhodopsin-2 is expressed within the sarcolemma and T-tubules of skeletal muscle fibres in transgenic mice. This expression pattern allows for optical control of muscle contraction with comparable forces to nerve stimulation. Force can be controlled by varying light pulse intensity, duration or frequency. Light-stimulated muscle fibres depolarize proportionally to light intensity and duration. Denervated triceps surae muscles transcutaneously stimulated optically on a daily basis for 10 days show a significant attenuation in atrophy resulting in significantly greater contractile forces compared with chronically denervated muscles. Together, this study shows that channelrhodopsin-2/H134R can be used to restore function to permanently denervated muscles and reduce pathophysiological changes associated with denervation pathologies. PMID:26460719

  2. ATP citrate lyase improves mitochondrial function in skeletal muscle.

    PubMed

    Das, Suman; Morvan, Frederic; Jourde, Benjamin; Meier, Viktor; Kahle, Peter; Brebbia, Pascale; Toussaint, Gauthier; Glass, David J; Fornaro, Mara

    2015-06-01

    Mitochondrial dysfunction is associated with skeletal muscle pathology, including cachexia, sarcopenia, and the muscular dystrophies. ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes mitochondria-derived citrate into oxaloacetate and acetyl-CoA. Here we report that activation of ACL in skeletal muscle results in improved mitochondrial function. IGF1 induces activation of ACL in an AKT-dependent fashion. This results in an increase in cardiolipin, thus increasing critical mitochondrial complexes and supercomplex activity, and a resultant increase in oxygen consumption and cellular ATP levels. Conversely, knockdown of ACL in myotubes not only reduces mitochondrial complex I, IV, and V activity but also blocks IGF1-induced increases in oxygen consumption. In vivo, ACL activity is associated with increased ATP. Activation of this IGF1/ACL/cardiolipin pathway combines anabolic signaling with induction of mechanisms needed to provide required ATP. PMID:26039450

  3. Muscle Atrophy in Response to Cytotoxic Chemotherapy Is Dependent on Intact Glucocorticoid Signaling in Skeletal Muscle

    PubMed Central

    Braun, Theodore P.; Szumowski, Marek; Levasseur, Peter R.; Grossberg, Aaron J.; Zhu, XinXia; Agarwal, Anupriya; Marks, Daniel L.

    2014-01-01

    Cancer cachexia is a syndrome of weight loss that results from the selective depletion of skeletal muscle mass and contributes significantly to cancer morbidity and mortality. The driver of skeletal muscle atrophy in cancer cachexia is systemic inflammation arising from both the cancer and cancer treatment. While the importance of tumor derived inflammation is well described, the mechanism by which cytotoxic chemotherapy contributes to cancer cachexia is relatively unexplored. We found that the administration of chemotherapy to mice produces a rapid inflammatory response. This drives activation of the hypothalamic-pituitary-adrenal axis, which increases the circulating level of corticosterone, the predominant endogenous glucocorticoid in rodents. Additionally, chemotherapy administration results in a significant loss of skeletal muscle mass 18 hours after administration with a concurrent induction of genes involved with the ubiquitin proteasome and autophagy lysosome systems. However, in mice lacking glucocorticoid receptor expression in skeletal muscle, chemotherapy-induced muscle atrophy is completely blocked. This demonstrates that cytotoxic chemotherapy elicits significant muscle atrophy driven by the production of endogenous glucocorticoids. Further, it argues that pharmacotherapy targeting the glucocorticoid receptor, given in concert with chemotherapy, is a viable therapeutic strategy in the treatment of cancer cachexia. PMID:25254959

  4. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

    NASA Astrophysics Data System (ADS)

    Stump, Craig S.; Short, Kevin R.; Bigelow, Maureen L.; Schimke, Jill M.; Sreekumaran Nair, K.

    2003-06-01

    Mitochondria are the primary site of skeletal muscle fuel metabolism and ATP production. Although insulin is a major regulator of fuel metabolism, its effect on mitochondrial ATP production is not known. Here we report increases in vastus lateralis muscle mitochondrial ATP production capacity (32-42%) in healthy humans (P < 0.01) i.v. infused with insulin (1.5 milliunits/kg of fat-free mass per min) while clamping glucose, amino acids, glucagon, and growth hormone. Increased ATP production occurred in association with increased mRNA levels from both mitochondrial (NADH dehydrogenase subunit IV) and nuclear [cytochrome c oxidase (COX) subunit IV] genes (164-180%) encoding mitochondrial proteins (P < 0.05). In addition, muscle mitochondrial protein synthesis, and COX and citrate synthase enzyme activities were increased by insulin (P < 0.05). Further studies demonstrated no effect of low to high insulin levels on muscle mitochondrial ATP production for people with type 2 diabetes mellitus, whereas matched nondiabetic controls increased 16-26% (P < 0.02) when four different substrate combinations were used. In conclusion, insulin stimulates mitochondrial oxidative phosphorylation in skeletal muscle along with synthesis of gene transcripts and mitochondrial protein in human subjects. Skeletal muscle of type 2 diabetic patients has a reduced capacity to increase ATP production with high insulin levels. cytochrome c oxidase | NADH dehydrogenase subunit IV | amino acids | citrate synthase

  5. Developmental Programming of Fetal Skeletal Muscle and Adipose Tissue Development

    PubMed Central

    Yan, Xu; Zhu, Mei-Jun; Dodson, Michael V.; Du, Min

    2013-01-01

    All important developmental milestones are accomplished during the fetal stage, and nutrient fluctuation during this stage produces lasting effects on offspring health, so called fetal programming or developmental programming. The fetal stage is critical for skeletal muscle development, as well as adipose and connective tissue development. Maternal under-nutrition at this stage affects the proliferation of myogenic precursor cells and reduces the number of muscle fibers formed. Maternal over-nutrition results in impaired myogenesis and elevated adipogenesis. Because myocytes, adipocytes and fibrocytes are all derived from mesenchymal stem cells, molecular events which regulate the commitment of stem cells to different lineages directly impact fetal muscle and adipose tissue development. Recent studies indicate that microRNA is intensively involved in myogenic and adipogenic differentiation from mesenchymal stem cells, and epigenetic changes such as DNA methylation are expected to alter cell lineage commitment during fetal muscle and adipose tissue development. PMID:25031653

  6. Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle

    PubMed Central

    Kerr, Jaclyn P.; Robison, Patrick; Shi, Guoli; Bogush, Alexey I.; Kempema, Aaron M.; Hexum, Joseph K.; Becerra, Natalia; Harki, Daniel A.; Martin, Stuart S.; Raiteri, Roberto; Prosser, Benjamin L.; Ward, Christopher W.

    2015-01-01

    In striated muscle, X-ROS is the mechanotransduction pathway by which mechanical stress transduced by the microtubule network elicits reactive oxygen species. X-ROS tunes Ca2+ signalling in healthy muscle, but in diseases such as Duchenne muscular dystrophy (DMD), microtubule alterations drive elevated X-ROS, disrupting Ca2+ homeostasis and impairing function. Here we show that detyrosination, a post-translational modification of α-tubulin, influences X-ROS signalling, contraction speed and cytoskeletal mechanics. In the mdx mouse model of DMD, the pharmacological reduction of detyrosination in vitro ablates aberrant X-ROS and Ca2+ signalling, and in vivo it protects against hallmarks of DMD, including workload-induced arrhythmias and contraction-induced injury in skeletal muscle. We conclude that detyrosinated microtubules increase cytoskeletal stiffness and mechanotransduction in striated muscle and that targeting this post-translational modification may have broad therapeutic potential in muscular dystrophies. PMID:26446751

  7. Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle.

    PubMed

    Kaur, Jasdeep; Machado, Tiago M; Alvarez, Alberto; Krishnan, Abhinav C; Hanna, Hanna W; Altamimi, Yasir H; Senador, Danielle; Spranger, Marty D; O'Leary, Donal S

    2015-12-15

    Metabolite accumulation due to ischemia of active skeletal muscle stimulates group III/IV chemosensitive afferents eliciting reflex increases in arterial blood pressure and sympathetic activity, termed the muscle metaboreflex. We and others have previously demonstrated sympathetically mediated vasoconstriction of coronary, renal, and forelimb vasculatures with muscle metaboreflex activation (MMA). Whether MMA elicits vasoconstriction of the ischemic muscle from which it originates is unknown. We hypothesized that the vasodilation in active skeletal muscle with imposed ischemia becomes progressively restrained by the increasing sympathetic vasoconstriction during MMA. We activated the metaboreflex during mild dynamic exercise in chronically instrumented canines via graded reductions in hindlimb blood flow (HLBF) before and after α1-adrenergic blockade [prazosin (50 μg/kg)], β-adrenergic blockade [propranolol (2 mg/kg)], and α1 + β-blockade. Hindlimb resistance was calculated as femoral arterial pressure/HLBF. During mild exercise, HLBF must be reduced below a threshold level before the reflex is activated. With initial reductions in HLBF, vasodilation occurred with the imposed ischemia. Once the muscle metaboreflex was elicited, hindlimb resistance increased. This increase in hindlimb resistance was abolished by α1-adrenergic blockade and exacerbated after β-adrenergic blockade. We conclude that metaboreflex activation during submaximal dynamic exercise causes sympathetically mediated α-adrenergic vasoconstriction in ischemic skeletal muscle. This limits the ability of the reflex to improve blood flow to the muscle. PMID:26475591

  8. Methods for the Organogenesis of Skeletal Muscle in Tissue Culture

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman; Shansky, Janet; DelTatto, Michael; Chromiak, Joseph

    1997-01-01

    Skeletal muscle structure is regulated by many factors, including nutrition, hormones, electrical activity, and tension. The muscle cells are subjected to both passive and active mechanical forces at all stages of development and these forces play important but poorly understood roles in regulating muscle organogenesis and growth. For example, during embryogenesis, the rapidly growing skeleton places large passive mechanical forces on the attached muscle tissue. These forces not only help to organize the proliferating mononucleated myoblasts into the oriented, multinucleated myofibers of a functional muscle but also tightly couple the growth rate of muscle to that of bone. Postnatally, the actively contracting, innervated muscle fibers are subjected to different patterns of active and passive tensions which regulate longitudinal and cross sectional myofiber growth. These mechanically-induced organogenic processes have been difficult to study under normal tissue culture conditions, resulting in the development of numerous methods and specialized equipment to simulate the in vivo mechanical environment.These techniques have led to the "engineering" of bioartificial muscles (organoids) which display many of the characteristics of in vivo muscle including parallel arrays of postmitotic fibers organized into fascicle-like structures with tendon-like ends. They are contractile, express adult isoforms of contractile proteins, perform directed work, and can be maintained in culture for long periods. The in vivo-like characteristics and durability of these muscle organoids make them useful for long term in vitro studies on mechanotransduction mechanisms and on muscle atrophy induced by decreased tension. In this report, we described a simple method for generating muscle organoids from either primary embrionic avain or neonatal rodent myoblasts.

  9. cap alpha. -skeletal and. cap alpha. -cardiac actin genes are coexpressed in adult human skeletal muscle and heart

    SciTech Connect

    Gunning, P.; Ponte, P.; Blau, H.; Kedes, L.

    1983-11-01

    The authors determined the actin isotypes encoded by 30 actin cDNA clones previously isolated from an adult human muscle cDNA library. Using 3' untranslated region probes, derived from ..cap alpha.. skeletal, ..beta..- and ..gamma..-actin cDNAs and from an ..cap alpha..-cardiac actin genomic clone, they showed that 28 of the cDNAs correspond to ..cap alpha..-skeletal actin transcripts. Unexpectedly, however, the remaining two cDNA clones proved to derive from ..cap alpha..-cardiac actin mRNA. Sequence analysis confirmed that the two skeletal muscle ..cap alpha..-cardiac actin cDNAs are derived from transcripts of the cloned ..cap alpha..-cardiac actin gene. Comparison of total actin mRNA levels in adult skeletal muscle and adult heart revealed that the steady-state levels in skeletal muscle are about twofold greater, per microgram of total cellular RNA, than those in heart. Thus, in skeletal muscle and in heart, both of the sarcomeric actin mRNA isotypes are quite abundant transcripts. They conclude that ..cap alpha..-skeletal and ..cap alpha..-cardiac actin genes are coexpressed as an actin pair in human adult striated muscles. Since the smooth-muscle actins (aortic and stomach) and the cytoplasmic actins (..beta.. and ..gamma..) are known to be coexpressed in smooth muscle and nonmuscle cells, respectively, they postulate that coexpression of actin pairs may be a common feature of mammalian actin gene expression in all tissues.

  10. Receptor Expression in Rat Skeletal Muscle Cell Cultures

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.

    1996-01-01

    One on the most persistent problems with long-term space flight is atrophy of skeletal muscles. Skeletal muscle is unique as a tissue in the body in that its ability to undergo atrophy or hypertrophy is controlled exclusively by cues from the extracellular environment. The mechanism of communication between muscle cells and their environment is through a group of membrane-bound and soluble receptors, each of which carries out unique, but often interrelated, functions. The primary receptors include acetyl choline receptors, beta-adrenergic receptors, glucocorticoid receptors, insulin receptors, growth hormone (i.e., somatotropin) receptors, insulin-like growth factor receptors, and steroid receptors. This project has been initiated to develop an integrated approach toward muscle atrophy and hypertrophy that takes into account information on the populations of the entire group of receptors (and their respective hormone concentrations), and it is hypothesized that this information can form the basis for a predictive computer model for muscle atrophy and hypertrophy. The conceptual basis for this project is illustrated in the figure below. The individual receptors are shown as membrane-bound, with the exception of the glucocorticoid receptor which is a soluble intracellular receptor. Each of these receptors has an extracellular signalling component (e.g., innervation, glucocorticoids, epinephrine, etc.), and following the interaction of the extracellular component with the receptor itself, an intracellular signal is generated. Each of these intracellular signals is unique in its own way; however, they are often interrelated.

  11. Mechanical stimulation improves tissue-engineered human skeletal muscle

    NASA Technical Reports Server (NTRS)

    Powell, Courtney A.; Smiley, Beth L.; Mills, John; Vandenburgh, Herman H.

    2002-01-01

    Human bioartificial muscles (HBAMs) are tissue engineered by suspending muscle cells in collagen/MATRIGEL, casting in a silicone mold containing end attachment sites, and allowing the cells to differentiate for 8 to 16 days. The resulting HBAMs are representative of skeletal muscle in that they contain parallel arrays of postmitotic myofibers; however, they differ in many other morphological characteristics. To engineer improved HBAMs, i.e., more in vivo-like, we developed Mechanical Cell Stimulator (MCS) hardware to apply in vivo-like forces directly to the engineered tissue. A sensitive force transducer attached to the HBAM measured real-time, internally generated, as well as externally applied, forces. The muscle cells generated increasing internal forces during formation which were inhibitable with a cytoskeleton depolymerizer. Repetitive stretch/relaxation for 8 days increased the HBAM elasticity two- to threefold, mean myofiber diameter 12%, and myofiber area percent 40%. This system allows engineering of improved skeletal muscle analogs as well as a nondestructive method to determine passive force and viscoelastic properties of the resulting tissue.

  12. Effect of microwave electromagnetic field on skeletal muscle fibre activity.

    PubMed

    Radicheva, N; Mileva, K; Vukova, T; Georgieva, B; Kristev, I

    2002-07-01

    The aim of the present study was to investigate the influence of microwave irradiation on fatiguing activity of isolated frog skeletal muscle fibres. The changes in the electrical and mechanical activity were used as criteria for the exposure effects. Repetitive suprathreshold stimulation with interstimulus interval of 200 ms for 3 min was applied. Intracellular (ICAP) and extracellular (ECAP) action potentials and twitch contractions (Tw) of muscle fibres after 1 hour microwave exposure (2.45 GHz, 20 mW/cm( 2) power density) were compared with those recorded after one hour sham exposure (control). The duration of uninterrupted activity in the trial (endurance time; ET) was not significantly affected by microwave field exposure. After microwave irradiation, the ICAP amplitude was higher, the rising time was shorter, and the resting membrane potential was more negative compared to controls. There was a slower rate of parameters changes during ET in potentials obtained from irradiated fibres. Microwave exposure increased the propagation velocity of excitation, the ECAP and Tw amplitudes, as well as shortened their time parameters. We concluded that a 2.45 GHz microwave field possesses a stimulating effect on muscle fibre activity, which is in part due to its specific, non-thermal properties. The microwave induced-changes in muscle fibre activity may reduce development of skeletal muscle fatigue. PMID:12221521

  13. The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis.

    PubMed

    Loeffler, Jean-Philippe; Picchiarelli, Gina; Dupuis, Luc; Gonzalez De Aguilar, Jose-Luis

    2016-03-01

    Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets. PMID:26780251

  14. Skeletal muscle responses to negative energy balance: effects of dietary protein.

    PubMed

    Carbone, John W; McClung, James P; Pasiakos, Stefan M

    2012-03-01

    Sustained periods of negative energy balance decrease body mass due to losses of both fat and skeletal muscle mass. Decreases in skeletal muscle mass are associated with a myriad of negative consequences, including suppressed basal metabolic rate, decreased protein turnover, decreased physical performance, and increased risk of injury. Decreases in skeletal muscle mass in response to negative energy balance are due to imbalanced rates of muscle protein synthesis and degradation. However, the underlying physiological mechanisms contributing to the loss of skeletal muscle during energy deprivation are not well described. Recent studies have demonstrated that consuming dietary protein at levels above the current recommended dietary allowance (0.8 g · kg(-1) · d(-1)) may attenuate the loss of skeletal muscle mass by affecting the intracellular regulation of muscle anabolism and proteolysis. However, the specific mechanism by which increased dietary protein spares skeletal muscle through enhanced molecular control of muscle protein metabolism has not been elucidated. This article reviews the available literature related to the effects of negative energy balance on skeletal muscle mass, highlighting investigations that assessed the influence of varying levels of dietary protein on skeletal muscle protein metabolism. Further, the molecular mechanisms that may contribute to the regulation of skeletal muscle mass in response to negative energy balance and alterations in dietary protein level are described. PMID:22516719

  15. An In Vitro Model of Skeletal Muscle Volume Regulation

    PubMed Central

    Wibberley, Anna; Staunton, Caroline A.; Feetham, Claire H.; Vereninov, Alexey A.; Barrett-Jolley, Richard

    2015-01-01

    Introduction Hypertonic media causes cells to shrink due to water loss through aquaporin channels. After acute shrinkage, cells either regulate their volume or, alternatively, undergo a number of metabolic changes which ultimately lead to cell death. In many cell types, hypertonic shrinkage is followed by apoptosis. Due to the complex 3D morphology of skeletal muscle and the difficulty in obtaining isolated human tissue, we have begun skeletal muscle volume regulation studies using the human skeletal muscle cell line TE671RD. In this study we investigated whether hypertonic challenge of the human skeletal muscle cell line TE671RD triggered cell death or evoked a cell volume recovery response. Methods The cellular volume of TE671RD cells was calculated from the 2D surface area. Cell death was assessed by both the trypan blue live/dead assay and the TUNEL assay. Results Medium osmolality was increased by addition of up to 200mM sucrose. Addition of 200mM sucrose resulted in mean cell shrinkage of 44±1% after 30mins. At later time points (2 and 4 hrs) two separate cell subpopulations with differing mean cell volume became apparent. The first subpopulation (15±2% of the total cell number) continued to shrink whereas the second subpopulation had an increased cell volume. Cell death was observed in a small proportion of cells (approximately 6-8%). Conclusion We have established that a substantial proportion of TE671RD cells respond to hypertonic challenge with RVI, but that these cells are resistant to hypertonicity triggered cell death. PMID:26029913

  16. Prioritization of skeletal muscle growth for emergence from hibernation.

    PubMed

    Hindle, Allyson G; Otis, Jessica P; Epperson, L Elaine; Hornberger, Troy A; Goodman, Craig A; Carey, Hannah V; Martin, Sandra L

    2015-01-15

    Mammalian hibernators provide an extreme example of naturally occurring challenges to muscle homeostasis. The annual hibernation cycle is characterized by shifts between summer euthermy with tissue anabolism and accumulation of body fat reserves, and winter heterothermy with fasting and tissue catabolism. The circannual patterns of skeletal muscle remodelling must accommodate extended inactivity during winter torpor, the motor requirements of transient winter active periods, and sustained activity following spring emergence. Muscle volume in thirteen-lined ground squirrels (Ictidomys tridecemlineatus) calculated from MRI upper hindlimb images (n=6 squirrels, n=10 serial scans) declined from hibernation onset, reaching a nadir in early February. Paradoxically, mean muscle volume rose sharply after February despite ongoing hibernation, and continued total body mass decline until April. Correspondingly, the ratio of muscle volume to body mass was steady during winter atrophy (October-February) but increased (+70%) from February to May, which significantly outpaced changes in liver or kidney examined by the same method. Generally stable myocyte cross-sectional area and density indicated that muscle remodelling is well regulated in this hibernator, despite vastly altered seasonal fuel and activity levels. Body composition analysis by echo MRI showed lean tissue preservation throughout hibernation amid declining fat mass by the end of winter. Muscle protein synthesis was 66% depressed in early but not late winter compared with a summer fasted baseline, while no significant changes were observed in the heart, liver or intestine, providing evidence that could support a transition in skeletal muscle regulation between early and late winter, prior to spring emergence and re-feeding. PMID:25452506

  17. Prioritization of skeletal muscle growth for emergence from hibernation

    PubMed Central

    Hindle, Allyson G.; Otis, Jessica P.; Epperson, L. Elaine; Hornberger, Troy A.; Goodman, Craig A.; Carey, Hannah V.; Martin, Sandra L.

    2015-01-01

    Mammalian hibernators provide an extreme example of naturally occurring challenges to muscle homeostasis. The annual hibernation cycle is characterized by shifts between summer euthermy with tissue anabolism and accumulation of body fat reserves, and winter heterothermy with fasting and tissue catabolism. The circannual patterns of skeletal muscle remodelling must accommodate extended inactivity during winter torpor, the motor requirements of transient winter active periods, and sustained activity following spring emergence. Muscle volume in thirteen-lined ground squirrels (Ictidomys tridecemlineatus) calculated from MRI upper hindlimb images (n=6 squirrels, n=10 serial scans) declined from hibernation onset, reaching a nadir in early February. Paradoxically, mean muscle volume rose sharply after February despite ongoing hibernation, and continued total body mass decline until April. Correspondingly, the ratio of muscle volume to body mass was steady during winter atrophy (October–February) but increased (+70%) from February to May, which significantly outpaced changes in liver or kidney examined by the same method. Generally stable myocyte cross-sectional area and density indicated that muscle remodelling is well regulated in this hibernator, despite vastly altered seasonal fuel and activity levels. Body composition analysis by echo MRI showed lean tissue preservation throughout hibernation amid declining fat mass by the end of winter. Muscle protein synthesis was 66% depressed in early but not late winter compared with a summer fasted baseline, while no significant changes were observed in the heart, liver or intestine, providing evidence that could support a transition in skeletal muscle regulation between early and late winter, prior to spring emergence and re-feeding. PMID:25452506

  18. Cell death, clearance and immunity in the skeletal muscle.

    PubMed

    Sciorati, C; Rigamonti, E; Manfredi, A A; Rovere-Querini, P

    2016-06-01

    The skeletal muscle is an immunologically unique tissue. Leukocytes, virtually absent in physiological conditions, are quickly recruited into the tissue upon injury and persist during regeneration. Apoptosis, necrosis and autophagy coexist in the injured/regenerating muscles, including those of patients with neuromuscular disorders, such as inflammatory myopathies, dystrophies, metabolic and mitochondrial myopathies and drug-induced myopathies. Macrophages are able to alter their function in response to microenvironment conditions and as a consequence coordinate changes within the tissue from the early injury throughout regeneration and eventual healing, and regulate the activation and the function of stem cells. Early after injury, classically activated macrophages ('M1') dominate the picture. Alternatively activated M2 macrophages predominate during resolution phases and regulate the termination of the inflammatory responses. The dynamic M1/M2 transition is increasingly felt to be the key to the homeostasis of the muscle. Recognition and clearance of debris originating from damaged myofibers and from dying stem/progenitor cells, stromal cells and leukocytes are fundamental actions of macrophages. Clearance of apoptotic cells and M1/M2 transition are causally connected and represent limiting steps for muscle healing. The accumulation of apoptotic cells, which reflects their defective clearance, has been demonstrated in various tissues to prompt autoimmunity against intracellular autoantigens. In the muscle, in the presence of type I interferon, apoptotic myoblasts indeed cause the production of autoantibodies, lymphocyte infiltration and continuous cycles of muscle injury and regeneration, mimicking human inflammatory myopathies. The clearance of apoptotic cells thus modulates the homeostatic response of the skeletal muscle to injury. Conversely, defects in the process may have deleterious local effects, guiding maladaptive tissue remodeling with collagen and fat accumulation and promoting autoimmunity itself. There is strong promise for novel treatments based on new knowledge of cell death, clearance and immunity in the muscle. PMID:26868912

  19. Postnatal ontogeny of skeletal muscle protein synthesis in pigs1,2

    PubMed Central

    Davis, T. A.; Suryawan, A.; Orellana, R. A.; Nguyen, H. V.; Fiorotto, M. L.

    2009-01-01

    The neonatal period is characterized by rapid growth and elevated rates of synthesis and accretion of skeletal muscle proteins. The fractional rate of muscle protein synthesis is very high at birth and declines rapidly with age. The elevated capacity for muscle protein synthesis in the neonatal pig is driven by the high ribosome content and, together with an increased efficiency of the translation process, promotes accelerated protein synthesis rates. Feeding profoundly stimulates muscle protein synthesis in neonatal pigs and the response decreases with age. The feeding-induced stimulation of muscle protein synthesis is modulated by an enhanced sensitivity to the postprandial increase in insulin and amino acids. The developmental decline in the response to insulin and amino acids parallels a marked decrease in the feeding-induced activation of translation initiation factors that regulate the binding of mRNA to the 40S ribosomal complex. The abundance and activation of many known positive regulators of the nutrient- and insulin-signaling pathways that are involved in translation initiation are high, whereas those of many negative regulators are low in skeletal muscle of younger pigs. Thus, the activation and(or) abundance of the positive regulators, such as the insulin receptor, insulin receptor-substrate-1, phosphoinositide-3 kinase, phosphoinositide-dependent kinase-1, protein kinase B, mammalian target of rapamycin, raptor, ribosomal protein S6 kinase-1, eukaryotic initiation factor (eIF) 4E-binding protein 1, and eIF4E associated with eIF4G, are greater in 7-d-old pigs than in 26-d-old pigs. The activation of negative regulators, including protein tyrosine phosphatase-1B, phosphatase and tensin homologue deleted on chromosome 10, protein phosphatase 2A, and tuberous sclerosis complex 1/2, are lower in 7-d-old pigs than in 26-d-old pigs. Thus, the developmental decline in the stimulation of skeletal muscle protein synthesis by insulin and amino acids is due in part to the developmentally related decrease in the activation of the signaling pathways that lead to translation initiation. PMID:17785597

  20. Low Intensity Exercise Training Improves Skeletal Muscle Regeneration Potential

    PubMed Central

    Pietrangelo, Tiziana; Di Filippo, Ester S.; Mancinelli, Rosa; Doria, Christian; Rotini, Alessio; Fanò-Illic, Giorgio; Fulle, Stefania

    2015-01-01

    Purpose: The aim of this study was to determine whether 12 days of low-to-moderate exercise training at low altitude (598 m a.s.l.) improves skeletal muscle regeneration in sedentary adult women. Methods: Satellite cells were obtained from the vastus lateralis skeletal muscle of seven women before and after this exercise training at low altitude. They were investigated for differentiation aspects, superoxide anion production, antioxidant enzymes, mitochondrial potential variation after a depolarizing insult, intracellular Ca2+ concentrations, and micro (mi)RNA expression (miR-1, miR-133, miR-206). Results: In these myogenic populations of adult stem cells, those obtained after exercise training, showed increased Fusion Index and intracellular Ca2+ concentrations. This exercise training also generally reduced superoxide anion production in cells (by 12–67%), although not in two women, where there was an increase of ~15% along with a reduced superoxide dismutase activity. miRNA expression showed an exercise-induced epigenetic transcription profile that was specific according to the reduced or increased superoxide anion production of the cells. Conclusions: The present study shows that low-to-moderate exercise training at low altitude improves the regenerative capacity of skeletal muscle in adult women. The differentiation of cells was favored by increased intracellular calcium concentration and increased the fusion index. This low-to-moderate training at low altitude also depicted the epigenetic signature of cells. PMID:26733888

  1. Signalling and the control of skeletal muscle size

    SciTech Connect

    Otto, Anthony; Patel, Ketan

    2010-11-01

    Skeletal muscle is highly adaptive to environmental stimuli and can alter its mass accordingly. This tissue is almost unique in that it can increase its size through two distinct mechanisms. It can grow through a cellular process mediated by cell fusion, or it can increase its size simply by increasing its protein content. Understanding how these processes are regulated is crucial for the development of potential therapies against debilitating skeletal muscle wasting diseases. Two key signalling molecules, Insulin like Growth Factor (IGF) and GDF-8/myostatin, have emerged in recent years to be potent regulators of skeletal muscle size. In this review we bring together recent data highlighting the important and novel aspects of both molecules and their signalling pathways, culminating in a discussion of the cellular and tissue phenotypic outcomes of their stimulation or antagonism. We emphasise the complex regulatory mechanisms and discuss the temporal and spatial differences that control their action, understanding of which is crucial to further their use as potential therapeutic targets.

  2. Negative Impact of Skeletal Muscle Loss after Systemic Chemotherapy in Patients with Unresectable Colorectal Cancer

    PubMed Central

    Miyamoto, Yuji; Baba, Yoshifumi; Sakamoto, Yasuo; Ohuchi, Mayuko; Tokunaga, Ryuma; Kurashige, Junji; Hiyoshi, Yukiharu; Iwagami, Shiro; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

    2015-01-01

    Background Skeletal muscle depletion (sarcopenia) is closely associated with limited physical ability and high mortality. This study evaluated the prognostic significance of skeletal muscle status before and after chemotherapy in patients with unresectable colorectal cancer (CRC). Methods We conducted a retrospective analysis of 215 consecutive patients with unresectable CRC who underwent systemic chemotherapy. Skeletal muscle cross-sectional area was measured by computed tomography. We evaluated the prognostic value of skeletal muscle mass before chemotherapy and the rate of skeletal muscle change in cross-sectional area after chemotherapy. Results One-hundred-eighty-two patients met our inclusion criteria. There were no significant differences in progression-free survival (PFS) or overall survival (OS) associated with skeletal muscle mass before chemotherapy. However, 22 patients with skeletal muscle loss (>5%) after chemotherapy showed significantly shorter PFS and OS compared with those without skeletal muscle loss (PFS, log-rank p = 0.029; OS, log-rank p = 0.009). Multivariate Cox regression analysis revealed that skeletal muscle loss after chemotherapy (hazard ratio, 2.079; 95% confidence interval, 1.194–3.619; p = 0.010) was independently associated with OS. Conclusions Skeletal muscle loss after chemotherapy was an independent, negative prognostic factor in unresectable CRC. PMID:26069972

  3. Data on skeletal muscle apoptosis, autophagy, and morphology in mice treated with doxorubicin.

    PubMed

    Campbell, Troy L; Quadrilatero, Joe

    2016-06-01

    Skeletal muscle apoptosis and autophagy are catabolic processes that contribute to muscle atrophy during aging, disease, and following muscle injury. In this article, we present data on skeletal muscle apoptosis, autophagy, and morphology in C57BL/6 mice following doxorubicin administration. More specifically, time-course data on caspase-3, caspase-8, caspase-9, calpain, and cathepsin activity are presented, along with data on ATG7, p62, LC3-I, and LC3-II protein expression. Data on skeletal muscle reactive oxygen species (ROS) production, muscle morphology, as well as body and muscle weights are also presented. PMID:27077080

  4. Data on skeletal muscle apoptosis, autophagy, and morphology in mice treated with doxorubicin

    PubMed Central

    Campbell, Troy L.; Quadrilatero, Joe

    2016-01-01

    Skeletal muscle apoptosis and autophagy are catabolic processes that contribute to muscle atrophy during aging, disease, and following muscle injury. In this article, we present data on skeletal muscle apoptosis, autophagy, and morphology in C57BL/6 mice following doxorubicin administration. More specifically, time-course data on caspase-3, caspase-8, caspase-9, calpain, and cathepsin activity are presented, along with data on ATG7, p62, LC3-I, and LC3-II protein expression. Data on skeletal muscle reactive oxygen species (ROS) production, muscle morphology, as well as body and muscle weights are also presented. PMID:27077080

  5. A communicational link between skeletal muscle, brain, and cells of the immune system.

    PubMed

    Parry-Billings, M; Blomstrand, E; McAndrew, N; Newsholme, E A

    1990-05-01

    The present paper reviews evidence for the role of specific amino acids in the etiology of fatigue and the overtraining syndrome in athletes. An increase in the plasma concentration ratio of free tryptophan: branched-chain amino acids may mediate an increase in 5-HT synthesis in the brain and thus induce fatigue during exercise. Glutamine is essential for the proper functioning of cells of the immune system and a decrease in plasma glutamine concentration post-exercise and in overtraining may induce an impairment in immune function. Branched-chain amino acids may play a central role in both these processes. Thus, they compete with free tryptophan for entry into the brain. Branched-chain amino acids may also be important precursors of nitrogen for the synthesis of glutamine in skeletal muscle or important in the control of glutamine release from muscle. Consequently, the metabolism of glutamine, tryptophan, and branched-chain amino acids may be the key to understanding some aspects of central fatigue and some aspects of immunosuppression that are very relevant to athletic endeavor. They may be also relevant to other physiological and pathological conditions. PMID:2193890

  6. An allometric analysis of the number of muscle spindles in mammalian skeletal muscles.

    PubMed

    Banks, R W

    2006-06-01

    An allometric analysis of the number of muscle spindles in relation to muscle mass in mammalian (mouse, rat, guinea-pig, cat, human) skeletal muscles is presented. It is shown that the trend to increasing number as muscle mass increases follows an isometric (length) relationship between species, whereas within a species, at least for the only essentially complete sample (human), the number of spindles scales, on average, with the square root rather than the cube root of muscle mass. An attempt is made to reconcile these apparently discrepant relationships. Use of the widely accepted spindle density (number of spindles g(-1) of muscle) as a measure of relative abundance of spindles in different muscles is shown to be grossly misleading. It is replaced with the residuals of the linear regression of ln spindle number against ln muscle mass. Significant differences in relative spindle abundance as measured by residuals were found between regional groups of muscles: the greatest abundance is in axial muscles, including those concerned with head position, whereas the least is in muscles of the shoulder girdle. No differences were found between large and small muscles operating in parallel, or between antigravity and non-antigravity muscles. For proximal vs. distal muscles, spindles were significantly less abundant in the hand than the arm, but there was no difference between the foot and the leg. PMID:16761976

  7. Characterization of methionine adenosyltransferase 2beta gene expression in skeletal muscle and subcutaneous adipose tissue from obese and lean pigs.

    PubMed

    Fang, Qian; Yin, Jingdong; Li, Fengna; Zhang, Jinxiao; Watford, Malcolm

    2010-06-01

    Methionine adenosyltransferase (MAT) catalyzes the biosynthesis of S-adenosylmethionine. Two genes (MAT1A and MAT2A) encode for the catalytic subunit of MAT, while a third gene (MAT2beta) encodes for a regulatory subunit (MAT II beta) that regulates the activity of the MAT2A-encoded isoenzyme and intracellular S-adenosylmethionine levels. Our previous work identified MAT2beta as a candidate gene for intramuscular fat (IMF) deposition in porcine skeletal muscle by microarray technology. Here, we cloned porcine MAT2beta cDNA and compared its expression pattern in subcutaneous adipose tissue and skeletal muscle from obese (Rongchang Breed) and lean (Pig Improvement Company, PIC) pigs (n = 6). The porcine MAT2beta cDNA was 1,800 bp long and encodes for 334 amino acids sharing high similarity with other species. MAT2beta is expressed at a higher level in liver and duodenum, followed by the stomach, fat and longissinus dorsi muscle. As expected, both subcutaneous fat content and IMF content were higher in obese than in lean pigs (both P < 0.01). MAT2beta mRNA abundance was lower in both subcutaneous adipose tissue and skeletal muscle in obese pigs compared with lean pigs (both P < 0.01). MAT II beta protein content was lower in skeletal muscle in obese than in lean pigs (P < 0.05), whereas the opposite was observed in subcutaneous adipose tissue (P < 0.01). These data demonstrated an obesity-related expression variation of the MAT II beta subunit in skeletal muscle and adipose tissue in pigs, and suggest a novel role for the MAT2beta gene in regulation of IMF deposition in skeletal muscle. PMID:19701798

  8. Chemerin-induced mitochondrial dysfunction in skeletal muscle.

    PubMed

    Xie, Qihai; Deng, Yujie; Huang, Chenglin; Liu, Penghao; Yang, Ying; Shen, Weili; Gao, Pingjin

    2015-05-01

    Chemerin is a novel adipocyte-derived factor that induces insulin resistance in skeletal muscle. However, the effect of chemerin on skeletal muscle mitochondrial function has received little attention. In the present study, we investigated whether mitochondrial dysfunction is involved in the pathogenesis of chemerin-mediated insulin resistance. In this study, we used recombinant adenovirus to express murine chemerin in C57BL/6 mice. The mitochondrial function and structure were evaluated in isolated soleus muscles from mice. The oxidative mechanism of mitochondrial dysfunction in cultured C2C12 myotubes exposed to recombinant chemerin was analysed by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction. The overexpression of chemerin in mice reduced the muscle mitochondrial content and increased mitochondrial autophagy, as determined by the increased conversion of LC3-I to LC3-II and higher expression levels of Beclin1 and autophagy-related protein-5 and 7. The chemerin treatment of C2C12 myotubes increased the generation of mitochondrial reactive oxygen species, concomitant with a reduced mitochondrial membrane potential and increased the occurrence of mitochondrial protein carbonyls and mitochondrial DNA deletions. Knockdown of the expression of chemokine-like receptor 1 or the use of mitochondria-targeting antioxidant Mito-TEMPO restored the mitochondrial dysfunction induced by chemerin. Furthermore, chemerin exposure in C2C12 myotubes not only reduced the insulin-stimulated phosphorylation of protein kinase B (AKT) but also dephosphorylated forkhead box O3α (FoxO3α). Chemerin-induced mitochondrial autophagy likely through an AKT-FoxO3α-dependent signalling pathway. These findings provide direct evidence that chemerin may play an important role in regulating mitochondrial remodelling and function in skeletal muscle. PMID:25754411

  9. Optical reflectance in fibrous tissues and skeletal muscles

    NASA Astrophysics Data System (ADS)

    Ranasinghesagara, Janaka C.

    We studied two biological tissues with optically anisotropic structures: high moisture soy protein extrudates and skeletal muscles. High moisture extrusion has been used to produce vegetable meat analogs that resemble real animal meat and have significant health benefits. Since visual and textural properties are key factors for consumer acceptance, assessing fiber formation in the extruded soy protein product is important for quality control purpose. A non-destructive method based on photon migration was developed to measure fiber formation in extruded soy proteins. The measured fiber formation index in intact samples showed good agreement with that obtained from image analysis on peeled samples. By implementing this new method in a fast laser scanning system, we have acquired two dimensional mappings of fiber formation and orientation in the entire sample in real time. In addition to fibrous structures, skeletal muscles have a unique periodic sarcomere structure which produces strong light diffractions. However, inconsistent experimental results have been reported in single fiber diffraction studies. By applying the three-dimensional coupled wave theory in a physical sarcomere model, we found that a variety of experimental observations can be explained if inhomogeneous muscle morphological profiles are considered. We also discovered that the sarcomere structure produced a unique optical reflectance pattern in whole muscle. None of the existing light propagation theories are able to describe this pattern. We developed a Monte Carlo model incorporating the sarcomere diffraction effect. The simulated results quantitatively resemble the unique patterns observed in experiments. We used a set of parameters to quantify the optical reflectance profiles produced by a point incident light in whole muscle. Two parameters, q and B, were obtained by numerically fitting the equi-intensity contours of the reflectance pattern. Two spatial gradients were calculated along the directions parallel and perpendicular to muscle fibers. The mean diffuse intensity was obtained by excluding the specular reflectance. These five parameters provide a comprehensive and complete description of the diffuse reflectance in muscle. In a study of 336 muscle samples, we found these optical parameters were subject to the effects of different muscle physical and biochemical factors. Different types of muscle have significantly different diffuse intensities. Aging shows different effects on the q parameter in different muscles. In addition, the mean diffuse intensity is significantly different (p<0.05) in different animal breeds. Optical parameters showed good correlations with Warner-Bratzler shear force. Further studies on a large sample group are necessary to develop a statistical model to predict muscle physical and chemical properties using these non-destructive optical measurements.

  10. Apoptosis-Inducing Factor Regulates Skeletal Muscle Progenitor Cell Number and Muscle Phenotype

    PubMed Central

    Djeghloul, Dounia; Lécolle, Sylvie; Bertrand, Anne T.; Biondi, Olivier; De Windt, Leon J.; Chanoine, Christophe

    2011-01-01

    Apoptosis Inducing Factor (AIF) is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal and cardiomyocyte apoptosis induced by oxidative stress. Conversely in vitro, AIF has been demonstrated to have a pro-apoptotic role upon induction of the mitochondrial death pathway, once AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. Given that the aif hypomorphic harlequin (Hq) mutant mouse model displays severe sarcopenia, we examined skeletal muscle from the aif hypomorphic mice in more detail. Adult AIF-deficient skeletal myofibers display oxidative stress and a severe form of atrophy, associated with a loss of myonuclei and a fast to slow fiber type switch, both in “slow” muscles such as soleus, as well as in “fast” muscles such as extensor digitorum longus, most likely resulting from an increase of MEF2 activity. This fiber type switch was conserved in regenerated soleus and EDL muscles of Hq mice subjected to cardiotoxin injection. In addition, muscle regeneration in soleus and EDL muscles of Hq mice was severely delayed. Freshly cultured myofibers, soleus and EDL muscle sections from Hq mice displayed a decreased satellite cell pool, which could be rescued by pretreating aif hypomorphic mice with the manganese-salen free radical scavenger EUK-8. Satellite cell activation seems to be abnormally long in Hq primary culture compared to controls. However, AIF deficiency did not affect myoblast cell proliferation and differentiation. Thus, AIF protects skeletal muscles against oxidative stress-induced damage probably by protecting satellite cells against oxidative stress and maintaining skeletal muscle stem cell number and activation. PMID:22076146

  11. Skeletal muscle volume following dehydration induced by exercise in heat

    PubMed Central

    2012-01-01

    Background Intracellular skeletal muscle water is redistributed into the extracellular compartment during periods of dehydration, suggesting an associated decline in muscle volume. The purpose of this study was to evaluate skeletal muscle volume in active (knee extensors (KE)) and less active (biceps/triceps brachii, deltoid) musculature following dehydration induced by exercise in heat. Methods Twelve participants (seven men, five women) cycled in the heat under two conditions: (1) dehydration (DHYD) resulting in 3% and 5% losses of estimated total body water (ETBW), which was assessed by changes in body mass, and (2) fluid replacement (FR) where 3% and 5% losses of ETBW were counteracted by intermittent (20 to 30 min) fluid ingestion via a carbohydrate-electrolyte beverage. During both conditions, serum osmolality and skeletal muscle volume (assessed by magnetic resonance imaging) were measured at baseline and at the 3% and 5% ETBW loss measurement points. Results In DHYD, serum osmolality increased at 3% (p?=?0.005) and 5% (p?muscle volume declined from 1,464??446 ml to 1,406??425 ml (3.9%, p?muscles. There were no changes in volume for the biceps/triceps (p?=?0.35) or deltoid (p?=?0.92) during DHYD. FR prevented the loss of KE muscle volume at 3% (1,430??435 ml, p?=?0.074) and 5% (1,431??439 ml, p?=?0.156) ETBW loss time points compared to baseline (1,445??436 ml). Conclusions Following exercise in the heat, the actively contracting muscles lost volume, while replacing lost fluids intermittently during exercise in heat prevented this decline. These results support the use of muscle volume as a marker of water loss. PMID:23849266

  12. Comprehensive analysis of tropomyosin isoforms in skeletal muscles by top-down proteomics.

    PubMed

    Jin, Yutong; Peng, Ying; Lin, Ziqing; Chen, Yi-Chen; Wei, Liming; Hacker, Timothy A; Larsson, Lars; Ge, Ying

    2016-04-01

    Mammalian skeletal muscles are heterogeneous in nature and are capable of performing various functions. Tropomyosin (Tpm) is a major component of the thin filament in skeletal muscles and plays an important role in controlling muscle contraction and relaxation. Tpm is known to consist of multiple isoforms resulting from different encoding genes and alternative splicing, along with post-translational modifications. However, a systematic characterization of Tpm isoforms in skeletal muscles is still lacking. Therefore, we employed top-down mass spectrometry (MS) to identify and characterize Tpm isoforms present in different skeletal muscles from multiple species, including swine, rat, and human. Our study revealed that Tpm1.1 and Tpm2.2 are the two major Tpm isoforms in swine and rat skeletal muscles, whereas Tpm1.1, Tpm2.2, and Tpm3.12 are present in human skeletal muscles. Tandem MS was utilized to identify the sequences of the major Tpm isoforms. Furthermore, quantitative analysis revealed muscle-type specific differences in the abundance of un-modified and modified Tpm isoforms in rat and human skeletal muscles. This study represents the first systematic investigation of Tpm isoforms in skeletal muscles, which not only demonstrates the capabilities of top-down MS for the comprehensive characterization of skeletal myofilament proteins but also provides the basis for further studies on these Tpm isoforms in muscle-related diseases. PMID:27090236

  13. Fast skeletal muscle troponin T increases the cooperativity of transgenic mouse cardiac muscle contraction

    PubMed Central

    Huang, Qi-Quan; Brozovich, Frank V; Jin, Jian-Ping

    1999-01-01

    To investigate the functional significance of different troponin T (TnT) isoforms in the Ca2+ activation of muscle contraction, transgenic mice have been constructed with a chicken fast skeletal muscle TnT transgene driven by a cardiac α-myosin heavy chain gene promoter. Cardiac muscle-specific expression of the fast skeletal muscle TnT has been obtained with significant myofibril incorporation. Expression of the endogenous cardiac muscle thin filament regulatory proteins, such as troponin I and tropomyosin, was not altered in the transgenic mouse heart, providing an authentic system for the functional characterization of TnT isoforms. Cardiac muscle contractility was analysed for the force vs. Ca2+ relationship in skinned ventricular trabeculae of transgenic mice in comparison with wild-type litter-mates. The results showed unchanged pCa50 values (5.1 ± 0.04 and 5.1 ± 0.1, respectively) but significantly steeper slopes (the Hill coefficient was 2.0 ± 0.2 vs. 1.0 ± 0.2, P < 0.05). The results demonstrate that the structural and functional variation of different TnT isoforms may contribute to the difference in responsiveness and overall cooperativity of the thin filament-based Ca2+ regulation between cardiac and skeletal muscles. PMID:10517814

  14. Expression of TPM1κ, a Novel Sarcomeric Isoform of the TPM1 Gene, in Mouse Heart and Skeletal Muscle

    PubMed Central

    Dube, Syamalima; Panebianco, Lauren; Matoq, Amr A.; Chionuma, Henry N.; Denz, Christopher R.; Poiesz, Bernard J.; Dube, Dipak K.

    2014-01-01

    We have investigated the expression of TPM1α and TPM1κ in mouse striated muscles. TPM1α and TMP1κ were amplified from the cDNA of mouse heart by using conventional RT-PCR. We have cloned the PCR amplified DNA and determined the nucleotide sequences. Deduced amino acid sequences show that there are three amino acid changes in mouse exon 2a when compared with the human TPM1κ. However, the deduced amino acid sequences of human TPM1α and mouse TPM1α are identical. Conventional RT-PCR data as well as qRT-PCR data, calculating both absolute copy number and relative expression, revealed that the expression of TPM1κ is significantly lower compared to TPM1α in both mouse heart and skeletal muscle. It was also found that the expression level of TPM1κ transcripts in mouse heart is higher than it is in skeletal muscle. To the best of our knowledge, this is the first report of the expression of TPM1κ in mammalian skeletal muscle. PMID:24876965

  15. Dietary nitrate reduces skeletal muscle oxygenation response to physical exercise: a quantitative muscle functional MRI study

    PubMed Central

    Bentley, Rachel; Gray, Stuart R.; Schwarzbauer, Christian; Dawson, Dana; Frenneaux, Michael; He, Jiabao

    2014-01-01

    Abstract Dietary inorganic nitrate supplementation (probably via conversion to nitrite) increases skeletal muscle metabolic efficiency. In addition, it may also cause hypoxia‐dependent vasodilation and this has the potential to augment oxygen delivery to exercising skeletal muscle. However, direct evidence for the latter with spatial localization to exercising muscle groups does not exist. We employed quantitative functional MRI (fMRI) to characterize skeletal muscle oxygen utilization and replenishment by assessment of tissue oxygenation maximal change and recovery change, respectively. Eleven healthy subjects were enrolled, of whom 9 (age 33.3 ± 4.4 years, five males) completed the study. Each subject took part in three MRI visits, with dietary nitrate (7cl concentrated beetroot juice) consumed before the third visit. During each visit fMRIs were conducted concurrently with plantar flexion exercise at workloads of 15% and 25% maximum voluntary contraction (MVC). No significant changes were found between visits 1 and 2 in the fMRI measures. A decrease in maximal change was found at 15% MVC in soleus between visits 2 and 3 (5.12 ± 2.36 to 2.55 ± 1.42, P = 0.004) and between visits 1 and 3 (4.43 ± 2.12 to 2.55 ± 1.42, P = 0.043), but not at 25% MVC or within gastrocnemius. There was no difference in recovery change between visits. We found that dietary nitrate supplementation reduces tissue oxygenation alterations during physical exercise in skeletal muscle. This effect is more prominent in muscles with predominantly type 1 fibers and at lower workloads. This indicates that in healthy subjects dietary nitrate predominantly affects skeletal muscle energy efficiency with no change in oxygen delivery. PMID:25052493

  16. Exercise influences circadian gene expression in equine skeletal muscle.

    PubMed

    Murphy, B A; Wagner, A L; McGlynn, O F; Kharazyan, F; Browne, J A; Elliott, J A

    2014-07-01

    Circadian rhythms are endogenously generated 24-h oscillations that coordinate numerous aspects of mammalian physiology, metabolism and behaviour. The existence of a molecular circadian clock in equine skeletal muscle has previously been demonstrated. This study investigates how the circadian 24-h expression of exercise-relevant genes in skeletal muscle is influenced by a regular exercise regime. Mid-gluteal, percutaneous muscle biopsies were obtained over a 24-h period from six Thoroughbred mares before and after an 8-week exercise programme. Real-time qPCR assays were used to assess the expression patterns of core clock genes ARNTL, PER2, NR1D1, clock-controlled gene DBP, and muscle genes MYF6, UCP3, VEGFA, FOXO1, MYOD1, PPARGC1A, PPARGC1B, FBXO32 and PDK4. Two-way repeated measures ANOVA revealed a significant interaction between circadian time and exercise for muscle genes MYF6, UCP3, MYOD1 and PDK4. A significant effect of time was observed for all genes with the exception of VEGFA, where a main effect of exercise was observed. By cosinor analysis, the core clock genes, ARNTL (P <0.01) and NR1D1 (P <0.05), showed 24-h rhythmicity both pre- and post-exercise, while PER2 expression was rhythmic post-exercise (P <0.05) but not pre-exercise. The expression profiles of muscle genes MYOD1 and MYF6 showed significant fits to a 24-h cosine waveform indicative of circadian rhythmicity post-exercise only (P <0.01). This study suggests that the metabolic capacity of muscle is influenced by scheduled exercise and that optimal athletic performance may be achieved when exercise times and competition times coincide. PMID:24888677

  17. Acylcarnitines: potential implications for skeletal muscle insulin resistance

    PubMed Central

    Aguer, Céline; McCoin, Colin S.; Knotts, Trina A.; Thrush, A. Brianne; Ono-Moore, Kikumi; McPherson, Ruth; Dent, Robert; Hwang, Daniel H.; Adams, Sean H.; Harper, Mary-Ellen

    2015-01-01

    Insulin resistance may be linked to incomplete fatty acid β-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid β-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20–30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitate-induced insulin resistance concomitant with an ∼25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2–3 times by short- or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid β-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.—Aguer, C., McCoin, C. S., Knotts, T. A., Thrush, A. B., Ono-Moore, K., McPherson, R., Dent, R., Hwang, D. H., Adams, S. H., Harper, M.-E. Acylcarnitines: potential implications for skeletal muscle insulin resistance. PMID:25342132

  18. MicroRNA transcriptome profiles during swine skeletal muscle development

    PubMed Central

    McDaneld, Tara G; Smith, Timothy PL; Doumit, Matthew E; Miles, Jeremy R; Coutinho, Luiz L; Sonstegard, Tad S; Matukumalli, Lakshmi K; Nonneman, Dan J; Wiedmann, Ralph T

    2009-01-01

    Background MicroRNA (miR) are a class of small RNAs that regulate gene expression by inhibiting translation of protein encoding transcripts. To evaluate the role of miR in skeletal muscle of swine, global microRNA abundance was measured at specific developmental stages including proliferating satellite cells, three stages of fetal growth, day-old neonate, and the adult. Results Twelve potential novel miR were detected that did not match previously reported sequences. In addition, a number of miR previously reported to be expressed in mammalian muscle were detected, having a variety of abundance patterns through muscle development. Muscle-specific miR-206 was nearly absent in proliferating satellite cells in culture, but was the highest abundant miR at other time points evaluated. In addition, miR-1 was moderately abundant throughout developmental stages with highest abundance in the adult. In contrast, miR-133 was moderately abundant in adult muscle and either not detectable or lowly abundant throughout fetal and neonate development. Changes in abundance of ubiquitously expressed miR were also observed. MiR-432 abundance was highest at the earliest stage of fetal development tested (60 day-old fetus) and decreased throughout development to the adult. Conversely, miR-24 and miR-27 exhibited greatest abundance in proliferating satellite cells and the adult, while abundance of miR-368, miR-376, and miR-423-5p was greatest in the neonate. Conclusion These data present a complete set of transcriptome profiles to evaluate miR abundance at specific stages of skeletal muscle growth in swine. Identification of these miR provides an initial group of miR that may play a vital role in muscle development and growth. PMID:19208255

  19. Design, evaluation, and application of engineered skeletal muscle.

    PubMed

    Juhas, Mark; Ye, Jean; Bursac, Nenad

    2016-04-15

    For over two decades, research groups have been developing methods to engineer three-dimensional skeletal muscle tissues. These tissues hold great promise for use in disease modeling and pre-clinical drug development, and have potential to serve as therapeutic grafts for functional muscle repair. Recent advances in the field have resulted in the engineering of regenerative muscle constructs capable of survival, vascularization, and functional maturation in vivo as well as the first-time creation of functional human engineered muscles for screening of therapeutics in vitro. In this review, we will discuss the methodologies that have progressed work in the muscle tissue engineering field to its current state. The emphasis will be placed on the existing procedures to generate myogenic cell sources and form highly functional muscle tissues in vitro, techniques to monitor and evaluate muscle maturation and performance in vitro and in vivo, and surgical strategies to both create diseased environments and ensure implant survival and rapid integration into the host. Finally, we will suggest the most promising methodologies that will enable continued progress in the field. PMID:26455485

  20. Fetal stem cells and skeletal muscle regeneration: a therapeutic approach.

    PubMed

    Pozzobon, Michela; Franzin, Chiara; Piccoli, Martina; De Coppi, Paolo

    2014-01-01

    More than 40% of the body mass is represented by muscle tissue, which possesses the innate ability to regenerate after damage through the activation of muscle-specific stem cells, namely satellite cells. Muscle diseases, in particular chronic degenerative states of skeletal muscle such as dystrophies, lead to a perturbation of the regenerative process, which causes the premature exhaustion of satellite cell reservoir due to continuous cycles of degeneration/regeneration. Nowadays, the research is focused on different therapeutic approaches, ranging from gene and cell to pharmacological therapy, but still there is no definitive cure in particular for genetic muscle disease. Keeping this in mind, in this article, we will give special consideration to muscle diseases and the use of fetal derived stem cells as a new approach for therapy. Cells of fetal origin, from cord blood to placenta and amniotic fluid, can be easily obtained without ethical concern, expanded and differentiated in culture, and possess immune-modulatory properties. The in vivo approach in animal models can be helpful to study the mechanism underneath the operating principle of the stem cell reservoir, namely the niche, which holds great potential to understand the onset of muscle pathologies. PMID:25221507

  1. Impact of Oxidative Stress on Exercising Skeletal Muscle

    PubMed Central

    Steinbacher, Peter; Eckl, Peter

    2015-01-01

    It is well established that muscle contractions during exercise lead to elevated levels of reactive oxygen species (ROS) in skeletal muscle. These highly reactive molecules have many deleterious effects, such as a reduction of force generation and increased muscle atrophy. Since the discovery of exercise-induced oxidative stress several decades ago, evidence has accumulated that ROS produced during exercise also have positive effects by influencing cellular processes that lead to increased expression of antioxidants. These molecules are particularly elevated in regularly exercising muscle to prevent the negative effects of ROS by neutralizing the free radicals. In addition, ROS also seem to be involved in the exercise-induced adaptation of the muscle phenotype. This review provides an overview of the evidences to date on the effects of ROS in exercising muscle. These aspects include the sources of ROS, their positive and negative cellular effects, the role of antioxidants, and the present evidence on ROS-dependent adaptations of muscle cells in response to physical exercise. PMID:25866921

  2. Role of calpain in skeletal-muscle protein degradation

    PubMed Central

    Huang, Jing; Forsberg, Neil E.

    1998-01-01

    Although protein degradation is enhanced in muscle-wasting conditions and limits the rate of muscle growth in domestic animals, the proteolytic system responsible for degrading myofibrillar proteins in skeletal muscle is not well defined. The goals of this study were to evaluate the roles of the calpains (calcium-activated cysteine proteases) in mediating muscle protein degradation and the extent to which these proteases participate in protein turnover in muscle. Two strategies to regulate intracellular calpain activities were developed: overexpression of dominant-negative m-calpain and overexpression of calpastatin inhibitory domain. To express these constructs, L8 myoblast cell lines were transfected with LacSwitch plasmids, which allowed for isopropyl β-d-thiogalactoside-dependent expression of the gene of interest. Inhibition of calpain stabilized fodrin, a well characterized calpain substrate. Under conditions of accelerated degradation (serum withdrawal), inhibition of m-calpain reduced protein degradation by 30%, whereas calpastatin inhibitory domain expression reduced degradation by 63%. Inhibition of calpain also stabilized nebulin. These observations indicate that calpains play key roles in the disassembly of sarcomeric proteins. Inhibition of calpain activity may have therapeutic value in treatment of muscle-wasting conditions and may enhance muscle growth in domestic animals. PMID:9770446

  3. Ex Vivo Assessment of Contractility, Fatigability and Alternans in Isolated Skeletal Muscles

    PubMed Central

    Park, Ki Ho; Brotto, Leticia; Lehoang, Oanh; Brotto, Marco; Ma, Jianjie; Zhao, Xiaoli

    2012-01-01

    Described here is a method to measure contractility of isolated skeletal muscles. Parameters such as muscle force, muscle power, contractile kinetics, fatigability, and recovery after fatigue can be obtained to assess specific aspects of the excitation-contraction coupling (ECC) process such as excitability, contractile machinery and Ca2+ handling ability. This method removes the nerve and blood supply and focuses on the isolated skeletal muscle itself. We routinely use this method to identify genetic components that alter the contractile property of skeletal muscle though modulating Ca2+ signaling pathways. Here, we describe a newly identified skeletal muscle phenotype, i.e., mechanic alternans, as an example of the various and rich information that can be obtained using the in vitro muscle contractility assay. Combination of this assay with single cell assays, genetic approaches and biochemistry assays can provide important insights into the mechanisms of ECC in skeletal muscle. PMID:23149471

  4. Age- and Stroke-Related Skeletal Muscle Changes: A Review for the Geriatric Clinician

    PubMed Central

    Sions, J. Megan; Tyrell, Christine M.; Knarr, Brian A.; Jancosko, Angela; Binder-Macleod, Stuart A.

    2011-01-01

    Independently, aging and stroke each have a significant negative impact on skeletal muscle, but the potential cumulative effects of aging and stroke have not been explored. Optimal interventions for individuals post-stroke may include those that specifically target skeletal muscle. Addressing changes in muscles may minimize activity limitations and enhance participation post-stroke. This paper reviews the impact of aging and stroke on muscle morphology and composition, including fiber atrophy, reductions in muscle cross-sectional area, changes in muscle fiber distributions, and increases in intramuscular fat. Relationships between changes in muscle structure, muscle function, and physical mobility are reviewed. Clinical recommendations that preserve and enhance skeletal muscle in the aging adult and individuals post-stroke are discussed. Future research directions that include systematic comparison of the differences in skeletal muscle between younger and older adults who have sustained a stroke are suggested. PMID:22107952

  5. Free fatty acids and skeletal muscle insulin resistance.

    PubMed

    Rachek, Lyudmila I

    2014-01-01

    Insulin resistance plays a key role in the development of type 2 diabetes mellitus and is also associated with several other diseases, such as obesity, hypertension, and cardiovascular diseases. Type 2 diabetes and obesity have become epidemic worldwide in the past few decades, and epidemiological and metabolic evidence indicates that the two conditions are linked closely through insulin resistance. The perturbation of free fatty acid (FFA) metabolism is now accepted to be a major factor contributing to whole-body insulin resistance, including that in skeletal muscle. Acute exposure to FFAs and excess dietary lipid intake are strongly associated with the pathogenesis of muscle insulin resistance. Despite an enormous amount of published research and the proposal of numerous hypotheses, however, the mechanisms underlying FFA-induced skeletal muscle insulin resistance have not been fully elucidated. This chapter describes existing hypotheses, recent findings, and debates about the role of FFAs in the development of muscle insulin resistance. Therapeutic options for this condition are also discussed. PMID:24373240

  6. Skeletal muscle vasodilatation during maximal exercise in health and disease

    PubMed Central

    Calbet, Jose A L; Lundby, Carsten

    2012-01-01

    Maximal exercise vasodilatation results from the balance between vasoconstricting and vasodilating signals combined with the vascular reactivity to these signals. During maximal exercise with a small muscle mass the skeletal muscle vascular bed is fully vasodilated. During maximal whole body exercise, however, vasodilatation is restrained by the sympathetic system. This is necessary to avoid hypotension since the maximal vascular conductance of the musculature exceeds the maximal pumping capacity of the heart. Endurance training and high-intensity intermittent knee extension training increase the capacity for maximal exercise vasodilatation by 20–30%, mainly due to an enhanced vasodilatory capacity, as maximal exercise perfusion pressure changes little with training. The increase in maximal exercise vascular conductance is to a large extent explained by skeletal muscle hypertrophy and vascular remodelling. The vasodilatory capacity during maximal exercise is reduced or blunted with ageing, as well as in chronic heart failure patients and chronically hypoxic humans; reduced vasodilatory responsiveness and increased sympathetic activity (and probably, altered sympatholysis) are potential mechanisms accounting for this effect. Pharmacological counteraction of the sympathetic restraint may result in lower perfusion pressure and reduced oxygen extraction by the exercising muscles. However, at the same time fast inhibition of the chemoreflex in maximally exercising humans may result in increased vasodilatation, further confirming a restraining role of the sympathetic nervous system on exercise-induced vasodilatation. This is likely to be critical for the maintenance of blood pressure in exercising patients with a limited heart pump capacity. PMID:23027820

  7. Skeletal muscle mass and composition during mammalian hibernation.

    PubMed

    Cotton, Clark J

    2016-01-01

    Hibernation is characterized by prolonged periods of inactivity with concomitantly low nutrient intake, conditions that would typically result in muscle atrophy combined with a loss of oxidative fibers. Yet, hibernators consistently emerge from winter with very little atrophy, frequently accompanied by a slight shift in fiber ratios to more oxidative fiber types. Preservation of muscle morphology is combined with down-regulation of glycolytic pathways and increased reliance on lipid metabolism instead. Furthermore, while rates of protein synthesis are reduced during hibernation, balance is maintained by correspondingly low rates of protein degradation. Proposed mechanisms include a number of signaling pathways and transcription factors that lead to increased oxidative fiber expression, enhanced protein synthesis and reduced protein degradation, ultimately resulting in minimal loss of skeletal muscle protein and oxidative capacity. The functional significance of these outcomes is maintenance of skeletal muscle strength and fatigue resistance, which enables hibernating animals to resume active behaviors such as predator avoidance, foraging and mating immediately following terminal arousal in the spring. PMID:26792334

  8. Expression and modification proteomics during skeletal muscle ageing.

    PubMed

    Baraibar, Martin A; Gueugneau, Marine; Duguez, Stephanie; Butler-Browne, Gillian; Bechet, Daniel; Friguet, Bertrand

    2013-06-01

    Skeletal muscle ageing is characterized by a progressive and dramatic loss of muscle mass and strength leading to decreased muscular function resulting in muscle weakness which is often referred to as sarcopenia. Following the standardisation of "omics" approaches to study the genome (genomics) and the transcriptome (transcriptomics), the study of the proteins encoded by the genome, referred to as proteomics, is a tremendous challenge. Unlike the genome, the proteome varies in response to many physiological or pathological factors. In addition, the proteome is orders of magnitude more complex than the transcriptome due to post-translational modifications, protein oxidation and limited protein degradation. Proteomic studies, including the analysis of protein abundance as well as post-translational modified proteins have been shown to provide valuable information to unravel the key molecular pathways implicated in complex biological processes, such as tissue and organ ageing. In this article, we will describe proteomic approaches for the analysis of protein abundance as well as the specific protein targets for oxidative damage upon oxidative stress and/or during skeletal muscle ageing. PMID:23624703

  9. Defective Homocysteine Metabolism: Potential Implications for Skeletal Muscle Malfunction

    PubMed Central

    Veeranki, Sudhakar; Tyagi, Suresh C.

    2013-01-01

    Hyperhomocysteinemia (HHcy) is a systemic medical condition and has been attributed to multi-organ pathologies. Genetic, nutritional, hormonal, age and gender differences are involved in abnormal homocysteine (Hcy) metabolism that produces HHcy. Homocysteine is an intermediate for many key processes such as cellular methylation and cellular antioxidant potential and imbalances in Hcy production and/or catabolism impacts gene expression and cell signaling including GPCR signaling. Furthermore, HHcy might damage the vagus nerve and superior cervical ganglion and affects various GPCR functions; therefore it can impair both the parasympathetic and sympathetic regulation in the blood vessels of skeletal muscle and affect long-term muscle function. Understanding cellular targets of Hcy during HHcy in different contexts and its role either as a primary risk factor or as an aggravator of certain disease conditions would provide better interventions. In this review we have provided recent Hcy mediated mechanistic insights into different diseases and presented potential implications in the context of reduced muscle function and integrity. Overall, the impact of HHcy in various skeletal muscle malfunctions is underappreciated; future studies in this area will provide deeper insights and improve our understanding of the association between HHcy and diminished physical function. PMID:23873298

  10. Exercise and nutrition to target protein synthesis impairments in aging skeletal muscle

    PubMed Central

    Dickinson, Jared M.; Volpi, Elena; Rasmussen, Blake B.

    2013-01-01

    The loss of skeletal muscle size and function with aging, sarcopenia, may be related, in part, to an age-related muscle protein synthesis impairment. In this review, we discuss to what extent aging affects skeletal muscle protein synthesis and how nutrition and exercise can be strategically employed to overcome age-related protein synthesis impairments and slow the progression of sarcopenia. PMID:23873131

  11. Smooth muscle and skeletal muscle myosins produce similar unitary forces and displacements in the laser trap.

    PubMed Central

    Guilford, W H; Dupuis, D E; Kennedy, G; Wu, J; Patlak, J B; Warshaw, D M

    1997-01-01

    Purified smooth muscle myosin in the in vitro motility assay propels actin filaments at 1/10 the velocity, yet produces 3-4 times more force than skeletal muscle myosin. At the level of a single myosin molecule, these differences in force and actin filament velocity may be reflected in the size and duration of single motion and force-generating events, or in the kinetics of the cross-bridge cycle. Specifically, an increase in either unitary force or duty cycle may explain the enhanced force-generating capacity of smooth muscle myosin. Similarly, an increase in attached time or decrease in unitary displacement may explain the reduced actin filament velocity of smooth muscle myosin. To discriminate between these possibilities, we used a laser trap to measure unitary forces and displacements from single smooth and skeletal muscle myosin molecules. We analyzed our data using mean-variance analysis, which does not rely on scoring individual events by eye, and emphasizes periods in the data with constant properties. Both myosins demonstrated multiple but similar event populations with discrete peaks at approximately +11 and -11 nm in displacement, and 1.5 and 3.5 pN in force. Mean attached times for smooth muscle myosin were longer than for skeletal-muscle myosin. These results explain much of the difference in actin filament velocity between these myosins, and suggest that an increased duty cycle is responsible for the enhanced force-generating capacity of smooth over skeletal-muscle myosin. Images FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 PMID:9138552

  12. Variability in training-induced skeletal muscle adaptation

    PubMed Central

    2011-01-01

    When human skeletal muscle is exposed to exercise training, the outcomes, in terms of physiological adaptation, are unpredictable. The significance of this fact has long been underappreciated, and only recently has progress been made in identifying some of the molecular bases for the heterogeneous response to exercise training. It is not only of great medical importance that some individuals do not substantially physiologically adapt to exercise training, but the study of the heterogeneity itself provides a powerful opportunity to dissect out the genetic and environmental factors that limit adaptation, directly in humans. In the following review I will discuss new developments linking genetic and transcript abundance variability to an individual's potential to improve their aerobic capacity or endurance performance or induce muscle hypertrophy. I will also comment on the idea that certain gene networks may be associated with muscle “adaptability” regardless the stimulus provided. PMID:21030666

  13. Biosynthesis of titin in cultured skeletal muscle cells

    SciTech Connect

    Isaacs, W.B.; Kim, I.S.; Struve, A.; Fulton, A.B. )

    1989-11-01

    Although significant progress has been made regarding the structure and function of titin, little data exist on the biosynthesis of this large protein in developing muscle. Using pulse-labeling with ({sup 35}S)methionine and immunoprecipitation with an anti-titin mAb, we have examined the biosynthesis of titin in synchronized cultures of skeletal muscle cells derived from day 12 chicken embryos. We find that: (a) titin synthesis increases greater than 4-fold during the first week in culture and during this same time period, synthesis of muscle-specific myosin heavy chain increases greater than 12-fold; (b) newly synthesized titin has a t1/2 of approximately 70 h; (c) titin is resistant to extraction with Triton X-100 both during and immediately after its synthesis. These observations suggest that newly synthesized titin molecules are stable proteins that rapidly associate with the cytoskeleton of developing myotubes.

  14. Primary skeletal muscle cells cultured on gelatin bead microcarriers develop structural and biochemical features characteristic of adult skeletal muscle.

    PubMed

    Kubis, Hans-Peter; Scheibe, Renate J; Decker, Brigitte; Hufendiek, Karsten; Hanke, Nina; Gros, Gerolf; Meissner, Joachim D

    2016-04-01

    A primary skeletal muscle cell culture, in which myoblasts derived from newborn rabbit hindlimb muscles grow on gelatin bead microcarriers in suspension and differentiate into myotubes, has been established previously. In the course of differentiation and beginning spontaneous contractions, these multinucleated myotubes do not detach from their support. Here, we describe the development of the primary myotubes with respect to their ultrastructural differentiation. Scanning electron microscopy reveals that myotubes not only grow around the surface of one carrier bead but also attach themselves to neighboring carriers, forming bridges between carriers. Transmission electron microscopy demonstrates highly ordered myofibrils, T-tubules, and sarcoplasmic reticulum. The functionality of the contractile apparatus is evidenced by contractile activity that occurs spontaneously or can be elicited by electrostimulation. Creatine kinase activity increases steadily until day 20 of culture. Regarding the expression of isoforms of myosin heavy chains (MHC), we could demonstrate that from day 16 on, no non-adult MHC isoform mRNAs are present. Instead, on day 28 the myotubes express predominantly adult fast MHCIId/x mRNA and protein. This MHC pattern resembles that of fast muscles of adult rabbits. In contrast, primary myotubes grown on matrigel-covered culture dishes express substantial amounts of non-adult MHC protein even on day 21. To conclude, primary myotubes grown on microcarriers in their later stages exhibit many features of adult skeletal muscle and characteristics of fast type II fibers. Thus, the culture represents an excellent model of adult fast skeletal muscle, for example, when investigating molecular mechanisms of fast-to-slow fiber-type transformation. PMID:26610066

  15. Human skeletal muscle protein breakdown during spaceflight

    NASA Technical Reports Server (NTRS)

    Stein, T. P.; Schluter, M. D.

    1997-01-01

    Human spaceflight is associated with a loss of body protein. Excretion of 3-methylhistidine (3-MH) in the urine is a useful measurement of myofibrillar protein breakdown. Bed rest, particularly with 6 degrees head-down tilt, is an accepted ground-based model for human spaceflight. The objectives of this report were to compare 3-MH excretion from two Life Sciences shuttle missions (duration 9.5 and 15 days, n = 9) and from 17 days of bed rest (n = 7) with 6 degrees head-down tilt. The bed rest study was designed to mimic an actual Life Sciences spaceflight and so incorporated an extensive battery of physiological tests focused on the musculoskeletal system. Results showed that nitrogen retention, based on excretion of nitrogen in the urine, was reduced during both bed rest [from 22 +/- 1 to 1 +/- 5 mg N x kg(-1) x day(-1) (n = 7; P < 0.05)] and spaceflight [from 57 +/- 9 to 19 +/- 3 mg N x kg(-1) x day(-1) (n = 9; P < 0.05)]. 3-MH excretion was unchanged with either bed rest [pre-bed rest 5.30 +/- 0.29 vs. bed rest 5.71 +/- 0.30 micromol 3-MH x kg(-1) x day(-1), n = 7; P = not significant (NS)] or spaceflight [preflight 4.98 +/- 0.37 vs. 4.59 +/- 0.39 micromol 3-MH x kg(-1) x day(-1) in-flight, n = 9; P = NS]. We conclude that 1) 3-MH excretion was unaffected by spaceflight on the shuttle or with bed rest plus exercise, and 2) because protein breakdown (elevated 3-MH) was increased on Skylab but not on the shuttle, it follows that muscle protein breakdown is not an inevitable consequence of spaceflight.

  16. Three-dimensionally printed biological machines powered by skeletal muscle.

    PubMed

    Cvetkovic, Caroline; Raman, Ritu; Chan, Vincent; Williams, Brian J; Tolish, Madeline; Bajaj, Piyush; Sakar, Mahmut Selman; Asada, H Harry; Saif, M Taher A; Bashir, Rashid

    2014-07-15

    Combining biological components, such as cells and tissues, with soft robotics can enable the fabrication of biological machines with the ability to sense, process signals, and produce force. An intuitive demonstration of a biological machine is one that can produce motion in response to controllable external signaling. Whereas cardiac cell-driven biological actuators have been demonstrated, the requirements of these machines to respond to stimuli and exhibit controlled movement merit the use of skeletal muscle, the primary generator of actuation in animals, as a contractile power source. Here, we report the development of 3D printed hydrogel "bio-bots" with an asymmetric physical design and powered by the actuation of an engineered mammalian skeletal muscle strip to result in net locomotion of the bio-bot. Geometric design and material properties of the hydrogel bio-bots were optimized using stereolithographic 3D printing, and the effect of collagen I and fibrin extracellular matrix proteins and insulin-like growth factor 1 on the force production of engineered skeletal muscle was characterized. Electrical stimulation triggered contraction of cells in the muscle strip and net locomotion of the bio-bot with a maximum velocity of ∼ 156 μm s(-1), which is over 1.5 body lengths per min. Modeling and simulation were used to understand both the effect of different design parameters on the bio-bot and the mechanism of motion. This demonstration advances the goal of realizing forward-engineered integrated cellular machines and systems, which can have a myriad array of applications in drug screening, programmable tissue engineering, drug delivery, and biomimetic machine design. PMID:24982152

  17. Role of hydrogen sulfide in skeletal muscle biology and metabolism

    PubMed Central

    Veeranki, Sudhakar; Tyagi, Suresh C.

    2014-01-01

    Hydrogen sulfide (H2S) is a novel endogenous gaseous signal transducer (gasotransmittor). Its emerging role in multiple facets of inter- and intra-cellular signaling as a metabolic, inflammatory, neuro and vascular modulator has been increasingly realized. Although H2S is known for its effects as an anti-hypertensive, anti-inflammatory and anti-oxidant molecule, the relevance of these effects in skeletal muscle biology during health and during metabolic syndromes is unclear. H2S has been implicated in vascular relaxation and vessel tone enhancement, which might lead to mitigation of vascular complications caused by the metabolic syndromes. Metabolic complications may also lead to mitochondrial remodeling by interfering with fusion and fission, therefore, leading to mitochondrial mitophagy and skeletal muscle myopathy. Mitochondrial protection by H2S enhancing treatments may mitigate deterioration of muscle function during metabolic syndromes. In addition, H2S might upregulate uncoupling proteins and might also cause browning of white fat, resulting in suppression of imbalanced cytokine signaling caused by abnormal fat accumulation. Likewise, as a source for H+ ions, it has the potential to augment anaerobic ATP synthesis. However, there is a need for studies to test these putative H2S benefits in different patho-physiological scenarios before its full-fledged usage as a therapeutic molecule. The present review highlights current knowledge with regard to exogenous and endogenous H2S roles in skeletal muscle biology, metabolism, exercise physiology and related metabolic disorders, such as diabetes and obesity, and also provides future directions. PMID:25461301

  18. The peculiar apoptotic behavior of skeletal muscle cells.

    PubMed

    Salucci, Sara; Burattini, Sabrina; Baldassarri, Valentina; Battistelli, Michela; Canonico, Barbara; Valmori, Aurelio; Papa, Stefano; Falcieri, Elisabetta

    2013-08-01

    Apoptosis plays an active role in maintaining skeletal muscle homeostasis. Its deregulation is involved in several skeletal muscle disorders such as dystrophies, myopathies, disuse and sarcopenia. The aim of this work was to study in vitro the apoptotic behavior induced by etoposide, staurosporine and hydrogen peroxide in the C2C12 skeletal muscle cell line, comparing myoblast vs myotube sensitivity, investigated by means of morphological and cytofluorimetric analyses. Myotubes appeared more resistant than myoblasts to apoptotic induction. In myoblasts treated with etoposide, nuclei with chromatin condensation were observed, in the presence of a diffuse DNA fragmentation, as shown by confocal microscopy. The latter also appeared in myotubes, where apoptotic and normal nuclei coexisted inside the same syncytium. After staurosporine treatment, myobalsts evidenced late apoptotic features and a high number of TUNEL-positive nuclei. Secondary necrosis appeared in myotubes, where myonuclei with cleaved DNA again coexisted with normal myonuclei. After H₂O₂ exposure, myotubes, differently from myoblasts, showed a poor sensitivity to cell death. Intriguingly, autophagic granules appeared abundantly in myotubes after each treatment. In myotubes, mitochondria were better preserved than in myoblasts since those which were damaged were probably degraded through autophagic processes. These findings demonstrate a scarce sensitivity of myotubes to apoptotic stimuli due to acquisition of an apoptosis-resistant phenotype during differentiation. The presence of nuclear-dependent "territorial" death domains in the syncytium could explain a slower death of myotubes compared to mononucleated cells. In addition, autophagy could preserve and protect muscle cell integrity against chemical stimuli, making C2C12 cells, in particular myotubes, more resistant to apoptosis induction. PMID:23400589

  19. Three-dimensionally printed biological machines powered by skeletal muscle

    PubMed Central

    Cvetkovic, Caroline; Raman, Ritu; Chan, Vincent; Williams, Brian J.; Tolish, Madeline; Bajaj, Piyush; Sakar, Mahmut Selman; Asada, H. Harry; Saif, M. Taher A.; Bashir, Rashid

    2014-01-01

    Combining biological components, such as cells and tissues, with soft robotics can enable the fabrication of biological machines with the ability to sense, process signals, and produce force. An intuitive demonstration of a biological machine is one that can produce motion in response to controllable external signaling. Whereas cardiac cell-driven biological actuators have been demonstrated, the requirements of these machines to respond to stimuli and exhibit controlled movement merit the use of skeletal muscle, the primary generator of actuation in animals, as a contractile power source. Here, we report the development of 3D printed hydrogel “bio-bots” with an asymmetric physical design and powered by the actuation of an engineered mammalian skeletal muscle strip to result in net locomotion of the bio-bot. Geometric design and material properties of the hydrogel bio-bots were optimized using stereolithographic 3D printing, and the effect of collagen I and fibrin extracellular matrix proteins and insulin-like growth factor 1 on the force production of engineered skeletal muscle was characterized. Electrical stimulation triggered contraction of cells in the muscle strip and net locomotion of the bio-bot with a maximum velocity of ∼156 μm s−1, which is over 1.5 body lengths per min. Modeling and simulation were used to understand both the effect of different design parameters on the bio-bot and the mechanism of motion. This demonstration advances the goal of realizing forward-engineered integrated cellular machines and systems, which can have a myriad array of applications in drug screening, programmable tissue engineering, drug delivery, and biomimetic machine design. PMID:24982152

  20. Role of hydrogen sulfide in skeletal muscle biology and metabolism.

    PubMed

    Veeranki, Sudhakar; Tyagi, Suresh C

    2015-04-30

    Hydrogen sulfide (H2S) is a novel endogenous gaseous signal transducer (gasotransmitter). Its emerging role in multiple facets of inter- and intra-cellular signaling as a metabolic, inflammatory, neuro and vascular modulator has been increasingly realized. Although H2S is known for its effects as an anti-hypertensive, anti-inflammatory and anti-oxidant molecule, the relevance of these effects in skeletal muscle biology during health and during metabolic syndromes is unclear. H2S has been implicated in vascular relaxation and vessel tone enhancement, which might lead to mitigation of vascular complications caused by the metabolic syndromes. Metabolic complications may also lead to mitochondrial remodeling by interfering with fusion and fission, therefore, leading to mitochondrial mitophagy and skeletal muscle myopathy. Mitochondrial protection by H2S enhancing treatments may mitigate deterioration of muscle function during metabolic syndromes. In addition, H2S might upregulate uncoupling proteins and might also cause browning of white fat, resulting in suppression of imbalanced cytokine signaling caused by abnormal fat accumulation. Likewise, as a source for H(+) ions, it has the potential to augment anaerobic ATP synthesis. However, there is a need for studies to test these putative H2S benefits in different patho-physiological scenarios before its full-fledged usage as a therapeutic molecule. The present review highlights current knowledge with regard to exogenous and endogenous H2S roles in skeletal muscle biology, metabolism, exercise physiology and related metabolic disorders, such as diabetes and obesity, and also provides future directions. PMID:25461301

  1. Muscle contractile activity regulates Sirt3 protein expression in rat skeletal muscles.

    PubMed

    Hokari, Fumi; Kawasaki, Emi; Sakai, Atsushi; Koshinaka, Keiichi; Sakuma, Kunihiro; Kawanaka, Kentaro

    2010-08-01

    Sirt3, a member of the sirtuin family, is known to control cellular mitochondrial function. Furthermore, because sirtuins require NAD for their deacetylase activity, nicotinamide phosphoribosyltransferase (Nampt), which is a rate-limiting enzyme in the intracellular NAD biosynthetic pathway, influences their activity. We examined the effects of exercise training and normal postural contractile activity on Sirt3 and Nampt protein expression in rat skeletal muscles. Male rats were trained by treadmill running at 20 m/min, 60 min/day, 7 days/wk for 4 wk. This treadmill training program increased the Sirt3 protein expression in the soleus and plantaris muscles by 49% and 41%, respectively (P < 0.05). Moreover, a 4-wk voluntary wheel-running program also induced 66% and 95% increases in Sirt3 protein in the plantaris and triceps muscles of rats, respectively (P < 0.05). Treadmill-running and voluntary running training induced no significant changes in Nampt protein expression in skeletal muscles. In resting rats, the soleus muscle, which is recruited during normal postural activity, possessed the greatest expression levels of the Sirt3 and Nampt proteins, followed by the plantaris and triceps muscles. Furthermore, the Sirt3, but not Nampt, protein level was reduced in the soleus muscles from immobilized hindlimbs compared with that shown in the contralateral control muscle. These results demonstrated that 1) Sirt3 protein expression is upregulated by exercise training in skeletal muscles and 2) local postural contractile activity plays an important role in maintaining a high level of Sirt3 protein expression in postural muscle. PMID:20413424

  2. Cardiac sarcalumenin: phosphorylation, comparison with the skeletal muscle sarcalumenin and modulation of ryanodine receptor.

    PubMed

    Hadad, N; Meyer, H E; Varsanyi, M; Fleischer, S; Shoshan-Barmatz, V

    1999-07-01

    Cardiac sarcoplasmic reticulum (SR) contains an endogenous phosphorylation system that under specific conditions phosphorylates two proteins with apparent molecular masses of 150 and 130 kDa. The conditions for their phosphorylation are as for the skeletal muscle sarcalumenin and the histidine-rich Ca2+ binding protein (HCP) with respect to: (i) Ca2+ and high concentrations of NaF are required; (ii) phosphorylation is obtained with no added Mg2+ and shows a similar time course and ATP concentration dependence; (iii) inhibition by similar concentrations of La3+; (iv) phosphorylation is obtained with [gamma-32P]GTP; (v) ryanodine binding is inhibited parallel to the phosphorylation of the two proteins. The endogenous kinase is identified as casein kinase II (CK II) based on its ability to use GTP as effectively as ATP, and its inhibition by La3+. The association of CK II with the cardiac SR, even after EGTA extraction at alkaline pH, is demonstrated using antibodies against CK II. The cardiac 130 kDa protein is identified as sarcalumenin based on its partial amino acid sequence and its blue staining with Stains-All. Cardiac sarcalumenin is different from the skeletal muscle protein based on electrophoretic mobilities, immunological analysis, peptide and phosphopeptide maps, as well as amino acid sequencing. Preincubation of SR with NaF and ATP, but not with NaF and AMP-PNP caused strong inhibition of ryanodine binding. This is due to decrease in Ca2+- and ryanodine-binding affinities of the ryanodine receptor (RyR) by about 6.6 and 18-fold, respectively. These results suggest that cardiac sarcalumenin is an isoform of the skeletal muscle protein. An endogenous CK II can phosphorylate sarcalumenin, and in parallel to its phosphorylation the properties of the ryanodine receptor are modified. PMID:10398759

  3. Dexamethasone regulates glutamine synthetase expression in rat skeletal muscles

    NASA Technical Reports Server (NTRS)

    Max, Stephen R.; Konagaya, Masaaki; Konagaya, Yoko; Thomas, John W.; Banner, Carl; Vitkovic, Ljubisa

    1986-01-01

    The regulation of glutamine synthetase by glucocorticoids in rat skeletal muscles was studied. Administration of dexamethasone strikingly enhanced glutamine synthetase activity in plantaris and soleus muscles. The dexamethasone-mediated induction of glutamine synthetase activity was blocked to a significant extent by orally administered RU38486, a glucocorticoid antagonist, indicating the involvement of intracellular glucocorticoid receptors in the induction. Northern blot analysis revealed that dexamethasone-mediated enhancement of glutamine synthetase activity involves dramatically increased levels of glutamine synthetase mRNA. The induction of glutamine synthetase was selective in that glutaminase activity of soleus and plantaris muscles was not increased by dexamethasone. Furthermore, dexamethasone treatment resulted in only a small increase in glutamine synthetase activity in the heart. Accordingly, there was only a slight change in glutamine synthetase mRNA level in this tissue. Thus, glucocorticoids regulate glutamine synthetase gene expression in rat muscles at the transcriptional level via interaction with intracellular glutamine production by muscle and to mechanisms underlying glucocorticoid-induced muscle atrophy.

  4. Viscoelasticity-based MR elastography of skeletal muscle

    NASA Astrophysics Data System (ADS)

    Klatt, Dieter; Papazoglou, Sebastian; Braun, Jürgen; Sack, Ingolf

    2010-11-01

    An in vivo multifrequency magnetic resonance elastography (MRE) protocol was developed for studying the viscoelastic properties of human skeletal muscle in different states of contraction. Low-frequency shear vibrations in the range of 25-62.5 Hz were synchronously induced into the femoral muscles of seven volunteers and measured in a cross-sectional view by encoding the fast-transverse shear wave component parallel to the muscle fibers. The so-called springpot model was used for deriving two viscoelastic constants, μ and α, from the dispersion functions of the complex shear modulus in relaxed and in loaded muscle. Representing the shear elasticity parallel to the muscle fibers, μ increased in all volunteers upon contraction from 2.68 ± 0.23 kPa to 3.87 ± 0.50 kPa. Also α varied with load, indicating a change in the geometry of the mechanical network of muscle from relaxation (α = 0.253 ± 0.009) to contraction (α = 0.270 ± 0.009). These results provide a reference for a future assessment of muscular dysfunction using rheological parameters.

  5. Leucine incorporation into mixed skeletal muscle protein in humans

    SciTech Connect

    Nair, K.S.; Halliday, D.; Griggs, R.C. Clinical Research Centre, Harrow )

    1988-02-01

    Fractional mixed skeletal muscle protein synthesis (FMPS) was estimated in 10 postabsorptive healthy men by determining the increment in the abundance of ({sup 13}C)-leucine in quadriceps muscle protein during an intravenous infusion of L-(1-{sup 13}C)leucine. Whole-body muscle protein synthesis (MPS) was calculated based on the estimation of muscle mass from creatinine excretion and compared with whole-body protein synthesis (WBPS) calculated from the nonoxidative portion of leucine flux. A significant correlation was found between MPS. The contribution of MPS to WBPS was 27 {plus minus} 1%, which is comparable to the reports in other species. Morphometric analyses of adjacent muscle samples in eight subjects demonstrated that the biopsy specimens consisted of 86.5 {plus minus} 2% muscular as opposed to other tissues. Because fiber type composition varies between biopsies, the authors examined the relationship between proportions of each fiber type and FMPS. Variation in the composition of biopsies and in fiber-type proportion did not affect the estimation of muscle protein synthesis rate. They conclude that stable isotope techniques using serial needle biopsies permit the direct measurement of FMPS in humans and that this estimation is correlated with an indirect estimation of WBPS.

  6. Interrelationship between bone substitution materials and skeletal muscle tissue.

    PubMed

    Kunert-Keil, Christiane; Botzenhart, Ute; Gedrange, Tomasz; Gredes, Tomasz

    2015-05-01

    Bone density and quantity are primary conditions for the insertion and stability of dental implants. In cases of a lack of adequate maxillary or mandibulary bone, bone augmentation will be necessary. The use of synthetic bioactive bone substitution materials is of increasing importance as alternatives to autogenously bone grafts. It is well known that bone can influence muscle function and muscle function can influence bone structures. Muscles have a considerable potential of adaptation and muscle tissue surrounding an inserted implant or bone surrogate can integrate changes in mechanical load of the muscle and hereupon induce signaling cascades with protein synthesis and arrangement of the cytoskeleton. The Musculus latissimus dorsi is very often used for the analyses of the in vivo biocompatibility of newly designed biomaterials. Beside macroscopically and histologically examination, biocompatibility can be assessed by analyses of the biomaterial influence of gene expression. This review discusses changes in the fiber type distribution, myosin heavy chain isoform composition, histological appearance and vascularization of the skeletal muscle after implantation of bone substitution materials. Especially, the effects of bone surrogates should be described at the molecular-biological and cellular level. PMID:25159858

  7. The effects of growth factors on skeletal muscle lesions

    PubMed Central

    GIGANTE, ANTONIO; CIANFORLINI, MARCO; MANZOTTI, SANDRA; ULISSE, SERENA

    2013-01-01

    Skeletal muscle injuries are common causes of severe long-term pain and physical disability, accounting for up to 55% of all sports injuries. The phases of the healing process after direct or indirect muscle injury are complex but clearly defined processes comprising well-coordinated steps: degeneration, inflammation, regeneration, and fibrosis. Despite this frequent occurrence and the presence of a body of data on the pathophysiology of muscle injuries, none of the treatment strategies adopted to date have been shown to be really effective in strictly controlled trials. Most current muscle injury treatments are based on limited experimental and clinical data and/or were only empirically tested. Platelet-rich plasma (PRP) is a promising alternative approach based on the ability of autologous growth factors (GFs) to accelerate tissue healing, improve muscular regeneration, increase neovascularization and reduce fibrosis, allowing rapid recovery after muscle lesions. Thus, further experimental studies that include the quantification of specific GFs released by PRP, as well as additional data on angiogenesis, myogenesis and functional recovery are needed to ultimately validate the hypothesis of PRP efficacy in the treatment of muscle lesions and open the way for its wide clinical application. PMID:25606531

  8. Acylcarnitines: potential implications for skeletal muscle insulin resistance.

    PubMed

    Aguer, Cline; McCoin, Colin S; Knotts, Trina A; Thrush, A Brianne; Ono-Moore, Kikumi; McPherson, Ruth; Dent, Robert; Hwang, Daniel H; Adams, Sean H; Harper, Mary-Ellen

    2015-01-01

    Insulin resistance may be linked to incomplete fatty acid ?-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid ?-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20-30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitate-induced insulin resistance concomitant with an ?25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2-3 times by short- or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid ?-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance. PMID:25342132

  9. Lower skeletal muscle capillarization in hypertensive elderly men.

    PubMed

    Gueugneau, Marine; Coudy-Gandilhon, Cécile; Meunier, Bruno; Combaret, Lydie; Taillandier, Daniel; Polge, Cécile; Attaix, Didier; Roche, Frédéric; Féasson, Léonard; Barthélémy, Jean-Claude; Béchet, Daniel

    2016-04-01

    Aging strongly affects the skeletal muscle and is associated with microvascular dysfunctions. Age is also a primary risk factor for the metabolic syndrome, which is a cluster of metabolic and cardiovascular symptoms. Among the metabolic syndrome components, hypertension is the most prevalent in elderly subjects and has a central role in vascular alterations. Despite critical clinical outcomes, the effects of hypertension and metabolic syndrome on skeletal muscle capillarization have poorly been investigated during aging. In the present study, muscle biopsies from normotensive young (YO) and elderly (ELc) men, and elderly men with hypertension (EL-HT) or metabolic syndrome (EL-MS) were assessed for the number of capillaries around a fiber (CAF), capillary-to-fiber perimeter exchange (CFPE), length of contact to perimeter of fiber ratio (LC/PF), capillary tortuosity, and for extracellular matrix (ECM) embedding capillaries. As capillarization and muscle mitochondrial oxidative capacity may be associated, we also investigated cytochrome c oxidase (COX) content. Our findings indicate that capillarization and COX did not change between normotensive adult and old individuals. They further reveal that hypertension in elderly men is associated with reduced CAF (ELc: 5.2±0.4, EL-HT: 4.1±0.2, P<0.02 for type I fibers; ELc: 4.1±0.2, EL-HT: 3.1±0.3, P<0.03 for type IIA fibers), CFPE (ELc: 7.9±0.7, EL-HT: 6.4±0.4 capillaries/1000μm, P<0.03 for type I fibers; ELc: 6.5±0.4, EL-HT: 5.2±0.4 capillaries/1000μm, P<0.03 for type IIA fibers), LC/PF (ELc: 23.3±1.2, EL-HT: 17.8±0.6%, P<0.01 for type I fibers; ELc: 19.8±1.1, EL-HT: 15.6±0.8%, P<0.01 for type IIA fibers) and capillary tortuosity, and with ECM endomysium fibrosis. Capillary rarefaction also correlated with lower COX content in the old hypertensive muscle. No further modification occurred with metabolic syndrome in elderly men. Collectively, our results suggest that hypertension plays a central role in muscle capillarization during aging, and that the other components of metabolic syndrome do not make major additional changes in the aged skeletal muscle capillary network. PMID:26826452

  10. Glutamine metabolism in rat skeletal muscle wounded with lambda-carrageenan

    SciTech Connect

    Albina, J.E.; Henry, W.; King, P.A.; Shearer, J.; Mastrofrancesco, B.; Goldstein, L.; Caldwell, M.D.

    1987-01-01

    Wounding with lambda-carrageenan results in a marked decrease in the intracellular-free glutamine content of rat skeletal muscle. The potential mechanisms for this finding, including alterations in glutamine release, glutamine utilization, and glutamine synthesis, were investigated in rats under pentobarbitol anesthesia. Wounding did not increase glutamine release from muscle during incubation or isolated hindlimb perfusion. Wounded muscle utilized more glutamine than nonwounded muscle, as measured both by the production of (/sup 14/C)O/sub 2/ and of -glutamate from labeled glutamine. Maximal glutamine synthetase activity was increased by wounding. The increase in glutamine synthetase activity in wounded muscle was prevented by adrenalectomy and restored by replacement doses of corticosterone in wounded adrenalectomized animals. The decrease in muscle free glutamine induced by wounding is therefore not mediated by an increase in the release of this amino acid, nor by a reduction in the tissue capacity for glutamine synthesis, but by an increase in glutamine utilization at the site of injury. This difference is apparently determined by the utilization of glutamine by the cellular components of the inflammatory infiltrate, which were shown to be capable of active glutaminolysis.

  11. A small volatile bacterial molecule triggers mitochondrial dysfunction in murine skeletal muscle.

    PubMed

    Tzika, A Aria; Constantinou, Caterina; Bandyopadhaya, Arunava; Psychogios, Nikolaos; Lee, Sangseok; Mindrinos, Michael; Martyn, J A Jeevendra; Tompkins, Ronald G; Rahme, Laurence G

    2013-01-01

    Mitochondria integrate distinct signals that reflect specific threats to the host, including infection, tissue damage, and metabolic dysfunction; and play a key role in insulin resistance. We have found that the Pseudomonas aeruginosa quorum sensing infochemical, 2-amino acetophenone (2-AA), produced during acute and chronic infection in human tissues, including in the lungs of cystic fibrosis (CF) patients, acts as an interkingdom immunomodulatory signal that facilitates pathogen persistence, and host tolerance to infection. Transcriptome results have led to the hypothesis that 2-AA causes further harm to the host by triggering mitochondrial dysfunction in skeletal muscle. As normal skeletal muscle function is essential to survival, and is compromised in many chronic illnesses, including infections and CF-associated muscle wasting, we here determine the global effects of 2-AA on skeletal muscle using high-resolution magic-angle-spinning (HRMAS), proton ((1)H) nuclear magnetic resonance (NMR) metabolomics, in vivo (31)P NMR, whole-genome expression analysis and functional studies. Our results show that 2-AA when injected into mice, induced a biological signature of insulin resistance as determined by (1)H NMR analysis-, and dramatically altered insulin signaling, glucose transport, and mitochondrial function. Genes including Glut4, IRS1, PPAR-γ, PGC1 and Sirt1 were downregulated, whereas uncoupling protein UCP3 was up-regulated, in accordance with mitochondrial dysfunction. Although 2-AA did not alter high-energy phosphates or pH by in vivo (31)P NMR analysis, it significantly reduced the rate of ATP synthesis. This affect was corroborated by results demonstrating down-regulation of the expression of genes involved in energy production and muscle function, and was further validated by muscle function studies. Together, these results further demonstrate that 2-AA, acts as a mediator of interkingdom modulation, and likely effects insulin resistance associated with a molecular signature of mitochondrial dysfunction in skeletal muscle. Reduced energy production and mitochondrial dysfunctional may further favor infection, and be an important step in the establishment of chronic and persistent infections. PMID:24098655

  12. Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation

    PubMed Central

    Touvier, T; De Palma, C; Rigamonti, E; Scagliola, A; Incerti, E; Mazelin, L; Thomas, J-L; D'Antonio, M; Politi, L; Schaeffer, L; Clementi, E; Brunelli, S

    2015-01-01

    Mitochondrial fission and fusion are essential processes in the maintenance of the skeletal muscle function. The contribution of these processes to muscle development has not been properly investigated in vivo because of the early lethality of the models generated so far. To define the role of mitochondrial fission in muscle development and repair, we have generated a transgenic mouse line that overexpresses the fission-inducing protein Drp1 specifically in skeletal muscle. These mice displayed a drastic impairment in postnatal muscle growth, with reorganisation of the mitochondrial network and reduction of mtDNA quantity, without the deficiency of mitochondrial bioenergetics. Importantly we found that Drp1 overexpression activates the stress-induced PKR/eIF2α/Fgf21 pathway thus leading to an attenuated protein synthesis and downregulation of the growth hormone pathway. These results reveal for the first time how mitochondrial network dynamics influence muscle growth and shed light on aspects of muscle physiology relevant in human muscle pathologies. PMID:25719247

  13. Ca2+-Dependent Regulations and Signaling in Skeletal Muscle: From Electro-Mechanical Coupling to Adaptation

    PubMed Central

    Gehlert, Sebastian; Bloch, Wilhelm; Suhr, Frank

    2015-01-01

    Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca2+ is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction. Furthermore and among others, Ca2+ regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca2+-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca2+ ions for the integrity of skeletal muscle tissue. In this review, we address the major functions of Ca2+ ions in adult muscle but also highlight recent findings of critical Ca2+-dependent mechanisms essential for skeletal muscle-regulation and maintenance. PMID:25569087

  14. The inflammatory response to skeletal muscle injury: illuminating complexities.

    PubMed

    Smith, Carine; Kruger, Maritza J; Smith, Robert M; Myburgh, Kathryn H

    2008-01-01

    Injury of skeletal muscle, and especially mechanically induced damage such as contusion injury, frequently occurs in contact sports, as well as in accidental contact sports, such as hockey and squash. The large variations with regard to injury severity and affected muscle group, as well as non-specificity of reported symptoms, complicate research aimed at finding suitable treatments. Therefore, in order to increase the chances of finding a successful treatment, it is important to understand the underlying mechanisms inherent to this type of skeletal muscle injury and the cellular processes involved in muscle healing following a contusion injury. Arguably the most important of these processes is inflammation since it is a consistent and lasting response. The inflammatory response is dependent on two factors, namely the extent of actual physical damage and the degree of muscle vascularization at the time of injury. However, long-term anti-inflammatory treatment is not necessarily effective in promoting healing, as indicated by various studies on NSAID treatment. Because of the factors named earlier, human studies on the inflammatory response to contusion injury are limited, but several experimental animal models have been designed to study muscle damage and regeneration. The early recovery phase is characterized by the overlapping processes of inflammation and occurrence of secondary damage. Although neutrophil infiltration has been named as a contributor to the latter, no clear evidence exists to support this claim. Macrophages, although forming part of the inflammatory response, have been shown to have a role in recovery, rather than in exacerbating secondary damage. Several probable roles for this cell type in the second phase of recovery, involving resolution processes, have been identified and include the following: (i) phagocytosis to remove cellular debris; (ii) switching from a pro- to anti-inflammatory phenotype in regenerating muscle; (iii) preventing muscle cells from undergoing apoptosis; (iv) releasing factors to promote muscle precursor cell activation and growth; and (v) secretion of cytokines and growth factors to facilitate vascular and muscle fibre repair. These many different roles suggest that a single treatment with one specific target cell population (e.g. neutrophils, macrophages or satellite cells) may not be equally effective in all phases of the post-injury response. To find the optimal targeted, but time-course-dependent, treatments requires substantial further investigations. However, the techniques currently used to induce mechanical injury vary considerably in terms of invasiveness, tools used to induce injury, muscle group selected for injury and contractile status of the muscle, all of which have an influence on the immune and/or cytokine responses. This makes interpretation of the complex responses more difficult. After our review of the literature, we propose that a standardized non-invasive contusion injury is the ideal model for investigations into the immune responses to mechanical skeletal muscle injury. Despite its suitability as a model, the currently available literature with respect to the inflammatory response to injury using contusion models is largely inadequate. Therefore, it may be premature to investigate highly targeted therapies, which may ultimately prove more effective in decreasing athlete recovery time than current therapies that are either not phase-specific, or not administered in a phase-specific fashion. PMID:18937524

  15. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle

    PubMed Central

    Okutsu, Mitsuharu; Akhtar, Yasir N.; Lira, Vitor A.

    2011-01-01

    Skeletal muscle exhibits superb plasticity in response to changes in functional demands. Chronic increases of skeletal muscle contractile activity, such as endurance exercise, lead to a variety of physiological and biochemical adaptations in skeletal muscle, including mitochondrial biogenesis, angiogenesis, and fiber type transformation. These adaptive changes are the basis for the improvement of physical performance and other health benefits. This review focuses on recent findings in genetically engineered animal models designed to elucidate the mechanisms and functions of various signal transduction pathways and gene expression programs in exercise-induced skeletal muscle adaptations. PMID:21030673

  16. Brain and muscle Arnt-like 1 promotes skeletal muscle regeneration through satellite cell expansion

    SciTech Connect

    Chatterjee, Somik; Yin, Hongshan; Nam, Deokhwa; Li, Yong; Ma, Ke

    2015-02-01

    Circadian clock is an evolutionarily conserved timing mechanism governing diverse biological processes and the skeletal muscle possesses intrinsic functional clocks. Interestingly, although the essential clock transcription activator, Brain and muscle Arnt-like 1 (Bmal1), participates in maintenance of muscle mass, little is known regarding its role in muscle growth and repair. In this report, we investigate the in vivo function of Bmal1 in skeletal muscle regeneration using two muscle injury models. Bmal1 is highly up-regulated by cardiotoxin injury, and its genetic ablation significantly impairs regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction. A similarly defective regenerative response is observed in Bmal1-null mice as compared to wild-type controls upon freeze injury. Lack of satellite cell expansion accounts for the regeneration defect, as Bmal1{sup −/−} mice display significantly lower satellite cell number with nearly abolished induction of the satellite cell marker, Pax7. Furthermore, satellite cell-derived primary myoblasts devoid of Bmal1 display reduced growth and proliferation ex vivo. Collectively, our results demonstrate, for the first time, that Bmal1 is an integral component of the pro-myogenic response that is required for muscle repair. This mechanism may underlie its role in preserving adult muscle mass and could be targeted therapeutically to prevent muscle-wasting diseases. - Highlights: • Bmal1 is highly inducible by muscle injury and myogenic stimuli. • Genetic ablation of Bmal1 significantly impairs muscle regeneration. • Bmal1 promotes satellite cell expansion during muscle regeneration. • Bmal1-deficient primary myoblasts display attenuated growth and proliferation.

  17. Nrf2 Protects Against TWEAK-mediated Skeletal Muscle Wasting

    NASA Astrophysics Data System (ADS)

    Al-Sawaf, Othman; Fragoulis, Athanassios; Rosen, Christian; Kan, Yuet Wai; Sönmez, Tolga Taha; Pufe, Thomas; Wruck, Christoph Jan

    2014-01-01

    Skeletal muscle (SM) regeneration after injury is impaired by excessive inflammation. Particularly, the inflammatory cytokine tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a potent inducer of skeletal muscle wasting and fibrosis. In this study we investigated the role of Nrf2, a major regulator of oxidative stress defence, in SM ischemia/reperfusion (I/R) injury and TWEAK induced atrophy. We explored the time-dependent expression of TWEAK after I/R in SM of Nrf2-wildtype (WT) and knockout (KO) mice. Nrf2-KO mice expressed significant higher levels of TWEAK as compared to WT mice. Consequently, Nrf2-KO mice present an insufficient regeneration as compared to Nrf2-WT mice. Moreover, TWEAK stimulation activates Nrf2 in the mouse myoblast cell line C2C12. This Nrf2 activation inhibits TWEAK induced atrophy in C2C12 differentiated myotubes. In summary, we show that Nrf2 protects SM from TWEAK-induced cell death in vitro and that Nrf2-deficient mice therefore have poorer muscle regeneration.

  18. Time-dependent behavior of passive skeletal muscle

    NASA Astrophysics Data System (ADS)

    Ahamed, T.; Rubin, M. B.; Trimmer, B. A.; Dorfmann, L.

    2016-03-01

    An isotropic three-dimensional nonlinear viscoelastic model is developed to simulate the time-dependent behavior of passive skeletal muscle. The development of the model is stimulated by experimental data that characterize the response during simple uniaxial stress cyclic loading and unloading. Of particular interest is the rate-dependent response, the recovery of muscle properties from the preconditioned to the unconditioned state and stress relaxation at constant stretch during loading and unloading. The model considers the material to be a composite of a nonlinear hyperelastic component in parallel with a nonlinear dissipative component. The strain energy and the corresponding stress measures are separated additively into hyperelastic and dissipative parts. In contrast to standard nonlinear inelastic models, here the dissipative component is modeled using an evolution equation that combines rate-independent and rate-dependent responses smoothly with no finite elastic range. Large deformation evolution equations for the distortional deformations in the elastic and in the dissipative component are presented. A robust, strongly objective numerical integration algorithm is used to model rate-dependent and rate-independent inelastic responses. The constitutive formulation is specialized to simulate the experimental data. The nonlinear viscoelastic model accurately represents the time-dependent passive response of skeletal muscle.

  19. Transcriptomic index of skeletal muscle of beef breeds bulls.

    PubMed

    S