Adaptive Response Of Skeletal Muscle Research Articles

Reactive oxygen and nitrogen species as intracellular signals in skeletal muscle

It is well established that contracting skeletal muscles produce free radicals. Given that radicals are known to play a prominent role in the pathogenesis of several diseases, the 1980s-90s dogma was that contraction-induced radical production was detrimental to muscle because of oxidative damage to macromolecules within the fibre. In contrast to this early outlook, it is now clear that both reactive oxygen species (ROS) and reactive nitrogen species (RNS) play important roles in cell signalling pathways involved in muscle adaptation to exercise and the remodelling that occurs in skeletal muscle during periods of prolonged inactivity. This review will highlight two important redox sensitive signalling pathways that contribute to ROS and RNS-induced skeletal muscle adaptation to endurance exercise. We begin with a historical overview of radical production in skeletal muscles followed by a discussion of the intracellular sites for ROS and RNS production in muscle fibres. We will then provide a synopsis of the redox-sensitive NF-B and PGC-1α signalling pathways that contribute to skeletal muscle adaptation in response to exercise training. We will conclude with a discussion of unanswered questions in redox signalling in skeletal muscle in the hope of promoting additional research interest in this field.

Age‐related changes in skeletal muscle reactive oxygen species generation and adaptive responses to reactive oxygen species

Skeletal muscle generates superoxide and nitric oxide at rest and this generation is increased by contractile activity. In young and adult animals and man, an increase in activities of these species and the secondary products derived from them (reactive oxygen species, ROS) stimulate redox-sensitive signalling pathways to modify the cellular content of cytoprotective regulatory proteins such as the superoxide dismutases, catalase and heat shock proteins that prevent oxidative damage to tissues. The mechanisms underlying these adaptive responses to contraction include activation of redox-sensitive transcription factors such as nuclear factor B (NFB), activator protein-1 (AP1) and heat shock factor 1 (HSF1). During ageing all tissues, including skeletal muscle, demonstrate an accumulation of oxidative damage that may contribute to loss of tissue homeostasis. The causes of this increased oxidative damage are uncertain, but substantial data now indicate that the ability of skeletal muscle from aged organisms to respond to an increase in ROS generation by increased expression of cytoprotective proteins through activation of redox-sensitive transcription factors is severely attenuated. This age-related lack of physiological adaptations to the ROS induced by contractile activity appears to contribute to a loss of ROS homeostasis and increased oxidative damage in skeletal muscle.

Effects of hypoxia on myogenesis and muscular differentiation

Oxygen (O2) is an environmental and developmental regulator during several events such as energy homeostasis, development and process of progenitor cells differentiation. Hypoxia corresponds to a decrease in oxygen partial pressure that leads to adaptive responses of skeletal muscle. Activation, proliferation and differentiation of myogenic precursor cells required for muscle growth seem to be mediated by recruitment of several intracellular pathways including calcineurin, p38–MAPK and Akt/mTOR. To examine the hypoxia-induced alterations in these main intracellular signalling pathways during myogenesis two models were used, myoblasts from the L6 line which differentiate in vitro and the embryonic myogenesis using Xenopus laevis embryos. In culture cells, hypoxia delays myoblast differentiation, affecting both calcineurin and Akt signalling pathways, as well as the mTOR downstream, the translation factor S6. In the embryo, hypoxia exposure causes growth retardation and affects differentiation of the myotome cells. These cell events were correlated to an activation of p38-MAPK and a cytoplasmic accumulation of the 4E-BP1 protein specifically in the axial tissues such as the notochord, somites and floor plate. The data show that the 4E-BP1 is a target of hypoxia that reversibly inhibits the cap-dependent translation of mRNA.

Dietary protein and exercise training in ageing

Ageing is accompanied by a progressive loss of skeletal muscle mass and strength, leading to the loss of functional capacity and an increased risk for developing chronic metabolic diseases such as diabetes. The age-related loss of skeletal muscle mass results from a chronic disruption in the balance between muscle protein synthesis and degradation. As basal muscle protein synthesis rates are likely not different between healthy young and elderly human subjects, it was proposed that muscles from older adults lack the ability to regulate the protein synthetic response to anabolic stimuli, such as food intake and physical activity. Indeed, the dose-response relationship between myofibrillar protein synthesis and the availability of essential amino acids and/or resistance exercise intensity is shifted down and to the right in elderly human subjects. This so-called 'anabolic resistance' represents a key factor responsible for the age-related decline in skeletal muscle mass. Interestingly, long-term resistance exercise training is effective as a therapeutic intervention to augment skeletal muscle mass, and improves functional performance in the elderly. The consumption of different types of proteins, i.e. protein hydrolysates, can have different stimulatory effects on muscle protein synthesis in the elderly, which may be due to their higher rate of digestion and absorption. Current research aims to elucidate the interactions between nutrition, exercise and the skeletal muscle adaptive response that will define more effective strategies to maximise the therapeutic benefits of lifestyle interventions in the elderly.

Effects of H2O2 on Oxidant Activity and Redox-Sensitive Gene Expression in C2C12 Muscle Cells

NFκB-mediated signal transduction is implicated as a key factor in the regulation of muscle adaptations to acute and chronic bouts of exercise. Reactive oxygen and nitrogen species (RONS) are generated during muscle contraction and are purported to stimulate NFκB -mediated upregulation of antioxidant (AO) gene expression. However, the magnitude of exercise-induced RONS activity that is required to induce NFκB-mediated adaptive responses in skeletal muscle is unknown. PURPOSE: 1) To understand the mechanisms by which RONS induce skeletal muscle adaptation by examining the relationship between oxidants (e.g. H2O2) and their redox-sensitive targets, and 2) To test the hypothesis that an acute dose of H2O2 (100μM) would elevate RONS activity and induce measurable gene expression changes in NFκB and AO defense pathways within 5 hrs in cultured skeletal muscle cells. METHODS: C2C12 muscle cells were grown to 70% confluence then supplemented with 2% horse serum to initiate differentiation into myotubes. At 4 days post-differentiation, myotubes were loaded with 10μM CM-H2DCFDA, a non-specific intracellular probe for RONS. After a baseline fluorescence measurement, culture media was supplemented with an acute dose of 100μM H2O2 and fluorescence measurements were taken at 1, 3, and 5 hrs post-H2O2 administration to examine intracellular RONS activity. Myotubes were harvested for total RNA at baseline, 1, and 5 hrs post-H2O2 using the Trizol® method. Quantitative RT-PCR Arrays were used to measure gene expression changes in 84 genes involved in the NFκB signaling pathway and 84 genes involved in the AO defense system at 1 and 5 hours post-H2O2 treatment. Results: Relative to untreated controls, myotubes treated with H2O2 showed higher DCF fluorescence at 1 hr (38%) and 3 hrs (9%) post-treatment, and no difference at 5 hrs of exposure (p<0.05). At 1 hr post-H2O2 treatment, only 3 of the 84 NFκB pathway-related genes (Nlrp12, Raf1, and Cd27) and only 1of 84 AO defense genes (Srxn) was significantly up or downregulated relative to untreated controls. After 5 hours of exposure to H2O2, the expression of 10 of 84 NFκB pathway-related genes (Akt1, Casp1, IL1β, JUN, Myd88, Raf1 Rela&b, Tgfbr2, and Cd27) was differentially altered, yet only 2 of 84 AO defense genes (Gpx4 and Txnrd) were differentially expressed relative to untreated controls. CONCLUSIONS: These findings demonstrate that an acute dose of 100μM H2O2 stimulated intracellular oxidant activity and induced expression of NFκB pathway and AO defense genes within 5 hours of exposure in cultured myotubes. The genes that were differentially expressed are likely sensitive to low level oxidant activity.

Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Promotes Skeletal Muscle Lipid Refueling in Vivo by Activating de Novo Lipogenesis and the Pentose Phosphate Pathway*

Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). PGC-1α enhances lipid oxidation and thereby provides energy for sustained muscle contraction. Its potential implication in promoting muscle refueling remains unresolved, however. Here, we investigated a possible role of elevated PGC-1α levels in skeletal muscle lipogenesis in vivo and the molecular mechanisms that underlie PGC-1α-mediated de novo lipogenesis. To this end, we studied transgenic mice with physiological overexpression of PGC-1α and human muscle biopsies pre- and post-exercise. We demonstrate that PGC-1α enhances lipogenesis in skeletal muscle through liver X receptor α-dependent activation of the fatty acid synthase (FAS) promoter and by increasing FAS activity. Using chromatin immunoprecipitation, we establish a direct interaction between PGC-1α and the liver X receptor-responsive element in the FAS promoter. Moreover, we show for the first time that increased glucose uptake and activation of the pentose phosphate pathway provide substrates for RNA synthesis and cofactors for de novo lipogenesis. Similarly, we observed increased lipogenesis and lipid levels in human muscle biopsies that were obtained post-exercise. Our findings suggest that PGC-1α coordinates lipogenesis, intramyocellular lipid accumulation, and substrate oxidation in exercised skeletal muscle in vivo.

Meal planning and nutritional supplements use among elite bodybuilders in Taiwan

The interaction between exercise and nutrition is important for bodybuilders. The intake of food during post-exercise recovery is necessary for hypertrophy to occur. Therefore, the current survey was performed to...

Carbohydrate feeding during recovery alters the skeletal muscle metabolic response to repeated sessions of high-intensity interval exercise in humans

Exercise training under conditions of reduced carbohydrate (CHO) availability has been reported to augment gains in skeletal muscle oxidative capacity; however, the underlying mechanisms are unclear. We examined the effect of manipulating CHO intake on the acute metabolic response to high-intensity interval exercise, including signaling cascades linked to mitochondrial biogenesis. Ten men performed two trials in random order separated by >or=1 wk. Each trial consisted of a morning (AM) and afternoon (PM) training session (5 x 4 min cycling at approximately 90-95% of heart rate reserve) separated by 3 h of recovery during which subjects ingested a high-CHO drink (HI-HI) or nonenergetic placebo (HI-LO) before PM exercise. Biopsies (vastus lateralis) revealed that muscle phosphocreatine and ATP content were similar after AM exercise but decreased to a greater extent during PM exercise in HI-LO vs. HI-HI. Phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) increased approximately 4-fold and 2-fold, respectively, during AM exercise with no difference between conditions. After PM exercise, p38 MAPK phosphorylation was higher in HI-LO vs. HI-HI, whereas AMPK was not different between conditions. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) gene expression increased approximately 8-fold during recovery from AM exercise and remained elevated during PM exercise with no differences between conditions. Cytochrome oxidase subunit 4 (COXIV) mRNA was also elevated 3 h after AM exercise, with no difference between conditions. These data provide evidence that p38 MAPK is a nutrient-sensitive signaling molecule that could be involved in the altered skeletal muscle adaptive response reported after exercise training under conditions of restricted CHO intake, but further research is required to confirm this hypothesis.

Exercise‐induced histone modifications in human skeletal muscle

Skeletal muscle adaptations to exercise confer many of the health benefits of physical activity and occur partly through alterations in skeletal muscle gene expression. The exact mechanisms mediating altered skeletal muscle gene expression in response to exercise are unknown. However, in recent years, chromatin remodelling through epigenetic histone modifications has emerged as a key regulatory mechanism controlling gene expression in general. The purpose of this study was to examine the effect of exercise on global histone modifications that mediate chromatin remodelling and transcriptional activation in human skeletal muscle in response to exercise. In addition, we sought to examine the signalling mechanisms regulating these processes. Following 60 min of cycling, global histone 3 acetylation at lysine 9 and 14, a modification associated with transcriptional initiation, was unchanged from basal levels, but was increased at lysine 36, a site associated with transcriptional elongation. We examined the regulation of the class IIa histone deacetylases (HDACs), which are enzymes that suppress histone acetylation and have been implicated in the adaptations to exercise. While we found no evidence of proteasomal degradation of the class IIa HDACs, we found that HDAC4 and 5 were exported from the nucleus during exercise, thereby removing their transcriptional repressive function. We also observed activation of the AMP-activated protein kinase (AMPK) and the calcium-calmodulin-dependent protein kinase II (CaMKII) in response to exercise, which are two kinases that induce phosphorylation-dependent class IIa HDAC nuclear export. These data delineate a signalling pathway that might mediate skeletal muscle adaptations in response to exercise.

Reactive oxygen species are signalling molecules for skeletal muscle adaptation

Increased reactive oxygen species (ROS) production is crucial to the remodelling that occurs in skeletal muscle in response to both exercise training and prolonged periods of disuse. This review discusses the redox-sensitive signalling pathways that are responsible for this ROS-induced skeletal muscle adaptation. We begin with a discussion of the sites of ROS production in skeletal muscle fibres. This is followed by an overview of the putative redox-sensitive signalling pathways that promote skeletal muscle adaptation. Specifically, this discussion highlights redox-sensitive kinases, phosphatases and the transcription factor nuclear factor-κB. We also discuss the evidence that connects redox signalling to skeletal muscle adaptation in response to increased muscular activity (i.e. exercise training) and during prolonged periods of muscular inactivity (i.e. immobilization). In an effort to stimulate further research, we conclude with a discussion of unanswered questions about redox signalling in skeletal muscle.

Redox regulation in skeletal muscle during contractile activity and aging 1

Skeletal muscle has the ability to adapt and remodel after functional, mechanical, and metabolic stresses by activation of different adaptation mechanisms that induce gene expression, biochemical changes, and structural remodeling. Skeletal muscle cells continuously generate reactive oxygen and nitrogen species (RONS), which can act as mediators in cellular signaling pathways that regulate the adaptation mechanisms. There is strong evidence that indicates that RONS are generated in skeletal muscle cells during contractile activity and this induces the activation of transcription factors which modulate gene expression of antioxidant and protective proteins. Thus, it has been proposed that RONS act as signals that modulate the adaptation mechanisms in skeletal muscle and other cells. Structural and functional changes occur in skeletal muscle during aging and are characterized by a reduction of muscle mass and force (sarcopenia). The causes are known, however, there is considerable support for an involvement of RONS in the process of aging and sarcopenia. Several studies indicate that adaptive responses of skeletal muscle that are activated and regulated by RONS are disrupted during aging. This reduction of skeletal muscle adaptation to contractile activity during aging might be responsible for the loss of muscle mass and function and the progressive deterioration of this organ. In summary, there is sufficient evidence that indicates that cellular redox regulation in skeletal muscle is crucial in the physiology and pathology of skeletal muscle. However, new methodologies and experimental models are required for understanding the complex biology of RONS in the cell. This will provide future interventions that mitigate pathologies and aging of skeletal muscle.

Up‐regulation of the peroxiredoxin‐6 related metabolism of reactive oxygen species in skeletal muscle of mice lacking neuronal nitric oxide synthase

Although neuronal nitric oxide synthase (nNOS) plays a substantial role in skeletal muscle physiology, nNOS-knockout mice manifest an only mild phenotypic malfunction in this tissue. To identify proteins that might be involved in adaptive responses in skeletal muscle of knockout mice lacking nNOS, 2D-PAGE with silver-staining and subsequent tandem mass spectrometry (LC-MS/MS) was performed using extracts of extensor digitorum longus muscle (EDL) derived from nNOS-knockout mice in comparison to C57Bl/6 control mice. Six proteins were significantly (P < or = 0.05) more highly expressed in EDL of nNOS-knockout mice than in that of C57 control mice, all of which are involved in the metabolism of reactive oxygen species (ROS). These included prohibitin (2.0-fold increase), peroxiredoxin-3 (1.9-fold increase), Cu(2+)/Zn(2+)-dependent superoxide dismutase (SOD; 1.9-fold increase), heat shock protein beta-1 (HSP25; 1.7-fold increase) and nucleoside diphosphate kinase B (2.6-fold increase). A significantly higher expression (4.1-fold increase) and a pI shift from 6.5 to 5.9 of peroxiredoxin-6 in the EDL of nNOS-knockout mice were confirmed by quantitative immunoblotting. The concentrations of the mRNA encoding five of these proteins (the exception being prohibitin) were likewise significantly (P < or = 0.05) higher in the EDL of nNOS-knockout mice. A higher intrinsic hydrogen peroxidase activity (P < or = 0.05) was demonstrated in EDL of nNOS-knockout mice than C57 control mice, which was related to the presence of peroxiredoxin-6. The treatment of mice with the chemical NOS inhibitor L-NAME for 3 days induced a significant 3.4-fold up-regulation of peroxiredoxin-6 in the EDL of C57 control mice (P < or = 0.05), but did not alter its expression in EDL of nNOS-knockout mice. ESR spectrometry demonstrated the levels of superoxide to be 2.5-times higher (P < or = 0.05) in EDL of nNOS-knockout mice than in C57 control mice while an in vitro assay based on the emission of 2,7-dichlorofluorescein fluorescence disclosed the concentration of ROS to be similar in both strains of mice. We suggest that the up-regulation of proteins that are implicated in the metabolism of ROS, particularly of peroxiredoxin-6, within skeletal muscles of nNOS-knockout mice functionally compensates for the absence of nNOS in scavenging of superoxide.

Both Membrane Depolarization And IL-6 Induce Calcium-Dependent Hsp70 Expression In Skeletal Muscle Cells

Adaptive response of skeletal muscle to challenges imposed by contractile activity is associated to changes in specific genes expression. IL-6 and Hsp70 are proteins involved in the maintenance of skeletal muscle homeostasis during stress episodes and are markedly expressed in skeletal muscle after physiological contraction. Muscle-derived IL-6 has systemic and local effects acting in a hormone-like fashion, nevertheless the molecular bases of its functional role on skeletal muscle is poorly understood. We have demonstrated that depolarization evoked IP3 mediated slow calcium transients, associated to cell nuclei are involved in the up-regulation of IL-6 transcriptional activity in skeletal muscle cells.The aim of this work was to investigate calcium involvement in Hsp70 expression in both depolarized and IL-6 treated skeletal muscle cells.We observed that electrical stimulation of myotubes increases Hsp70 mRNA level and protein expression. Depolarization performed in the presence of the intracellular calcium chelator BAPTA-AM resulted in a complete inhibition of Hsp70 induced expression. Inhibitors of IP3-dependent calcium signals like 2-aminoethoxydiphenyl borate (2-APB) and LY294002, decreased Hsp70 mRNA induction and the protein expression in depolarized cells. In addition we determined that inhibitors of calcium dependent PKC abolished Hsp70 mRNA induction.We established that IL-6 treatment of myotubes induced changes in intracellular calcium and promoted the increase of Hsp70 mRNA levels. Observed calcium transients could be associated to early events of IL-6-mediated Hsp70 expression.Our results provide evidence for the involvement of slow calcium transients and PKC in the activation of Hsp70 expression in skeletal muscle cells and suggest that intracellular calcium signals also participate in IL-6 induced Hsp70 expression.FONDAP 15010006

Local Detection Of Intracellular Reactive Oxygen Species In Single Intact Contracting Skeletal Muscle Fibers

Skeletal muscles produce low levels of reactive oxygen species (ROS) under resting conditions while during contractile activity the rate of ROS production increases. Low levels of ROS production may act to stimulate adaptive responses in skeletal muscle, while increased ROS dependent oxidation at sarcoplasmic reticulum, myofilaments and other EC coupling components likely lead to decrements in contractile function. Multiple sites exist for ROS production, including mitochondria and NADPH oxidase; however, the contribution of each of these and the factors that regulate the increased production of ROS during contractile activity remains to be determined. Here we use repetitive field stimulation of single FDB myofibers as a model of ROS secondary to repetitive activity. In FDB's loaded with the cytosolic, non-specific ROS probe DCFH, we have imposed intermittent (0.5 Hz) trains (150msec, 0.5msec sq. pulse @, 50Hz) of tetanic stimulation to establish a reliable in vitro model for activity dependent ROS production. In recent studies with this model, we have begun to explore site dependent generation of ROS with a redox sensitive variant of green fluorescent protein (roGFP) that is targeted to the mitochondria (mito-roGFP). Following cDNA electroporation in vivo, expression of mito-roGFP, and FDB isolation, we report evidence of the fidelity and specificity of this probe in mitochondria and the activity dependent mitochondrial redox status during our stimulation paradigm.

Protein supplementation before and after exercise does not further augment skeletal muscle hypertrophy after resistance training in elderly men

Background:Considerable discrepancy exists in the literature on the proposed benefits of protein supplementation on the adaptive response of skeletal muscle to resistance-type exercise training in the elderly.Objective: The objective was to assess the benefits of timed protein supplementation on the increase in muscle mass and strength during prolonged resistance-type exercise training in healthy elderly men who habitually consume adequate amounts of dietary protein.Design: Healthy elderly men (n = 26) aged 72 ± 2 y were randomly assigned to a progressive, 12-wk resistance-type exercise training program with (protein group) or without (placebo group) protein provided before and immediately after each exercise session (3 sessions/wk, 20 g protein/session). One-repetition maximum (1RM) tests were performed regularly to ensure a progressive workload during the intervention. Muscle hypertrophy was assessed at the whole-body (dual-energy X-ray absorptiometry), limb (computed tomography), and muscle fiber (biopsy) level.Results: The 1RM strength increased ≈25–35% in both groups (P < 0.001). Dual-energy X-ray absorptiometry and computed tomography scans showed similar increases in leg muscle mass (6 ± 1% in both groups; P < 0.001) and in the quadriceps (9 ± 1% in both groups), from 75.9 ± 3.7 and 73.8 ± 3.2 to 82.4 ± 3.9 and 80.0 ± 3.0 cm2 in the placebo and protein groups, respectively (P < 0.001). Muscle fiber hypertrophy was greater in type II (placebo: 28 ± 6%; protein: 29 ± 4%) than in type I (placebo: 5 ± 4%; protein: 13 ± 6%) fibers, but the difference between groups was not significant.Conclusion: Timed protein supplementation immediately before and after exercise does not further augment the increase in skeletal muscle mass and strength after prolonged resistance-type exercise training in healthy elderly men who habitually consume adequate amounts of dietary protein. This trial was registered at clinicaltrials.gov as NCT00744094.

Aging, exercise, and muscle protein metabolism

Aging is accompanied by a progressive loss of skeletal muscle mass and strength, leading to the loss of functional capacity and an increased risk of developing chronic metabolic disease. The age-related loss of skeletal muscle mass is attributed to a disruption in the regulation of skeletal muscle protein turnover, resulting in an imbalance between muscle protein synthesis and degradation. As basal (fasting) muscle protein synthesis rates do not seem to differ substantially between the young and elderly, many research groups have started to focus on the muscle protein synthetic response to the main anabolic stimuli, i.e., food intake and physical activity. Recent studies suggest that the muscle protein synthetic response to food intake is blunted in the elderly. The latter is now believed to represent a key factor responsible for the age-related decline in skeletal muscle mass. Physical activity and/or exercise stimulate postexercise muscle protein accretion in both the young and elderly. However, the latter largely depends on the timed administration of amino acids and/or protein before, during, and/or after exercise. Prolonged resistance type exercise training represents an effective therapeutic strategy to augment skeletal muscle mass and improve functional performance in the elderly. The latter shows that the ability of the muscle protein synthetic machinery to respond to anabolic stimuli is preserved up to very old age. Research is warranted to elucidate the interaction between nutrition, exercise, and the skeletal muscle adaptive response. The latter is needed to define more effective strategies that will maximize the therapeutic benefits of lifestyle intervention in the elderly.

Skeletal Muscle Morphology Following Chronic Stretch-Shortening Contraction Exposure: Effects of Glutathione Depletion and Age

The involvement of glutathione in the adaptive response of skeletal muscle following repetitive, high-intensity mechanical loading is not known. PURPOSE: The purpose of this research was to examine the influence that dietary supplementation of a glutathione antagonist (L-Buthionine Sulfoximine (BSO)) has on skeletal muscle adaptation during chronic high-intensity mechanical loading via stretch-shortening contractions (SSCs) in young and old rodents. METHODS: Left dorsiflexor muscles of young (3 months, N= 16) and old (30 months, N = 16), vehicle- and BSO-treated rodents were exposed 3 times per week for 4.5-weeks to a protocol of 80 maximal SSCs per exposure in vivo. Skeletal muscle response was characterized by muscle wet-weight and quantitative morphological analyses following the exposure period. RESULTS: Muscle-wet weight was increased following loading of the exposed limb compared with the contra-lateral control limb, irrespective of age. Further, young rodents had significantly increased muscle wet-weight compared to old rodents. No degenerative myofibers were noted in either age group, but a significant increase was observed in the volume of non-cellular interstitium, indicative of edema, as a result of aging. Muscle cross-sectional area increased in the young, vehicle rodents (a shift from 46% to 68% of Fibers ≥2,000 um2), and in old, vehicle rodents (a shift from 50% to 62% of fibers ≥ 2,000 um2); glutathione depletion had no additional affect on muscle area. CONCLUSIONS: Even though muscle area changes are observed with old rodents, aging negatively influences the adaptive response to chronic SSC exposure by limiting performance as well as morphological adaptation compared with young counterparts; however glutathione depletion does not adversely affect nor exacerbate this adaptive profile.

Impact of metallothionein deficiency on soleus muscle function following acute spinal cord injury

Metallothioneins (Mts) are small molecular weight proteins that possess metal binding and free radical scavenging properties. Furthermore, Mt is a stress protein that likely participates in the adaptive response of skeletal muscle to stressful stimuli and is up‐regulated following acute spinal cord injury (SCI). We tested the hypothesis that loss of Mt (Mt1 and Mt2; Mt−/ −) would lead to exacerbated atrophy and contractile dysfunction of the soleus muscle following acute SCI (7 days, T9 transection) in Mt−/ − mice compared to control strain mice. Transected control strain (CT; n=5) and transected Mt−/ − (MT; n=6) mice experienced an equivalent % loss of body weight by day 7 of recovery compared to pre‐surgery weight (CT = −8.6 ± 1.6; MT = −11.6 ± 2.4). Soleus muscle mass (mg) of CT (4.3 ± 0.2) and MT (4.6 ± 0.1) groups was lower (p&lt;0.05) than the non‐surgical control strain (NS; n=5; 5.6 ± 0.3). However, preliminary data (n=1–3/group) indicate that a lower maximal specific tension (N/cm2) is generated by the soleus in MT vs. controls (NS=23.7 ± 2.5; CT=22.1; MT 19.0 ± 0.0). In summary, deficiency of Mt1 and Mt2 does not alter the loss of muscle mass but may lead to lower maximal force generating ability of the soleus in response to disuse resulting from spinal cord injury.Supported by Syracuse University SOE

Effect of High-Frequency Resistance Exercise on Adaptive Responses in Skeletal Muscle

Regulation of skeletal muscle mass is highly dependent on contractile loading. The purpose of this study was to examine changes in growth factor and inflammatory pathways following high-frequency resistance training. Using a novel design in which male Sprague-Dawley rats undertook a "stacked" resistance training protocol designed to generate a summation of transient exercise-induced signaling responses (four bouts of three sets x 10 repetitions of squat exercise, separated by 3 h of recovery), we determined the effects of high training frequency on signaling pathways and transcriptional activity regulating muscle mass. The stacked training regimen resulted in acute suppression of insulin-like growth factor 1 mRNA abundance (P < 0.05) and Akt phosphorylation (P < 0.05), an effect that persisted 48 h after the final training bout. Conversely, stacked training elicited a coordinated increase in the expression of tumor necrosis factor alpha, inhibitor kappa B kinase alpha/beta activity (P < 0.05), and p38 mitogen-activated protein kinase phosphorylation (P < 0.05) at 3 h after each training bout. In addition, the stacked series of resistance exercise bouts induced an increase in p70 S6 kinase phosphorylation 3 h after bouts x3 and x4, independent of the phosphorylation state of Akt. Our results indicate that high resistance training frequency extends the transient activation of inflammatory signaling cascades, concomitant with persistent suppression of key mediators of anabolic responses. We provide novel insights into the effects of the timing of exercise-induced overload and recovery on signal transduction pathways and transcriptional activity regulating skeletal muscle mass in vivo.

Engineered Muscle

Recent advances in skeletal muscle tissue engineering have resulted in an in vitro tissue model that can be used for studying the effects of genetic alterations, pharmacological interventions, and exercise on muscle physiology and function. Here, we present applications for this technology to further our understanding of the molecular mechanisms underlying skeletal muscle adaptation in response to exercise.