Identification of a muscle-specific isoform of VMA21 as a potent actor in X-linked myopathy with excessive autophagy pathogenesis.

Defective lysosomal acidification is responsible for a large range of multi-systemic disorders associated with impaired autophagy. Diseases caused by mutations in the VMA21 gene stand as exceptions, specifically affecting skeletal muscle (X-linked Myopathy with Excessive Autophagy, XMEA) or liver (Congenital Disorder of Glycosylation). VMA21 chaperones vacuolar (v-) ATPase assembly, which is ubiquitously required for proper lysosomal acidification. The reason VMA21 deficiencies affect specific, but divergent tissues remains unknown. Here, we show that VMA21 encodes a yet-unreported long protein isoform, in addition to the previously described short isoform, which we name VMA21-120 and VMA21-101, respectively. In contrast to the ubiquitous pattern of VMA21-101, VMA21-120 was predominantly expressed in skeletal muscle, and rapidly up-regulated upon differentiation of mouse and human muscle precursors. Accordingly, VMA21-120 accumulated during development, regeneration and denervation of mouse skeletal muscle. In contrast, neither induction nor blockade of autophagy, in vitro and in vivo, strongly affected VMA21 isoform expression. Interestingly, VMA21-101 and VMA21-120 both localized to the sarcoplasmic reticulum of muscle cells, and interacted with the v-ATPase. While VMA21 deficiency impairs autophagy, VMA21-101 or VMA21-120 overexpression had limited impact on autophagic flux in muscle cells. Importantly, XMEA-associated mutations lead to both VMA21-101 deficiency and loss of VMA21-120 expression. These results provide important insights into the clinical diversity of VMA21-related diseases and uncover a muscle-specific VMA21 isoform that potently contributes to XMEA pathogenesis.

Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis.

Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity.

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle.

Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie restriction (CR) potently extends health and lifespan, but is largely unachievable in humans, making "CR mimetics" of great interest. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, is considered a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging.

Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia.

Sarcopenia, the age-related loss of skeletal muscle mass and function, affects 5-13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

The TOR Pathway at the Neuromuscular Junction: More Than a Metabolic Player?

The neuromuscular junction (NMJ) is the chemical synapse connecting motor neurons and skeletal muscle fibers. NMJs allow all voluntary movements, and ensure vital functions like breathing. Changes in the structure and function of NMJs are hallmarks of numerous pathological conditions that affect muscle function including sarcopenia, the age-related loss of muscle mass and function. However, the molecular mechanisms leading to the morphological and functional perturbations in the pre- and post-synaptic compartments of the NMJ remain poorly understood. Here, we discuss the role of the metabolic pathway associated to the kinase TOR (Target of Rapamycin) in the development, maintenance and alterations of the NMJ. This is of particular interest as the TOR pathway has been implicated in aging, but its role at the NMJ is still ill-defined. We highlight the respective functions of the two TOR-associated complexes, TORC1 and TORC2, and discuss the role of localized protein synthesis and autophagy regulation in motor neuron terminals and sub-synaptic regions of muscle fibers and their possible effects on NMJ maintenance.

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia.

With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.

mTORC1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice.

BACKGROUND: The balance between protein synthesis and degradation (proteostasis) is a determining factor for muscle size and function. Signalling via the mammalian target of rapamycin complex 1 (mTORC1) regulates proteostasis in skeletal muscle by affecting protein synthesis and autophagosomal protein degradation. Indeed, genetic inactivation of mTORC1 in developing and growing muscle causes atrophy resulting in a lethal myopathy. However, systemic dampening of mTORC1 signalling by its allosteric inhibitor rapamycin is beneficial at the organismal level and increases lifespan. Whether the beneficial effect of rapamycin comes at the expense of muscle mass and function is yet to be established. METHODS: We conditionally ablated the gene coding for the mTORC1-essential component raptor in muscle fibres of adult mice [inducible raptor muscle-specific knockout (iRAmKO)]. We performed detailed phenotypic and biochemical analyses of iRAmKO mice and compared them with muscle-specific raptor knockout (RAmKO) mice, which lack raptor in developing muscle fibres. We also used polysome profiling and proteomics to assess protein translation and associated signalling in skeletal muscle of iRAmKO mice. RESULTS: Analysis at different time points reveal that, as in RAmKO mice, the proportion of oxidative fibres decreases, but slow-type fibres increase in iRAmKO mice. Nevertheless, no significant decrease in body and muscle mass or muscle fibre area was detected up to 5 months post-raptor depletion. Similarly, ex vivo muscle force was not significantly reduced in iRAmKO mice. Despite stable muscle size and function, inducible raptor depletion significantly reduced the expression of key components of the translation machinery and overall translation rates. CONCLUSIONS: Raptor depletion and hence complete inhibition of mTORC1 signalling in fully grown muscle leads to metabolic and morphological changes without inducing muscle atrophy even after 5 months. Together, our data indicate that maintenance of muscle size does not require mTORC1 signalling, suggesting that rapamycin treatment is unlikely to negatively affect muscle mass and function.

Glycine Protects Muscle Cells From Wasting in vitro via mTORC1 Signaling.

Glycine supplementation can protect skeletal muscles of mice from cancer-induced wasting, but the mechanisms underlying this protection are not well-understood. The aim of this study was to determine whether exogenous glycine directly protects skeletal muscle cells from wasting. C2C12 muscle cells were exposed to non-inflammatory catabolic stimuli via two models: serum withdrawal (SF) for 48 h; or incubation in HEPES buffered saline (HBS) for up to 5 h. Cells were supplemented with glycine or equimolar concentrations of L-alanine. SF- and HBS-treated myotubes (with or without L-alanine) were ~20% and ~30% smaller than control myotubes. Glycine-treated myotubes were up to 20% larger (P < 0.01) compared to cells treated with L-alanine in both models of muscle cell atrophy. The mTORC1 inhibitor rapamycin prevented the glycine-stimulated protection of myotube diameter, and glycine-stimulated S6 phosphorylation, suggesting that mTORC1 signaling may be necessary for glycine's protective effects in vitro. Increasing glycine availability may be beneficial for muscle wasting conditions associated with inadequate nutrient intake.

Glycine administration attenuates progression of dystrophic pathology in prednisolone-treated dystrophin/utrophin null mice.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease characterized by progressive muscle wasting and weakness and premature death. Glucocorticoids (e.g. prednisolone) remain the only drugs with a favorable impact on DMD patients, but not without side effects. We have demonstrated that glycine preserves muscle in various wasting models. Since glycine effectively suppresses the activity of pro-inflammatory macrophages, we investigated the potential of glycine treatment to ameliorate the dystrophic pathology. Dystrophic mdx and dystrophin-utrophin null (dko) mice were treated with glycine or L-alanine (amino acid control) for up to 15 weeks and voluntary running distance (a quality of life marker and strong correlate of lifespan in dko mice) and muscle morphology were assessed. Glycine increased voluntary running distance in mdx mice by 90% (P < 0.05) after 2 weeks and by 60% (P < 0.01) in dko mice co-treated with prednisolone over an 8 week treatment period. Glycine treatment attenuated fibrotic deposition in the diaphragm by 28% (P < 0.05) after 10 weeks in mdx mice and by 22% (P < 0.02) after 14 weeks in dko mice. Glycine treatment augmented the prednisolone-induced reduction in fibrosis in diaphragm muscles of dko mice (23%, P < 0.05) after 8 weeks. Our findings provide strong evidence that glycine supplementation may be a safe, simple and effective adjuvant for improving the efficacy of prednisolone treatment and improving the quality of life for DMD patients.

BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle.

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases.

A method for developing organisation-wide manual handling based physical employment standards in a military context.

The benefit of job-related employment standards in physically demanding occupations are well known. A number of methodological frameworks have been established to guide the development of physical employment standards for single job functions. In the case of an organisation comprised of multiple and diverse employment specialisations, such as the Australian Army, it is impractical to develop unique employment standards for each occupation. OBJECTIVES: To present an approach to organisational level physical employment standards development that seeks to retain occupationally specific task characteristics by applying a movement cluster approach. DESIGN: Structured methodological overview. METHODS: An outline of the research process used in performing job tasks analysis are presented, including the identification, quantification and characterisation, and verification of physically demanding manual handling tasks. The methodology used to filter task information collected from this job analyses to group manual handling tasks with similar characteristics (termed clusters), across a range of employment specialisations is given. Finally, we provide examples of test development based on these key manual handling clusters to develop a limited suite of tests with high content, criterion and face validity that may be implementable across a large organisation. RESULTS: Job task analysis was performed on 57 employment specialisations, identifying 458 tasks that were grouped into 10 movement based clusters. The rationalisation of criterion tasks through clustering informed the development of a limited suite of tests with high content, criterion and face validity that may be implementable across a large organisation. CONCLUSION: This approach could be applied when developing physical employment standards across other multi-occupation organisations.

Glycine metabolism in skeletal muscle: implications for metabolic homeostasis.

PURPOSE OF REVIEW: The review summarizes the recent literature on the role of glycine in skeletal muscle during times of stress. RECENT FINDINGS: Supplemental glycine protects muscle mass and function under pathological conditions. In addition, mitochondrial dysfunction in skeletal muscle leads to increased cellular serine and glycine production and activation of NADPH-generating pathways and glutathione metabolism. These studies highlight how glycine availability modulates cellular homeostasis and redox status. SUMMARY: Recent studies demonstrate that supplemental glycine effectively protects muscles in a variety of wasting models, including cancer cachexia, sepsis, and reduced caloric intake. The underlying mechanisms responsible for the effects of glycine remain unclear but likely involve receptor-mediated responses and modulation of intracellular metabolism. Future research to understand these mechanisms will provide insight into glycine's therapeutic potential. Our view is that glycine holds considerable promise for improving health by protecting muscles during different wasting conditions.

Predicting Endurance Time in a Repetitive Lift and Carry Task Using Linear Mixed Models.

OBJECTIVES: Repetitive manual handling tasks account for a substantial portion of work-related injuries. However, few studies report endurance time in repetitive manual handling tasks. Consequently, there is little guidance to inform expected work time for repetitive manual handling tasks. We aimed to investigate endurance time and oxygen consumption of a repetitive lift and carry task using linear mixed models. METHODS: Fourteen male soldiers (age 22.4 ± 4.5 yrs, height 1.78 ± 0.04 m, body mass 76.3 ± 10.1 kg) conducted four assessment sessions that consisted of one maximal box lifting session and three lift and carry sessions. The relationships between carry mass (range 17.5-37.5 kg) and the duration of carry, and carry mass and oxygen consumption, were assessed using linear mixed models with random effects to account for between-subject variation. RESULTS: Results demonstrated that endurance time was inversely associated with carry mass (R2 = 0.24), with significant individual-level variation (R2 = 0.85). Normalising carry mass to performance in a maximal box lifting test improved the prediction of endurance time (R2 = 0.40). Oxygen consumption presented relative to total mass (body mass, external load and carried mass) was not significantly related to lift and carry mass (ß1 = 0.16, SE = 0.10, 95%CI: -0.04, 0.36, p = 0.12), indicating that there was no change in oxygen consumption relative to total mass with increasing lift and carry mass. CONCLUSION: Practically, these data can be used to guide work-rest schedules and provide insight into methods assessing the physical capacity of workers conducting repetitive manual handling tasks.

Glycine restores the anabolic response to leucine in a mouse model of acute inflammation.

Amino acids, especially leucine, potently stimulate protein synthesis and reduce protein breakdown in healthy skeletal muscle and as a result have received considerable attention as potential treatments for muscle wasting. However, the normal anabolic response to amino acids is impaired during muscle-wasting conditions. Although the exact mechanisms of this anabolic resistance are unclear, inflammation and ROS are believed to play a central role. The nonessential amino acid glycine has anti-inflammatory and antioxidant properties and preserves muscle mass in calorie-restricted and tumor-bearing mice. We hypothesized that glycine would restore the normal muscle anabolic response to amino acids under inflammatory conditions. Relative rates of basal and leucine-stimulated protein synthesis were measured using SUnSET methodology 4 h after an injection of 1 mg/kg lipopolysaccharide (LPS). Whereas leucine failed to stimulate muscle protein synthesis in LPS-treated mice pretreated with l-alanine (isonitrogenous control), leucine robustly stimulated protein synthesis (+51%) in mice pretreated with 1 g/kg glycine. The improvement in leucine-stimulated protein synthesis was accompanied by a higher phosphorylation status of mTOR, S6, and 4E-BP1 compared with l-alanine-treated controls. Despite its known anti-inflammatory action in inflammatory cells, glycine did not alter the skeletal muscle inflammatory response to LPS in vivo or in vitro but markedly reduced DHE staining intensity, a marker of oxidative stress, in muscle cross-sections and attenuated LPS-induced wasting in C2C12 myotubes. Our observations in male C57BL/6 mice suggest that glycine may represent a promising nutritional intervention for the attenuation of skeletal muscle wasting.

A Box Lift and Place Assessment is Related to Performance of Several Military Manual Handling Tasks.

Soldiers undergo regular physical testing to assess their functional capacity. However, current physical tests, such as push-ups, sit-ups, and pull-ups, do not necessarily assess job-specific physical capability. This article assesses the utility of generic predictive tests and a task-related predictive test in predicting performance against four job-critical military manual handling tasks. The box lift and place test was found to be the superior predictor in performance of four job tasks; a pack lift and place (R(2) = 0.76), artillery gunner loading simulation (R(2) = 0.36), bombing up an M1 tank simulation, (R(2) = 0.47) and a bridge building simulation (R(2) = 0.63). Pull-ups and push-ups were poor predictors of performance in the majority of job tasks. Although the box lift and place had a larger correlation with the artillery gunner loading task than the generic assessment, it only accounted for 36% of the variance, indicating that a task simulation may be more appropriate to assess soldiers' capacity to perform this job task. These results support the use of a box lift and place rather than generic fitness tests for the evaluation of military manual handling tasks.

Lift performance and lumbar loading in standing and seated lifts.

This study investigated the effect of posture on lifting performance. Twenty-three male soldiers lifted a loaded box onto a platform in standing and seated postures to determine their maximum lift capacity and maximum acceptable lift. Lift performance, trunk kinematics, lumbar loads, anthropometric and strength data were recorded. There was a significant main effect for lift effort but not for posture or the interaction. Effect sizes showed that lumbar compression forces did not differ between postures at lift initiation (Standing 5566.2 ± 627.8 N; Seated 5584.0 ± 16.0) but were higher in the standing posture (4045.7 ± 408.3 N) when compared with the seated posture (3655.8 ± 225.7 N) at lift completion. Anterior shear forces were higher in the standing posture at both lift initiation (Standing 519.4 ± 104.4 N; Seated 224.2 ± 9.4 N) and completion (Standing 183.3 ± 62.5 N; Seated 71.0 ± 24.2 N) and may have been a result of increased trunk flexion and a larger horizontal distance of the mass from the L5-S1 joint. Practitioner Summary: Differences between lift performance and lumbar forces in standing and seated lifts are unclear. Using a with-in subjects repeated measures design, we found no difference in lifted mass or lumbar compression force at lift initiation between standing and seated lifts.

Amino acid sensing and activation of mechanistic target of rapamycin complex 1: implications for skeletal muscle.

PURPOSE OF REVIEW: This article evaluates recent studies on the mechanisms involved in sensing changes in amino acid availability and activation of the mechanistic target of rapamycin complex 1 (mTORC1). RECENT FINDINGS: mTORC1 is sensitive to changes in amino acid availability and a well known regulator of protein turnover. The mechanisms of amino acid sensing and mTORC1 signaling are emerging with multiple potential sensors (e.g., solute carrier family 38, member 9, lysosomal protein transmembrane 4 beta/solute carrier family 7, member 5-solute carrier family 3, member 2) and signal transducers (e.g., Sestrins, ADP-ribosylation factor 1, and microspherule protein 1) identified. Studies in various cell lines have unveiled the importance of the lysosome in amino acid sensing and signal transmission. SUMMARY: Recent discoveries in amino acid sensing highlight a complex scenario, whereby mTORC1 is not merely sensitive to some amino acids and not others, but where specific amino acids are sensed by specific pathways under specific conditions. The physiological purpose of such an arrangement remains to be unraveled, but it would allow mTORC1 to precisely regulate growth during different metabolic conditions. Understanding the mechanisms responsible for sensing amino acid availability and regulating mTORC1 activity is an important prerequisite for the development of nutritional strategies to combat skeletal muscle wasting disorders.

Glycine supplementation during calorie restriction accelerates fat loss and protects against further muscle loss in obese mice.

BACKGROUND & AIM: Calorie restriction (CR) reduces co-morbidities associated with obesity, but also reduces lean mass thereby predisposing people to weight regain. Since we demonstrated that glycine supplementation can reduce inflammation and muscle wasting, we hypothesized that glycine supplementation during CR would preserve muscle mass in mice. METHODS: High-fat fed male C57BL/6 mice underwent 20 days CR (40% reduced calories) supplemented with glycine (1 g/kg/day; n = 15, GLY) or l-alanine (n = 15, ALA). Body composition and glucose tolerance were assessed and hindlimb skeletal muscles and epididymal fat were collected. RESULTS: Eight weeks of a high-fat diet (HFD) induced obesity and glucose intolerance. CR caused rapid weight loss (ALA: 20%, GLY: 21%, P < 0.01), reduced whole-body fat mass (ALA: 41%, GLY: 49% P < 0.01), and restored glucose tolerance to control values in ALA and GLY groups. GLY treated mice lost more whole-body fat mass (14%, p < 0.05) and epididymal fat mass (26%, P < 0.05), less lean mass (27%, P < 0.05), and had better preserved quadriceps muscle mass (4%, P < 0.01) than ALA treated mice after 20 d CR. Compared to the HFD group, pro-inflammatory genes were lower (P < 0.05), metabolic genes higher (P < 0.05) and S6 protein phosphorylation lower after CR, but not different between ALA and GLY groups. There were significant correlations between %initial fat mass (pre CR) and the mRNA expression of genes involved in inflammation (r = 0.51 to 0.68, P < 0.05), protein breakdown (r = -0.66 to -0.37, P < 0.05) and metabolism (r = -0.59 to -0.47, P < 0.05) after CR. CONCLUSION: Taken together, these findings suggest that glycine supplementation during CR may be beneficial for preserving muscle mass and stimulating loss of adipose tissue.

L-Citrulline Protects Skeletal Muscle Cells from Cachectic Stimuli through an iNOS-Dependent Mechanism.

Dietary L-citrulline is thought to modulate muscle protein turnover by increasing L-arginine availability. To date, the direct effects of increased L-citrulline concentrations in muscle have been completely neglected. Therefore, we determined the role of L-citrulline in regulating cell size during catabolic conditions by depriving mature C2C12 myotubes of growth factors (serum free; SF) or growth factors and nutrients (HEPES buffered saline; HBS). Cells were treated with L-citrulline or equimolar concentrations of L-arginine (positive control) or L-alanine (negative control) and changes in cell size and protein turnover were assessed. In myotubes incubated in HBS or SF media, L-citrulline improved rates of protein synthesis (HBS: +63%, SF: +37%) and myotube diameter (HBS: +18%, SF: +29%). L-citrulline treatment substantially increased iNOS mRNA expression (SF: 350%, HBS: 750%). The general NOS inhibitor L-NAME and the iNOS specific inhibitor aminoguanidine prevented these effects in both models. Depriving myotubes in SF media of L-arginine or L-leucine, exacerbated wasting which was not attenuated by L-citrulline. The increased iNOS mRNA expression was temporally associated with increases in mRNA of the endogenous antioxidants SOD1, SOD3 and catalase. Furthermore, L-citrulline prevented inflammation (LPS) and oxidative stress (H2O2) induced muscle cell wasting. In conclusion, we demonstrate a novel direct protective effect of L-citrulline on skeletal muscle cell size independent of L-arginine that is mediated through induction of the inducible NOS (iNOS) isoform. This discovery of a nutritional modulator of iNOS mRNA expression in skeletal muscle cells could have substantial implications for the treatment of muscle wasting conditions.