Mechanisms regulating skeletal muscle growth and atrophy

Role of satellite cells in muscle growth and maintenance of muscle mass

The SCF-Fbxo40 Complex Induces IRS1 Ubiquitination in Skeletal Muscle, Limiting IGF1 Signaling

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Reversing Cachexia

Mammalian glycerophosphodiester phosphodiesterases (GP-PDEs) have been identified recently and shown to be implicated in several physiological functions. This study isolated a novel GP-PDE, GDE5, and showed that GDE5 selectively hydrolyzes glycerophosphocholine (GroPCho) and controls skeletal muscle development. We show that GDE5 expression was reduced in atrophied skeletal muscles in mice and that decreasing GDE5 abundance promoted myoblastic differentiation, suggesting that decreased GDE5 expression has a counter-regulatory effect on the progression of skeletal muscle atrophy. Forced expression of full-length GDE5 in cultured myoblasts suppressed myogenic differentiation. Unexpectedly, a truncated GDE5 construct (GDE5DeltaC471), which contained a GP-PDE sequence identified in other GP-PDEs but lacked GroPCho phosphodiesterase activity, showed a similar inhibitory effect. Furthermore, transgenic mice specifically expressing GDE5DeltaC471 in skeletal muscle showed less skeletal muscle mass, especially type II fiber-rich muscle. These results indicate that GDE5 negatively regulates skeletal muscle development even without GroPCho phosphodiesterase activity, providing novel insight into the biological significance of mammalian GP-PDE function in a non-enzymatic mechanism.

skeletal muscle atrophy is driven by an imbalance of protein synthesis and degradation, generally in favor of the latter. The ubiquitin-proteasome system (UPS) is commonly regarded as the major proteolytic system involved in breakdown of muscle protein under atrophy-inducing conditions ([6][1]), and

CrossTalk proposal: The dominant mechanism causing disuse muscle atrophy is decreased protein synthesis.

Involvement of released sphingosine 1-phosphate/sphingosine 1-phosphate receptor axis in skeletal muscle atrophy

From animals to humans: evidence linking oxidative stress as a causative factor in muscle atrophy

Skeletal muscle atrophy occurs under a variety of conditions and can result from alterations in both protein synthesis and protein degradation. The muscle-specific E3 ubiquitin ligases, MuRF1 and MAFbx, are excellent markers of muscle atrophy and increase under divergent atrophy-inducing conditions such as denervation and glucocorticoid treatment. While deletion of MuRF1 or MAFbx has been reported to spare muscle mass following 14 days of denervation, their role in other atrophy-inducing conditions is unclear. The goal of this study was to determine whether deletion of MuRF1 or MAFbx attenuates muscle atrophy after 2 weeks of treatment with the synthetic glucocorticoid dexamethasone (DEX). The response of the triceps surae (TS) and tibialis anterior (TA) muscles to 14 days of DEX treatment (3 mg kg(-1) day(-1)) was examined in 4 month-old male and female wild type (WT) and MuRF1 or MAFbx knock out (KO) mice. Following 14 days of DEX treatment, muscle wet weight was significantly decreased in the TS and TA of WT mice. Comparison of WT and KO mice following DEX treatment revealed significant sparing of mass in both sexes of the MuRF1 KO mice, but no muscle sparing in MAFbx KO mice. Further analysis of the MuRF1 KO mice showed significant sparing of fibre cross-sectional area and tension output in the gastrocnemius (GA) after DEX treatment. Muscle sparing in the MuRF1 KO mice was related to maintenance of protein synthesis, with no observed increases in protein degradation in either WT or MuRF1 KO mice. These results demonstrate that MuRF1 and MAFbx do not function similarly under all atrophy models, and that the primary role of MuRF1 may extend beyond controlling protein degradation via the ubiquitin proteasome system.

Skeletal muscle is crucial for human daily life. It is essential for locomotion and breathing and it affects whole-body metabolism. Preservation of muscle mass is thus critical to maintain body function and health. Current views indicate that muscle mass is controlled by the tight balance between protein synthesis and protein degradation, called proteostasis. Perturbation of this balance by extrinsic factors, as for example seen in cachexia (i.e., muscle loss as a secondary consequence of e.g. cancer, AIDS, or cardiac and kidney disease) or in sarcopenia (i.e., loss of muscle mass and function as a consequence of aging), is a main cause of loss of life quality and increased mortality. Thus, a better molecular understanding of muscle proteostasis is of fundamental importance to develop possible treatment strategies to counteract the above diseases. Two major regulators of muscle proteostasis are the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) and the forkhead box O (FoxO) transcription factors. While mTORC1 controls proteostasis by increasing translation and protein synthesis, FoxO regulates catabolic processes by increasing the expression of genes encoding for proteins involved in protein degradation. Thus, increased activation of FoxO causes muscle loss (atrophy), whereas activation of mTORC1 is associated with muscle gain (hypertrophy). However and in striking contrast to the expected outcome of muscle gain, sustained activation of mTORC1 in muscle by knockout of its upstream inhibitor TSC1 (TSCmKO mice) results in atrophy. This phenotype is observed despite the marked increase in protein synthesis. Hence, the mechanisms involved in muscle atrophy in TSCmKO mice remain unresolved. The purpose of this thesis was to provide new insights on the role of mTORC1 in regulating muscle proteostasis. Particularly, to characterize the mechanism of this mTORC1-driven atrophy observed in TSCmKO mice. Furthermore, the aim was to investigate if sustained activation of mTORC1 increases overall protein degradation via the thymoma viral proto-oncogene (Akt)-FoxO-signaling or by distinct other catabolic pathways. In this thesis, it was established that sustained activation of mTORC1 in muscles of TSCmKO mice leads to a significant increase of the ubiquitin-proteasome system (UPS). This was characterized by increased expression of ubiquitin-E3-ligases, increased ubiquitinylation, increased proteasomal biosynthesis and increased proteasome activity. The increase of the UPS was reversed by short-term treatment with the mTORC1-inhibitor rapamycin. Interestingly, the same increase of the UPS was observed upon acute muscle-specific deletion of Tsc1 for 3 weeks. Surprisingly, constitutive activation of Akt in muscle resulted in a similar induction of proteasomal biosynthesis and proteasome activity as observed in TSCmKO mice. Hence, this suggests a mechanism, which is independent of the activation of FoxO transcription factors. Finally, it was established that the increased UPS activity was accompanied by a concomitant increase of the transcription factor “nuclear factor, erythroid-derived 2,-like 1” (NFE2L1, hereafter called Nrf1). In short, this thesis demonstrated that mTORC1 activation is a major driver of the ubiquitin-proteasome system in skeletal muscle and identified Nrf1, together with FoxO transcription factors, as a key mediator of this pathway. Both, mTORC1 signaling as well as the UPS are considered as potential treatment targets in a large variety of distinct muscle wasting diseases. Therefore, understanding the underlying regulatory mechanisms of how mTORC1 controls muscle mass is of fundamental importance to eventually develop new therapeutic agents that could slow-down the massive muscle wasting observed in cachexia and sarcopenia.

Atrophy of skeletal muscle reduces both the quality and quantity of life of patients with cancer cachexia. Loss of muscle mass is thought to arise from a reduction in protein synthesis combined with an enhanced rate of protein degradation, and few treatments are available to counteract this process. Eicosapentaenoic acid (EPA) has been shown to attenuate the enhanced protein degradation, but to have no effect on protein synthesis. This study examines the effect of EPA combined with a protein and amino-acid supplementation on protein synthesis and degradation in gastrocnemius muscle of mice bearing the cachexia-inducing MAC16 tumour. Muscles from cachectic mice showed an 80% reduction in protein synthesis and about a 50-fold increase in protein degradation compared with muscles from nontumour-bearing mice of the same age and weight. Treatment with EPA (1 g kg−1) daily reduced protein degradation by 88%, but had no effect on protein synthesis. Combination of EPA with casein (5.35 g kg−1) also had no effect on protein synthesis, but when combined with the amino acids leucine, arginine and methionine there was almost a doubling of protein synthesis. The addition of carbohydrate (10.7 g kg−1) to stimulate insulin release had no additional effect. The combination involving the amino acids produced almost a doubling of the ratio of protein synthesis to protein degradation in gastrocnemius muscle over that of EPA alone. No treatment had a significant effect on tumour growth rate, but the inclusion of amino acids had a more significant effect on weight loss induced by the MAC16 tumour than that of EPA alone. The results suggest that combination therapy of cancer cachexia involving both inhibition of the enhanced protein degradation and stimulation of the reduced protein synthesis may be more effective than either treatment alone.

Mitochondria are crucial organelles in the production of energy and in the control of signalling cascades. A machinery of pro-fusion and fission proteins regulates their morphology and subcellular localization. In muscle this results in an orderly pattern of intermyofibrillar and subsarcolemmal mitochondria. Muscular atrophy is a genetically controlled process involving the activation of the autophagy-lysosome and the ubiquitin-proteasome systems. Whether and how the mitochondria are involved in muscular atrophy is unknown. Here, we show that the mitochondria are removed through autophagy system and that changes in mitochondrial network occur in atrophying muscles. Expression of the fission machinery is per se sufficient to cause muscle wasting in adult animals, by triggering organelle dysfunction and AMPK activation. Conversely, inhibition of the mitochondrial fission inhibits muscle loss during fasting and after FoxO3 overexpression. Mitochondrial-dependent muscle atrophy requires AMPK activation as inhibition of AMPK restores muscle size in myofibres with altered mitochondria. Thus, disruption of the mitochondrial network is an essential amplificatory loop of the muscular atrophy programme.

Proteolytic Mechanisms, Not Malnutrition, Cause Loss of Muscle Mass in Kidney Failure

The purpose of this study was to determine if age-related muscle atrophy is associated with an increased rate of protein degradation in extensor digitorum longus (EDL) muscles from young (YG; 2-4 months), middle-aged (MA; 12-17 months), and aged (AG; 22-24 months) B6C3F1 mice. EDL muscles from AG mice weighed less than EDL muscles from MA mice (p =.01). EDL muscles from MA mice weighed more than EDL muscles from YG mice (p =.02). The rate of protein degradation, as assessed by tyrosine release during in vitro incubations, was higher in EDL muscles from AG mice than it was in those from MA mice (p =.03). The rate of protein degradation was higher in EDL muscles from YG mice than it was in those from MA mice (p =.04). An inverse relationship existed between muscle mass and protein degradation (r = -.67; p =.0001). We conclude that skeletal muscle protein degradation rates decrease with maturation and increase with advancing age.