Autophagy Is Required to Maintain Muscle Mass

Dulbecco Telethon Institute, 35129 Padova, Italy.
Cell metabolism (Impact Factor: 17.57). 12/2009; 10(6):507-15. DOI: 10.1016/j.cmet.2009.10.008
Source: PubMed


The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes for protein and organelle clearance. In skeletal muscle, both systems are under FoxO regulation and their excessive activation induces severe muscle loss. Although altered autophagy has been observed in various myopathies, the specific role of autophagy in skeletal muscle has not been determined by loss-of-function approaches. Here, we report that muscle-specific deletion of a crucial autophagy gene, Atg7, resulted in profound muscle atrophy and age-dependent decrease in force. Atg7 null muscles showed accumulation of abnormal mitochondria, sarcoplasmic reticulum distension, disorganization of sarcomere, and formation of aberrant concentric membranous structures. Autophagy inhibition exacerbated muscle loss during denervation and fasting. Thus, autophagy flux is important to preserve muscle mass and to maintain myofiber integrity. Our results suggest that inhibition/alteration of autophagy can contribute to myofiber degeneration and weakness in muscle disorders characterized by accumulation of abnormal mitochondria and inclusions.

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Available from: Eva Masiero, Jul 05, 2015
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    • "Nevertheless, the functional status of autophagy in skeletal muscle has been neglected until recent investigations. Skeletal muscle, as the most abundant tissue comprising 40–55% of body mass, is a major metabolic organ in human (Masiero et al., 2009). The activation of autophagy appears to mediate a significant suppression on the loss of skeletal muscle through multiple signaling pathways, including phosphatidylinositol-3-kinase (PI3K), myostatin, proteasome, and autophagy-lysosome pathways (Fig. 1). "
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    ABSTRACT: Sarcopenia is an aging-related disease with a significant reduction in mass and strength of skeletal muscle due to the imbalance between protein synthesis and protein degradation. The loss of skeletal muscle is an inevitable event during aging process, which can result in the significant impact on the quality of life, and also can increase the risk for other aging-associated diseases in the elderly. However, the underlying molecular mechanism of aging-related skeletal muscle loss is still poorly understood. Autophagy is a degradation pathway for the clearance of dysfunctional organelles and damaged macromolecules during aging process. Appropriate induction or accurate regulation of autophagic process and improved quality control of mitochondria through autophagy or other strategies are required for the maintenance of skeletal muscle mass. In this article, we have summarized the current understanding of autophagic pathways in sarcopenia, and discussed the functional status of autophagy and autophagy-associated quality control of mitochondria in the pathogenesis of sarcopenia. Moreover, this article will provide some theoretical references for the exploration of scientific and optimal intervention strategies such as exercise and caloric restriction for the prevention and treatment of sarcopenia through the regulation of autophagic pathways. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2015 · Journal of Cellular Physiology
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    • "The gene profiles emphasize the physiological functions of skeletal muscles in response to exercise [18] [19] [20] [21]. Importantly, exercise-induced autophagy is required to maintain skeletal muscle mass and contribute to improving glucose metabolism [22] [23] [24] [25]. However, aberrant autophagy flux is detrimental for muscle health and leads to muscle atrophy and degeneration, while sufficient autophagy flux helps maintain healthy myofibers [26]. "
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    ABSTRACT: Purpose: We examined whether resistance exercise training restores impaired autophagy functions caused by Chloroquine (CQ)-induced Sporadic Inclusion Body Myositis (sIBM) in rat skeletal muscle. Methods: Male wistar rats were randomly assigned into three groups: Sham (n = 6), CQ (n = 6), and CQ + Exercise (CE, n = 6). To create a rat model of sIBM, rats in the CQ and CE group were intraperitoneally injected with CQ 5 days a week for 16 weeks. Rats in the CE group performed resistance exercise training 3 times a week for 8 weeks in conjunction with CQ starting from week 9 to week 16. During the training period, maximal carrying load, body weight, muscle weight, and relative muscle weight were measured. Autophagy responses were examined by measuring specific markers. Results: While maximal carrying capacity for resistance exercise training was dramatically increased in the CE group, no significant changes occurred in the skeletal muscle weight as well as in the relative muscle weight of CE compared to the other groups. CQ treatment caused significant increases in the levels of Beclin-1 and p62, and decreases in the levels of LAMP-2 proteins. Interestingly, no significant differences in the LC3-II/I ratio or the LC3-II protein levels were observed. Although CQ-treatment groups suppressed the levels of the potent autophagy inducer, BNIP3, p62 levels were decreased in only the CE group. Conclusion: Our findings demonstrate that sIBM induced by CQ treatment results in muscle degeneration via impaired autophagy and that resistance exercise training improves movable loading activity. Finally, regular exercise training may provide protection against sIBM by enhancing the autophagy flux through p62 protein.
    Full-text · Article · Nov 2015
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    • "The above described models of skeletal muscle autophagy deficiency [9] [27] and mitochondrial dysfunction [8] [26] show severe muscle disease phenotypes. Thus, we made use of UCP1 transgenic (TG) mice with an ectopic expression of the uncoupling protein 1 (UCP1) in skeletal muscle [28], an established model of metabolic perturbations by muscle-specific decrease in mitochondrial efficiency through increased respiratory uncoupling [29] linked to robust metabolic adaptations [30] [31], obesity resistance and increased longevity [32] [33]. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood.
    Full-text · Article · Nov 2015 · Molecular Metabolism
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