Autophagy Is Required to Maintain Muscle Mass
ABSTRACT 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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ABSTRACT: Alterations in skeletal muscle contractile activity necessitate an efficient remodeling mechanism. In particular, mitochondrial turnover is essential for tissue homeostasis during muscle adaptations to chronic use and disuse. While mitochondrial biogenesis appears to be largely governed by the transcriptional co-activator peroxisome proliferator co-activator 1 alpha (PGC-1α), selective mitochondrial autophagy (mitophagy) is thought to mediate organelle degradation. However, whether PGC-1α plays a direct role in autophagy is currently unclear. To investigate the role of the co-activator in autophagy and mitophagy during skeletal muscle remodeling, PGC-1α knockout (KO) and overexpressing (Tg) animals were unilaterally denervated, a common model of chronic muscle disuse. Animals lacking PGC-1α exhibited diminished mitochondrial density alongside myopathic characteristics reminiscent of autophagy-deficient muscle. Denervation promoted an induction in autophagy and lysosomal protein expression in wild-type (WT) animals, which was partially attenuated in KO animals, resulting in reduced autophagy and mitophagy flux. PGC-1α overexpression led to an increase in lysosomal capacity as well as indicators of autophagy flux but exhibited reduced localization of LC3II and p62 to mitochondria, compared to WT animals. A correlation was observed between the levels of the autophagy-lysosome master regulator transcription factor EB (TFEB) and PGC-1α in muscle, supporting their coordinated regulation. Our investigation has uncovered a regulatory role for PGC-1α in mitochondrial turnover, not only through biogenesis but also via degradation using the autophagy-lysosome machinery. This implies a PGC-1α-mediated cross-talk between these two opposing processes, working to ensure mitochondrial homeostasis during muscle adaptation to chronic disuse.01/2015; 5:9. DOI:10.1186/s13395-015-0033-y
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ABSTRACT: Chronic alcohol consumption leads to muscle weakness and atrophy in part by suppressing protein synthesis and mTORC1-mediated signaling. However, it is unknown whether moderate alcohol consumption also prevents overload-induced muscle growth and related anabolic signaling. Hypertrophy of the plantaris muscle was induced by removal of a section of the gastrocnemius and soleus muscles from one leg of C57BL/6 adult male mice while the contralateral leg remained intact as the sham control. A nutritionally complete alcohol-containing liquid diet (EtOH) or isocaloric, alcohol-free liquid diet (Con) was provided for 14 days post-surgery. EtOH intake was increased progressively (day 1-5) before being maintained at ~20 g/day/kg BW. The plantaris muscle from the sham and OL leg was removed after 14 days at which time there was no difference in body weight between Con and EtOH-fed mice. OL increased muscle weight (90%) and protein synthesis (125%) in both Con and EtOH mice. The overload-induced increase in mTOR (Ser2448), 4E-BP1 (Thr37/46), S6K1 (Thr389), rpS6 (Ser240/244), and eEF2 (Thr56) were comparable in muscle from Con and EtOH mice. Modulation of signaling upstream of mTORC1 including REDD1 protein expression, Akt (Thr308), PRAS40 (Thr246), and ERK (Thr202/Tyr204) also did not differ between Con and EtOH mice. Markers of autophagy (ULK1, p62, and LC3) suggested inhibition of autophagy with overload and activation with alcohol feeding. These data show that moderate alcohol consumption does not impair muscle growth, and therefore imply that resistance exercise may be an effective therapeutic modality for alcoholic-related muscle disease. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.03/2015; 3(3). DOI:10.14814/phy2.12333
American Journal of Respiratory and Critical Care Medicine 03/2015; 191(6):616-619. DOI:10.1164/rccm.201412-2189OE · 11.99 Impact Factor