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.
Article: Autophagy and aging[Show abstract] [Hide abstract]
ABSTRACT: Autophagy is a critical quality control pathway that is conserved across diverse systems ranging from simple unicellular organisms like yeast to more complex systems, for instance mammals. Although, the fundamental role of autophagy is to maintain cellular quality control through lysosomal degradation of unwanted proteins and organelles, recent studies have mapped several new functions of this pathway that range from fuel utilization, cellular differentiation to protection against cell death. Given the importance of this pathway in maintaining cellular homeostasis, it has been considered that compromised autophagy could contribute to several of the commonly observed age-associated pathologies including neurodegeneration, reduction of muscle mass, cardiac malfunction, excessive lipid accumulation in tissues and glucose intolerance. The present chapter describes the two best-characterized autophagy pathways—macroautophagy and chaperone-mediated autophagy, and discusses how changes in these pathways associate with age-associated disorders. Understanding how to maintain “clean cells” by activation of autophagy could be an attractive strategy to maintain healthspan in aged individuals.Advances in Experimental Medicine and Biology 04/2015; 847:73-87. DOI:10.1007/978-1-4939-2404-2_3. · 2.01 Impact Factor
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ABSTRACT: In humans, nutrient deprivation and extreme endurance exercise both activate autophagy. We hypothesized that cumulating fasting and cycling exercise would potentiate activation of autophagy in skeletal muscle. Well-trained athletes were divided into control (n = 8), low-intensity (LI, n = 8), and high-intensity (HI, n = 7) exercise groups and submitted to fed and fasted sessions. Muscle biopsy samples were obtained from the vastus lateralis before, at the end, and 1 h after a 2 h LI or HI bout of exercise. Phosphorylation of ULK1(Ser317) was higher after exercise (P < 0.001). In both the fed and the fasted states, LC3bII protein level and LC3bII/I were decreased after LI and HI (P < 0.05), while p62/SQSTM1 was decreased only 1 h after HI (P < 0.05), indicating an increased autophagic flux after HI. The autophagic transcriptional program was also activated, as evidenced by the increased level of LC3b, p62/SQSTM1, GabarapL1, and Cathepsin L mRNAs observed after HI but not after LI. The increased autophagic flux after HI exercise could be due to increased AMP-activated protein kinase α (AMPKα) activity, as both AMPKα(Thr172) and ACC(Ser79) had a higher phosphorylation state after HI (P < 0.001). In summary, the most effective strategy to activate autophagy in human skeletal muscle seems to rely on exercise intensity more than diet.-Schwalm, C., Jamart, C., Benoit, N., Naslain, D., Prémont, C., Prévet, J., Van Thienen, R., Deldicque, L., Francaux, M. Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. © FASEB.The FASEB Journal 05/2015; DOI:10.1096/fj.14-267187 · 5.48 Impact Factor
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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