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

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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Available from: Eva Masiero, Jul 05, 2015
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    • "Aged AMPK-MKO mice have increased centrally located nuclei, increased muscle collagen, and impaired muscle function compared to WT. These features resemble the accelerated age-induced myopathy and mitochondrial dysfunction observed in mice lacking Atg7 in muscle (Carnio et al., 2014; Masiero et al., 2009). In parallel to the pronounced myopathy, the mitochondria of aged AMPK-MKO mice have an aberrant enlarged morphology and an increased amount of mtDNA deletions, indicative of accelerated mitochondrial dysfunction. "
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    ABSTRACT: The AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPK-MKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 06/2015; 21(6):883-90. DOI:10.1016/j.cmet.2015.05.016 · 17.57 Impact Factor
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    • "Conversely, BNIP3 expression transiently increased, in line with literature [127], and subsequently decreased throughout further RL. Compared to the UPS markers, this differential response of BNIP3 to reloading is corresponding to the notion that autophagy is involved in the remodeling and maintenance of the skeletal muscle [130]. Although the reduction of MuRF1 and BNIP3 levels were slightly accelerated in MGSK-3β KO muscle, overall no defining role of GSK-3β absence on reloadinginduced suppression of effectors of proteolysis was apparent. "
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    ABSTRACT: Muscle wasting impairs physical performance, increases mortality and reduces medical intervention efficacy in chronic diseases and cancer. Developing proficient intervention strategies requires improved understanding of the molecular mechanisms governing muscle mass wasting and recovery. Involvement of muscle protein- and myonuclear turnover during recovery from muscle atrophy has received limited attention. The insulin-like growth factor (IGF)-I signaling pathway has been implicated in muscle mass regulation. As glycogen synthase kinase 3 (GSK-3) is inhibited by IGF-I signaling, we hypothesized that muscle-specific GSK-3β deletion facilitates the recovery of disuse-atrophied skeletal muscle. Wild-type mice and mice lacking muscle GSK-3β (MGSK-3β KO) were subjected to a hindlimb suspension model of reversible disuse-induced muscle atrophy and followed during recovery. Indices of muscle mass, protein synthesis and proteolysis, and post-natal myogenesis which contribute to myonuclear accretion, were monitored during the reloading of atrophied muscle. Early muscle mass recovery occurred more rapidly in MGSK-3β KO muscle. Reloading-associated changes in muscle protein turnover were not affected by GSK-3β ablation. However, coherent effects were observed in the extent and kinetics of satellite cell activation, proliferation and myogenic differentiation observed during reloading, suggestive of increased myonuclear accretion in regenerating skeletal muscle lacking GSK-3β. This study demonstrates that muscle mass recovery and post-natal myogenesis from disuse-atrophy are accelerated in the absence of GSK-3β. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 12/2014; 1852(3). DOI:10.1016/j.bbadis.2014.12.006 · 4.88 Impact Factor
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    • "The latter actions of IF enhance the ability of cells to eliminate damaged proteins and organelles such as mitochondria . Indeed, autophagy is required for the maintenance of muscle mass (Masiero et al., 2009), consistent with the preservation of muscle mass during IF (Harvie et al., 2010). IF decreases levels of circulating leptin and increases levels of adiponectin, changes associated with improved energy metabolism and cardioprotection (Wan et al., 2010; Hui et al., 2012). "
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    ABSTRACT: Humans and their predecessors evolved in environments where they were challenged intermittently with: 1) food scarcity; 2) the need for aerobic fitness to catch/kill prey and avoid or repel attackers; and 3) exposure to biological toxins present in foodstuffs. Accordingly, cells and organ systems acquired and retained molecular signaling and metabolic pathways through which the environmental challenges enhanced the functionality and resilience of the cells and organisms. Within the past 60 years there has been a precipitous diminution of such challenges in modern societies because of the development of technologies that provide a continuous supply of energy-dense processed foods and that largely eliminate the need for physical exertion. As a consequence of the modern 'couch potato' lifestyle, signaling pathways that mediate beneficial effects of environmental challenges on health and disease resistance are disengaged, thereby rendering people vulnerable to obesity, diabetes, cardiovascular disease, cancers and neurodegenerative disorders. Reversal of the epidemic of diseases caused by unchallenging lifestyles will require a society-wide effort to re-introduce intermittent fasting, exercise and consumption of plants containing hormetic phytochemicals into daily and weekly routines.
    Dose-Response 12/2014; 12(4):600-18. DOI:10.2203/dose-response.14-028.Mattson · 1.22 Impact Factor
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