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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    • "Both parameters will be affected by changes in protein homeostasis, reflected in changes in both mitochondrial protein abundance and turnover. Aging is associated with altered mitochondrial protein homeostasis with documented effects on both biogenesis and mitochondrial autophagy (mitophagy) (Lee et al., 2002; Masiero et al., 2009; Schneider et al., 2014). "
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    ABSTRACT: Changes in mitochondrial function with age vary between different muscle types, and mechanisms underlying this variation remain poorly defined. We examined whether the rate of mitochondrial protein turnover contributes to this variation. Using heavy label proteomics, we measured mitochondrial protein turnover and abundance in slow-twitch soleus (SOL) and fast-twitch extensor digitorum longus (EDL) from young and aged mice. We found that mitochondrial proteins were longer lived in EDL than SOL at both ages. Proteomic analyses revealed that age-induced changes in protein abundance differed between EDL and SOL with the largest change being increased mitochondrial respiratory protein content in EDL. To determine how altered mitochondrial proteomics affect function, we measured respiratory capacity in permeabilized SOL and EDL. The increased mitochondrial protein content in aged EDL resulted in reduced complex I respiratory efficiency in addition to increased complex I-derived H2 O2 production. In contrast, SOL maintained mitochondrial quality, but demonstrated reduced respiratory capacity with age. Thus, the decline in mitochondrial quality with age in EDL was associated with slower protein turnover throughout life that may contribute to the greater decline in mitochondrial dysfunction in this muscle. Furthermore, mitochondrial-targeted catalase protected respiratory function with age suggesting a causal role of oxidative stress. Our data clearly indicate divergent effects of age between different skeletal muscles on mitochondrial protein homeostasis and function with the greatest differences related to complex I. These results show the importance of tissue-specific changes in the interaction between dysregulation of respiratory protein expression, oxidative stress, and mitochondrial function with age.
    Aging cell 10/2015; DOI:10.1111/acel.12412 · 6.34 Impact Factor
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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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