FoxO3 Coordinately Activates Protein Degradation by the Autophagic/Lysosomal and Proteasomal Pathways in Atrophying Muscle Cells
ABSTRACT Muscle atrophy occurs in many pathological states and results primarily from accelerated protein degradation and activation of the ubiquitin-proteasome pathway. However, the importance of lysosomes in muscle atrophy has received little attention. Activation of FoxO transcription factors is essential for the atrophy induced by denervation or fasting, and activated FoxO3 by itself causes marked atrophy of muscles and myotubes. Here, we report that FoxO3 does so by stimulating overall protein degradation and coordinately activating both lysosomal and proteasomal pathways. Surprisingly, in C2C12 myotubes, most of this increased proteolysis is mediated by lysosomes. Activated FoxO3 stimulates lysosomal proteolysis in muscle (and other cell types) by activating autophagy. FoxO3 also induces the expression of many autophagy-related genes, which are induced similarly in mouse muscles atrophying due to denervation or fasting. These studies indicate that decreased IGF-1-PI3K-Akt signaling activates autophagy not only through mTOR but also more slowly by a transcription-dependent mechanism involving FoxO3.
- SourceAvailable from: Fabio Di Domenico
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- "Recently, much attention is given to the regulation of FoxO, that has been shown to directly control the transcription of autophagy genes, including members of the Atg8 family (LC3) and regulators of autophagy (Mammucari et al., 2007). Upregulation of FoxO is able to activate autophagy in Drosophila (Juhasz et al., 2007), C. elegans (Mammucari et al., 2007) and mouse muscle fibres (Zhao et al., 2007). In addition, the results obtained in C. elegans showed that the upregulation of autophagy in skeletal muscle via DAF-16 was independent of mTOR, as demonstrated by inhibition of mTOR by rapamycin or knockdown (Mammucari et al., 2007). "
ABSTRACT: Compelling evidence indicates that the mammalian target of rapamycin (mTOR) signaling pathway is involved in cellular senescence, organismal aging and age-dependent diseases. mTOR is a conserved serine/threonine kinase that is known to be part of two different protein complexes: mTORC1 and mTORC2, which differ in some components and in upstream and downstream signalling. In multicellular organisms, mTOR regulates cell growth and metabolism in response to nutrients, growth factors and cellular energy conditions. Growing studies highlight that disturbance in mTOR signalling in the brain affects multiple pathways including glucose metabolism, energy production, mitochondrial function, cell growth and autophagy. All these events are key players in age-related cognitive decline such as development of Alzheimer disease (AD). The current review discusses the main regulatory roles of mTOR signalling in the brain, in particular focusing on autophagy, glucose metabolism and mitochondrial functions. Targeting mTOR in the CNS can offer new prospective for drug discovery; however further studies are needed for a comprehensive understanding of mTOR, which lies at the crossroads of multiple signals involved in AD etiology and pathogenesis. Copyright © 2015. Published by Elsevier Inc.Neurobiology of Disease 03/2015; 101. DOI:10.1016/j.nbd.2015.03.014 · 5.20 Impact Factor
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- "Akt induces activation of protein synthesis by blocking repression of mTOR and, hence, allowing TORC1 and TORC2 complex signals. TORC1 signals to the p70S6 kinase and 4E-BP pathways, which induces ribosome formation , while TORC2 controls the autophagy process mentioned above  . Our preliminary data indicate that AET increases IGF-1 and Akt protein content in the skeletal muscle of sympathetic hyperactivity-induced HF mice model (Bacurau et al. — unpublished observations ). "
ABSTRACT: Aerobic exercise training (AET) induces several skeletal muscle changes, improving aerobic exercise capacity and health. Conversely, to the positive effects of AET, the cachexia syndrome is characterized by skeletal muscle wasting. Cachexia is a multifactorial disorder that occurs and is associated with other chronic diseases such as heart failure and cancer. In these diseases, an overactivation of ubiquitin-proteasome and autophagy systems associated with a reduction in protein synthesis culminates in severe skeletal muscle wasting and, in the last instance, patient's death. In contrast, AET may recycle and enhance many protein expression and enzyme activities, counteracting metabolism impairment and muscle atrophy. Therefore, the aim of the current review was to discuss the supposed therapeutic effects of AET on skeletal muscle wasting in both cardiac and cancer cachexia. Copyright © 2014. Published by Elsevier Inc.Life Sciences 12/2014; 125. DOI:10.1016/j.lfs.2014.11.029 · 2.30 Impact Factor
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- "and transcription factors    . ALP-regulated autophagy clears longlived proteins and dysfunctional organelles through autophagosome formation, which is initiated or aided by proteins like LC3, Gabarapl1  and BNIP3 , whose presence is increased in atrophying muscle   . Quiescent satellite cells, located between the skeletal muscle basement and sarcolemmal membranes , are activated in response to muscle injury or exercise stimulation leading to muscle recovery   . "
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 · 5.09 Impact Factor