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: Ariadna Bargiela
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- "Autophagy is considered a pro-survival mechanism as it eliminates toxic proteins and damaged organelles in the cell. Overactivation, however, leads to alterations in protein homeostasis, muscular atrophy and cell death (Mammucari et al., 2007; Zhao et al., 2007). Several observations have suggested that there is a pathogenic activation of apoptosis and autophagy in DM1 models. "
ABSTRACT: Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis. © 2015. Published by The Company of Biologists Ltd.Disease Models and Mechanisms 07/2015; 8(7):679-90. DOI:10.1242/dmm.018127 · 5.54 Impact Factor
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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