FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.

By Jinghui Zhao, J. Brault, A. Schild, Pei-rang Cao, M. Sandri, S. Schiaffino, S. Lecker, A. Goldberg. Cell Metabolism, 2007

1,513 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Molecular Biology, Rehabilitation

View Paper: https://www.semanticscholar.org/paper/48aa9f3ade27f154dcf468af82ea18e00525777c

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Citations in the corpus

FOXO/4E-BP Signaling in Drosophila Muscles Regulates Organism-wide Proteostasis During Aging (2010, background): “Consistent with this view, the autophagy pathway has also been involved in both muscle atrophy (Mammucari et al., 2007; Zhao et al., 2007) and in the preservation of muscle sarcomere organization (Arndt et al., 2010; Masiero et al., 2009), highlighting the importance of fine-tuning the degree of…”
Autophagy: a lysosomal degradation pathway with a central role in health and disease. (2009, background): “This transcription factor was shown to be necessary and sufficient for autophagy induction in skeletalmuscle [76,77].”
Selective autophagy: ubiquitin-mediated recognition and beyond (2010, background): “The transcription factor FoxO3, for example, induces the transcription of genes whose products are involved in the upregulation of both proteasomal and autophagic degradatio”
Cancer cachexia: mediators, signaling, and metabolic pathways. (2012, background): “TORC2 signaling controls autophagy, which also plays a role in muscle maintenance (Mammucari et al., 2007; Mieulet et al., 2007; Zhao et al., 2007).”
Mitochondrial fission and remodelling contributes to muscle atrophy (2010, methodology): “In vivo muscle transfection was achieved by injection with GFP and either mock vector or Bnip3, Fis1, Fis1K148R, c.a.FoxO3 plasmids followed by in vivo electroporation as described earlier (Zhao et al, 2007).”
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “FOXO transcription factors, especially FOXO1 and FOXO3, also play critical roles in the regulation of autophagy gene expression.(468,603,642) A zinc finger family DNA-binding protein, ZKSCAN3 is a master”
Autophagy is required to maintain muscle mass. (2009, positive): “Excessive activation of autophagy aggravates muscle wasting (Dobrowolny et al., 2008; Mammucari et al., 2007; Wang et al., 2005; Zhao et al., 2007) by removing portion of cytoplasm, proteins, and organelles.”
Molecular mechanisms of diabetic cardiomyopathy (2014, neutral): “Phosphatidylinositol 3-kinase (PI3K)/Akt signalling can negatively regulate autophagy by inhibiting the mammalian target of rapamycin (MTOR) and, accordingly, changes in autophagy were associated with reduced PI3K/Akt signalling in these insulin-resistant hearts, raising the possibility that myocard”
Autophagy mediates the mitotic senescence transition. (2009, background): “Recent studies identified FoxO3a as a transcription factor responsible for a subset of autophagyrelated (ATG) genes as well as other autophagy regulators (Mammucari et al. 2007; Zhao et al. 2007).”
Regulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy (2015, positive): “Importantly, we have also found that FoxO3 regulates autophagy coordinating the proteasomal-dependent removal of proteins with the autophagy-dependent clearance of organelles 2,10 .”
Long live FOXO: unraveling the role of FOXO proteins in aging and longevity (2015, background): “which induces the expression of several autophagy genes and increases autophagosome formation (Mammucari et al., 2007; Zhao et al., 2007; Webb & Brunet, 2014).”