Article

FoxO3 Coordinately Activates Protein Degradation by the Autophagic/Lysosomal and Proteasomal Pathways in Atrophying Muscle Cells

Department of Molecular and Cell Biology, Harvard University, Cambridge, Massachusetts, United States
Cell Metabolism (Impact Factor: 17.57). 01/2008; 6(6):472-83. DOI: 10.1016/j.cmet.2007.11.004
Source: PubMed

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.

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    • "FOXO3 gene expression responded to Lysine and Leucine deficiencies in gilthead sea bream myocytes showing a decrease, mainly at day 2. It is well-known in mammals that FOXO1 and FOXO3 are downstream targets of the IGF-AKT pathway. They can enhance autophagyrelated genes in muscle, being sufficient to activate this process causing muscle degradation[74,75]. In a catabolic situation like nutrient starvation, we would expect an increase in FOXO3 phosphorylation and therefore an increase in the autophagy flux. "

    Full-text · Dataset · Jan 2016
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    • "FOXO3 gene expression responded to Lysine and Leucine deficiencies in gilthead sea bream myocytes showing a decrease, mainly at day 2. It is well-known in mammals that FOXO1 and FOXO3 are downstream targets of the IGF-AKT pathway. They can enhance autophagyrelated genes in muscle, being sufficient to activate this process causing muscle degradation [74, 75]. In a catabolic situation like nutrient starvation, we would expect an increase in FOXO3 phosphorylation and therefore an increase in the autophagy flux. "
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    • "In the muscle, FOXO1 and FOXO3 elevate the autophagic flux by increasing the expression of autophagy genes mainly working as part of the core machinery and additionally increase protein degradation via the proteasomal pathway (Sanchez et al. 2014). In particular, FOXO3 increases the capacity of the lysosome to degrade incoming cargo, indicating a role for lysosomal function in muscle atrophy (Zhao et al. 2007). Other FOXOs (FOXO1, FOXO4, and FOXO6) also play roles in proteostasis and autophagy (Lapierre et al. 2015). "
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