Article

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

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell Metabolism (Impact Factor: 16.75). 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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    • "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). "
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