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: 17.57). 01/2008; 6(6):472-83. DOI: 10.1016/j.cmet.2007.11.004
Source: PubMed


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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    • "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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    • "When working with T47D cells, knockdown of PSMD2 was introduced for 3 days with doxycycline before bortezomib treatment. For measuring overall rates of protein degradation, pulse-labeling with 3 H-phenylalanine for 24 hr was done before the bortezomib treatment as previously described (Zhao et al., 2007). "
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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. "
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