Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 29, Issue 17, Pages 4798-4811Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01347-08
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Funding
- Ground Research Announcement for Space Utilization
- Japan Aerospace Exploration Agency (JAXA)
- Japan Space Forum
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Japan Science and Technology Agency
- Bio-Oriented Technology Research Advancement Institution of Japan
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [21500632, 21300149] Funding Source: KAKEN
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Skeletal muscle atrophy caused by unloading is characterized by both decreased responsiveness to myogenic growth factors (e.g., insulin-like growth factor 1 [IGF-1] and insulin) and increased proteolysis. Here, we show that unloading stress resulted in skeletal muscle atrophy through the induction and activation of the ubiquitin ligase Cbl-b. Upon induction, Cbl-b interacted with and degraded the IGF-1 signaling intermediate IRS-1. In turn, the loss of IRS-1 activated the FOXO3-dependent induction of atrogin-1/MAFbx, a dominant mediator of proteolysis in atrophic muscle. Cbl-b-deficient mice were resistant to unloading-induced atrophy and the loss of muscle function. Furthermore, a pentapeptide mimetic of tyrosine(608)-phosphorylated IRS-1 inhibited Cbl-b-mediated IRS-1 ubiquitination and strongly decreased the Cbl-b-mediated induction of atrogin-1/MAFbx. Our results indicate that the Cbl-b-dependent destruction of IRS-1 is a critical dual mediator of both increased protein degradation and reduced protein synthesis observed in unloading-induced muscle atrophy. The inhibition of Cbl-b-mediated ubiquitination may be a new therapeutic strategy for unloading-mediated muscle atrophy.
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