2007 Fiscal Year Final Research Report Summary
Development of oligopeptides against skeletal muscle fatigue and atrophy caused by unloading
| Project/Area Number |
18590218
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental physiology (including Physical medicine and Nutritional physiology)
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| Research Institution | The University of Tokushima |
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Principal Investigator |
OGURI Sachiko The University of Tokushima, Institute of Health Biosciences, Graduate School, Technician (50380085)
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| Co-Investigator(Kenkyū-buntansha) |
NIKAWA Takeshi The University of Tokushima, Institute of Health Biosciences, Graduate School, Professor (20263824)
YASUI Natsuo The University of Tokushima, Institute of Health Biosciences, Graduate School, Professor (00157984)
NEMOTO Hisao The University of Tokushima, Institute of Health Biosciences, Graduate School, Associate Professor (30208293)
KISHI Kyoichi Nagoya University of Arts and Sciences, Department of Nutritional Sciences, Professor (80035435)
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| Project Period (FY) |
2006 – 2007
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| Keywords | denervation / oligopeptides / IGF-1 signaling / ubiquitin ligase / unloading-mediated muscle atrophy / anti-aging diet |
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| Research Abstract |
Skeletal muscle unloading during prolonged bed rest, paralysis, and spaceflight results in mechanical stress that can lead to debilitating atrophy. This atrophic response is characterized by both decreased responsiveness to myogenic growth factors IGF-1/insulin and increased proteolysis. Here we show that unloading stress activated a redox-dependent atrophic signaling pathway that ultimately led to the induction of the ubiquitin ligase Cbl-b downstream of Egr transcription factors. Upon induction, Cbl-b interacted with and degraded the IGF-1 signaling intermediate IRS-1, leading to FOXO3-dependent induction of atrogin-1, a dominant mediator of proteolysis in atrophic muscle. Cbl-b expression alone was sufficient to induce IRS-1 ubiquitination and atrophy in rat tibialis anterior muscle. In contrast, Cbl-b-deficient mice were resistant to unloading-induced atrophy, weakness (tetanic force), and loss of coordination. Furthermore, a penta-peptide mimetic of tyrosine^<612>-phosphorylated IRS-1 inhibited Cbl-b-mediated IRS-1 ubiquitination and strongly decreased Cbl-b-mediated induction of atrogin-1. Our results indicate that the Cbl-b-dependent destruction of IRS-1 is a critical dual mediator of both the growth refractory and proteolytic arms of the atrophic response. Inhibition of Cbl-b-mediated ubiquitination may be a new therapeutic strategy for unloading-mediated muscle atrophy.
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