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The Ubiquitin Ligase Cbl-b Mediates Skeletal Muscle Atrophy during Unloading  T. Nikawa1, K. Hirasaka1, K. Ishidoh2, M. Ikemoto3, I. Nonaka3, T. Ogawa1, N. Yasui1, K. Yasutomo1, G. R. Adams4, K. M. Baldwin4, E. Kominami2, H. Gu5, E. M. Mills6, S. Takeda3, K. Kishi1   1The University of Tokushima School of Medicine, Tokushima; 2Department of Biochemistry, Juntendo University School of Medicine, Tokyo; 3National Center of Neurology and Psychiatry, Tokyo, Japan; 4University of California, Irvine, California; 5Columbia University, New York; 6National Institutes of Health, Bethesda, Maryland, USA.

Skeletal muscle unloading during prolonged bed rest, paralysis, or spaceflight can result in debilitating skeletal muscle atrophy.  Reduced muscle mass is characterized by a combination of decreased protein synthesis and increased protein degradation.  Currently, there is no treatment to reverse the progression of atrophy.  Here we show that Cbl-b, a RING-type member of the ubiquitin ligase family, is essential for skeletal muscle atrophy.  Expression of Cbl-b in vivo induces significant atrophy in rat tibialis anterior muscle.  In contrast, Cbl-b deficient mice are resistant to muscle atrophy and dysfunction induced during unloading by tail suspension.  Upon tail suspension or zero gravity, Cbl-b interacts with and thereby degrades the skeletal muscle growth factor signaling intermediate IRS-1.  Thus, Cbl-b activation appears to underlie the refractoriness of atrophic muscle tissue to growth factor stimulation by IGF/insulin and likely accounts for the overall decrease in protein synthesis observed during muscle wasting.  These data suggest that Cbl-b may be a novel target for the development of therapeutics aimed at the preservation of muscle mass and function during a variety of muscle wasting diseases.

(Supported by JAXA and Japan Space Forum)