[67]

The ubiquitin ligase Cbl-b decreases IGF-1 signaling and induces expression of atrogin-1 in skeletal muscle atrophied by unloading   T. Nikawa1, K. Hirasaka1, K. Ishidoh2, Y. Onishi1, H. Furochi1, J. Goto1, R. Nakao, C. Yamada, M. Mameoka, G. R. Adams4, K. M. Baldwin4, H. Gu5, E. M. Mills6, S. Takeda3, K. Kishi1 1The University of Tokushima School of Medicine, Tokushima; 2Tokushima Bunri University, Tokushima; 3National Center of Neurology and Psychiatry, Tokyo, Japan; 4University of California, Irvine, California; 5Columbia University, New York; 6National Institutes of Health, Bethesda, Maryland, USA.

   At the last meeting, we reported that Cbl-b played an important role in skeletal muscle atrophy cause by unloading, such as spaceflight and tail-suspension.  In the serial study, we here examined the relationship between Cbl-b and other muscle atrophy-related genes (atrogenes), including atrogin-1.  In unloading conditions, highly expressed Cbl-b ubiquitinated and degraded IRS-1, a growth factor signaling intermediate, leading to the resistance of skeletal muscle cells to IGF-1/insulin.  In C2C12 myotubes, Cbl-b-mediated loss of IGF-IRS signaling mainly contributes to decreased phosphorylation of FOXO transcription factors and increased expression of atrogin-1.  In addition, tail-suspension decreased phosphorylation of FOXO in gastrocnemius muscle of wild-type mice, leading to increased expression of atrogin-1.  Interestingly, the deficiency of Cbl-b gene canceled these alterations caused by tail-suspension and prevented the muscle atrophy.  Thus, we suggest that Cbl-b increases expression of atrogin-1 via down-regulating IGF-1 signaling in skeletal muscle atrophied by unlading. (Supported by JAXA and Japan Space Forum)