Molecular Mechanism and Nutritional Approach for Unloading-mediated Muscle Atrophy

(JSNFS Award for Excellence in Research (2016) )

Abstract

Since unloading conditions stimulate the ubiquitination of muscle proteins, we comprehensively examined the types of ubiquitin ligases that are activated by unloading. We found that unloading stress resulted in skeletal muscle atrophy through 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 resulting loss of muscle function. A DG (p) YMP pentapeptide mimetic of tyrosine⁶⁰⁸-phosphorylated IRS-1, named Cblin (Cbl-b inhibitor) , inhibited Cbl-b-mediated IRS-1 ubiquitination and strongly decreased the Cbl-b-mediated induction of atrogin-1/MAFbx. Furthermore, we also found a Cblin-like peptide in soy glicinine that similarly inhibited the IRS-1 ubiquitination and skeletal muscle volume loss caused by denervation in vitro and in vivo. In particular, a soy protein isolate-supplemented diet increased the extension power of the knee in bedridden patients. Our results indicate that Cbl-b-dependent destruction of IR-1 is a critical dual mediator of both increased protein degradation and reduced protein synthesis observed in unloading-induced muscle atrophy. Inhibition of Cbl-b-mediated ubiquitination may be a new therapeutic strategy for unloading-mediated muscle atrophy.