FIG. 7.

Mechanistic model of unloading-mediated muscle atrophy. Unloading induces ubiquitin ligase Cbl-b in myocytes. Cbl-b stimulates ubiquitination and the degradation of IRS-1, an important intermediate in IGF-1 signaling pathway, resulting in IGF-1 resistance in myocytes during unloading. IGF-1 resistance induces impaired protein synthesis and enhances protein degradation in muscle, leading to muscle atrophy. Cbl-b and PI3K may interact with phosphotyrosine⁶⁰⁸ of IRS-1. The inhibition of Cbl-b and IRS-1 interaction by oligopeptides may restore this impairment of IGF-1 signaling (see Discussion for more details). GSK3, glycogen synthase kinase 3; mTOR, mammalian target of rapamycin; S6K, p70 S6 kinase; Ub, ubiquitin.