Mechanisms of insulin-like growth factor (IGF)-II-induced IGF-I receptor down-regulation in BC3H-1 muscle cells.

Muscle is an important target tissue for insulin-like growth factor (IGF) action. We have previously demonstrated that treatment of myoblasts with IGF-II decreased IGF-I receptor biosynthesis and steady-state mRNA levels. In addition, muscle cell differentiation was associated with a marked increase in the expression and secretion of IGF-II followed by similar down-regulation of the IGF-I receptor, suggesting an autocrine role for IGF-II in this process. To explore further the mechanisms by which IGF-II decreases IGF-I receptor expression in BC3H-1 muscle cells, dose-response studies of IGF-I and -II treatment on the amount of IGF-I receptor mRNA were carried out. In addition, to determine whether IGF-II decreases IGF-I receptor expression by stimulating receptor protein degradation, pulse/chase experiments with [35S]methionine/cysteine were carried out. Both IGF-I and -II induced significant down-regulation of IGF-I receptor mRNA. At low concentrations, IGF-I was more potent than IGF-II in inhibiting IGF-I receptor mRNA accumulation, suggesting that IGF-I receptor down-regulation induced by IGF-II is mediated principally through the IGF-I receptor in these cells. In addition, IGF-II decreased IGF-I receptor expression by stimulating receptor protein degradation as demonstrated by pulse/chase analysis of metabolically labelled receptors. Thus, IGF-II induces IGF-I receptor down-regulation in muscle cells through multiple mechanisms, including decreasing IGF-I receptor mRNA and stimulating IGF-I receptor protein degradation.