TRANSFORMING GROWTH-FACTOR-BETA ISOFORM EXPRESSION IN INSULIN-LIKE GROWTH-FACTOR STIMULATED MYOGENESIS

Transforming growth factor betas (TGF-beta s) are the defining members of a super-family of small proteins that are involved in the regulation of development and morphogenesis in a wide array of systems. Previous studies have demonstrated that TGF-beta s both inhibit and, under specialized conditions, induce the differentiation of myoblasts. TGF-beta s have been shown to be secreted by mouse C2C12 myoblast cultures undergoing differentiation. Insulin-like growth factors (IGFs) have also been shown to be secreted by myoblasts and to induce myogenesis. This study characterizes the effects of IGF treatment on the expression and secretion of TGF-beta s in the IGF-sensitive L6A1 myoblast line. IGF downregulated the expression of TGF-beta 3 in a concentration-dependent man ner at 24 and 48 hours; TGF-beta 1 was not sensitive to IGF treatment at 24 hours but was downregulated by IGFs at 48 hours. This downregulation was mediated by the type I IGF receptor and modulated by IGF binding proteins secreted by the myoblasts. Some reexpression of TGF-beta 1 and TGF-beta 3 mRNAs was observed after extensive morphological differentiation had occurred. These results support the hypothesis that IGFs act through the IGF type I receptor as part of a concerted mechanism to modulate expression of the TGF-beta genes, as part of a coordinated set of changes associated with terminal myogenic differentiation. (C) 1995 Wiley-Liss, Inc.