Acting through humoral and/or autocrine/paracrine mechanisms, the insulin-like growth factors stimulate the differentiation of muscle cells. Whereas both IGF-I and IGF-II stimulate myogenesis, IGF-II is the principle IGF peptide expressed by muscle cells and is, therefore, likely to play a more fundamental role in the differentiation process.Studies in this proposal will test the hypothesis that IGF-II stimulates muscle cell differentiation by increasing the expression and action of myogenin, a differentiation master control gene for skeletal muscle.In addition, studies will test the hypothesis that the effects of IGF-II on myogenin expression are mediated through the IGF-I receptor and that IGF-binding proteins modulate the effects of IGF on myogenin expression and skeletal muscle differentiation. To test these hypotheses, studies will address the following specific aims: (1) To examine the effects of IGF-II on the mRNA abundance, transcription, protein biosynthesis, and binding of myogenin onto DNA regulatory elements, and on the expression of the transcription factors, E12 and Id, the principal peptides with which myogenin dimerizes; (2) to examine which IGF- receptor subtypes mediate the effects of IGF-II on the expression of myogenin and E12 and Id, using recently defined IGF-II analogs that have selective affinity for the IGF-II receptor in binding, cross-linking, and mRNA abundance studies; and (3) to explore the potential role of IGF- binding proteins and IGF-induced myogenin gene expression with an IGF analog with reduced affinity for binding proteins but unaltered affinity for IGF receptors.
| Silverman, L A; Cheng, Z Q; Hsiao, D et al. (1995) Skeletal muscle cell-derived insulin-like growth factor (IGF) binding proteins inhibit IGF-I-induced myogenesis in rat L6E9 cells. Endocrinology 136:720-6 |
| Rosenthal, S M; Cheng, Z Q (1995) Opposing early and late effects of insulin-like growth factor I on differentiation and the cell cycle regulatory retinoblastoma protein in skeletal myoblasts. Proc Natl Acad Sci U S A 92:10307-11 |
| Rosenthal, S M; Hsiao, D; Silverman, L A (1994) An insulin-like growth factor-II (IGF-II) analog with highly selective affinity for IGF-II receptors stimulates differentiation, but not IGF-I receptor down-regulation in muscle cells. Endocrinology 135:38-44 |
| Rosenthal, S M; Brown, E J (1994) Mechanisms of insulin-like growth factor (IGF)-II-induced IGF-I receptor down-regulation in BC3H-1 muscle cells. J Endocrinol 141:69-74 |
