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.
The insulin-like growth factors (IGFs) stimulate the growth and differentiation of muscle cells. IGF-II, the principal IGF peptide expressed by differentiating muscle cells, has been implicated in at least two autocrine/paracrine actions in this tissue: stimulation of differentiation and down-regulation of the IGF-I receptor. To determine which IGF receptor subtypes mediate these effects of IGF-II, we treated mouse BC3H-1 muscle cells with native IGF-II or [Leu27]IGF-II, an analog with high affinity for IGF-II receptors (comparable to that seen with native IGF-II) but markedly reduced affinity for IGF-I and insulin receptors. Muscle cell differentiation was assessed by the expression of myogenin mRNA and by the binding of alpha-bungarotoxin to the nicotinic acetylcholine receptor. IGF-I receptor down-regulation was assessed by receptor binding and mRNA abundance. Although less potent than IGF-II, the [Leu27]IGF-II analog stimulated myogenin gene expression and acetylcholine receptor binding in concentrations at which the analog interacted with IGF-II receptors, but not significantly with IGF-I receptors. In IGF-I receptor down-regulation studies, IGF-II pretreatment significantly decreased binding of IGF-I to the IGF-I receptor and decreased IGF-I receptor mRNA, whereas the IGF-II analog had only minimal effects. Thus, in addition to the IGF-I receptor which has been previously found to signal IGF-induced myogenesis, these results implicate a role for the IGF-II receptor in this process. In contrast, IGF-I receptor down-regulation induced by IGF-II is mediated through IGF-I, but not IGF-II, receptors in muscle cells.
Department of Pediatrics, University of California, San Francisco 94143.
S M
SM
Rosenthal
D
D
Hsiao
L A
LA
Silverman
D000818:Animals; D001667:Binding, Competitive; D002454:Cell Differentiation; D002478:Cells, Cultured; D015536:Down-Regulation; D007335:Insulin-Like Growth Factor II / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism
D017527:Receptor, IGF Type 2; D013002:Somatomedins; C067045:insulin-like growth factor II, Leu(27)-; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1