Tumor necrosis factor-alpha and basic fibroblast growth factor differentially inhibit the insulin-like growth factor-I induced expression of myogenin in C2C12 myoblasts.
Tumor necrosis factor-alpha (TNF-alpha) plays a role in several disease states such as sepsis, cachexia, and non-insulin-dependent diabetes. TNF-alpha interferes with insulin signaling and inhibits differentiation-specific gene expression in adipose tissue and skeletal muscle. We have examined the mechanisms by which TNF-alpha, in comparison to basic fibroblast growth factor (bFGF), inhibits the insulin-like growth factor-I (IGF-I)-induced differentiation of C2C12 myoblasts. Adhesion of quiescent, suspended myoblasts to collagen in high concentrations of IGF-I (10 nM) induced these cells to proliferate during the initial 24 h postplating and in so doing transiently inhibited the expression of myogenin, an essential transcription factor controlling myoblast differentiation. Low doses of IGF-I (1 nM) were minimally mitogenic and enhanced muscle-specific gene expression. Quiescent myoblasts treated with bFGF in combination with IGF-I did not express myogenin, but expressed proliferating cell nuclear antigen and underwent DNA synthesis. In contrast, TNF-alpha in the presence or absence of 1 nM IGF-I, did not stimulate DNA synthesis in myoblasts. However, TNF-alpha inhibited myogenin mRNA and protein expression. Expression of the cyclin-dependent kinase inhibitor p21 correlated with myogenin expression and myoblast differentiation, but not with growth arrest. These results indicate that both TNF-alpha and bFGF inhibit myogenin expression but differentially influence myoblast proliferation.
D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D003864:Depression, Chemical; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018008:Myogenin / Q000096:biosynthesis* / Q000235:genetics; D010641:Phenotype; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*