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Submitted on December 5, 2005
Accepted on June 2, 2006
Suppression of Differentiation in Myoblasts
Laboratories of Immunophysiology and Integrative Biology, Department of Animal Sciences and Department of Pathology, College of Medicine, University of Illinois, Urbana, IL 61801 and Neurobiologie Intégrative, UMR INRA-Université de Bordeaux 2, FRE CNRS, Rue Camille Saint-SaNns, 33077 Bordeaux Cedex, France
* To whom correspondence should be addressed. E-mail: kwkelley{at}uiuc.edu.
The stress kinase JNK was recently shown to be involved in the pathophysiology of major inflammatory conditions, including Alzheimer's disease, stroke, obesity and type II diabetes. However, the role of JNK in regulating inflammatory events in skeletal muscle is only beginning to be explored. IGF-I is the major hormone that promotes muscle growth and development. Here we used a novel, JIP-derived JNK peptide inhibitor to establish that JNK suppresses the biological activity of IGF-I in skeletal muscle progenitor cells. In these myoblasts, TNF
and its downstream receptor substrates, N-SMase and C2-ceramide, induce JNK kinase activity in a time-dependent manner. Consistent with these results, TNF induces JNK binding to IRS-1 but is unable to inhibit IGF-I-induced IRS-1 tyrosine phosphorylation in myoblasts that are treated with the JNK peptide inhibitor. More importantly, JNK activation induced by TNF, C2-ceramide and N-SMase is associated with reduced expression of the critical muscle transcription factor, myogenin, as well as the differentiation marker, MHC. The JNK peptide inhibitor, but not the control peptide, completely reverses this inhibition of both myogenin and MHC. In the absence of IGF-I, TNF, C2-ceramide, N-SMase and the JNK inhibitor are inactive, as shown by their inability to affect IRS tyrosine phosphorylation and protein expression of myogenin and MHC. These results establish that the resistance of muscle progenitor cells to IGF-I, which is caused by inflammatory stimuli, is mediated by the JNK stress kinase pathway.
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