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Cytokine-Hormone Interactions: Tumor Necrosis Factor Impairs Biologic Activity and Downstream Activation Signals of the Insulin-Like Growth Factor I Receptor in Myoblasts

Laboratories of Immunophysiology (S.R.B., R.H.M., K.S., W.H.S., K.W.K.), Developmental Endocrinology (J.E.N.) and Integrative Biology (R.W.J.), Departments of Animal Sciences and Pathology and College of Medicine (G.G.F.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and Institut National de la Recherche Agronomique-Institut National de la Santé et de la Recherche Médicale, Unité 394, Unité de Recherches de Neurobiologie Integrative (R.D.), 33077 Bordeaux, France

Address all correspondence and requests for reprints to: Suzanne Broussard, University of Illinois, Laboratory of Immunophysiology, 207 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, Illinois 61801. E-mail: broussar{at}uiuc.edu.

TNF is elevated following damage to skeletal muscle. Here we provide evidence that TNF acts on muscle cells to induce a state of IGF-I receptor resistance. We establish that TNF inhibits IGF-I-stimulated protein synthesis in primary porcine myoblasts. Similar results were observed in C₂C₁₂ murine myoblasts, where as little as 0.01 ng/ml TNF significantly inhibits protein synthesis induced by IGF-I. TNF also impairs the ability of IGF-I to induce expression of a key myogenic transcription factor, myogenin. The inhibition by TNF of IGF-I-induced protein synthesis and expression of myogenin is not due to direct killing of myoblasts by TNF. Although IGF-I induces an approximately 19-fold induction in tyrosine phosphorylation of the ß-chains of its receptor, TNF does not inhibit this autophosphorylation. Instead, TNF significantly reduces by approximately 50% IGF-I-stimulated tyrosine phosphorylation of two of the major downstream receptor docking molecules, insulin receptor substrate (IRS)-1 and IRS-2. These results establish that low picogram concentrations of TNF acts on both porcine and murine myoblasts to impair tyrosine phosphorylation of both IRS-1 and IRS-2, but not the receptor itself. These data are consistent with the notion that very low physiological concentrations of TNF interfere with both protein synthesis and muscle cell development by inducing a state of IGF-I receptor resistance.

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