Cytokine-hormone interactions: tumor necrosis factor alpha impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor in myoblasts

Endocrinology. 2003 Jul;144(7):2988-96. doi: 10.1210/en.2003-0087.


TNFalpha is elevated following damage to skeletal muscle. Here we provide evidence that TNFalpha acts on muscle cells to induce a state of IGF-I receptor resistance. We establish that TNFalpha inhibits IGF-I-stimulated protein synthesis in primary porcine myoblasts. Similar results were observed in C(2)C(12) murine myoblasts, where as little as 0.01 ng/ml TNFalpha significantly inhibits protein synthesis induced by IGF-I. TNFalpha also impairs the ability of IGF-I to induce expression of a key myogenic transcription factor, myogenin. The inhibition by TNFalpha of IGF-I-induced protein synthesis and expression of myogenin is not due to direct killing of myoblasts by TNFalpha. Although IGF-I induces an approximately 19-fold induction in tyrosine phosphorylation of the beta-chains of its receptor, TNFalpha does not inhibit this autophosphorylation. Instead, TNFalpha 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 TNFalpha 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 TNFalpha interfere with both protein synthesis and muscle cell development by inducing a state of IGF-I receptor resistance.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Death / drug effects
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Myoblasts, Skeletal / cytology
  • Myoblasts, Skeletal / drug effects
  • Myoblasts, Skeletal / metabolism*
  • Myogenin / biosynthesis
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Biosynthesis
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / drug effects*
  • Swine
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tyrosine / metabolism


  • Antineoplastic Agents
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Myogenin
  • Phosphoproteins
  • Tumor Necrosis Factor-alpha
  • Tyrosine
  • Receptor, IGF Type 1