Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor‐κΒ

Abstract

Muscle wasting is often associated with chronic inflammation. Because tumor necrosis factor α (TNF‐α) has been implicated as a major mediator of cachexia, its effects on C2C12 myocytes were examined. TNF‐α activated nuclear factor‐κΒ (NF‐κΒ) and interfered with the expression of muscle proteins in differentiating myoblasts. Introduction of a mutant form of inhibitory protein κΒα (IκBα) restored myogenic differentiation in myoblasts treated with TNF‐α or interleukin 1β. Conversely, activation of NF‐KBby overexpression of IΚB kinase was sufficient to block myogenesis, illustrating the causal link between NF‐ΚB activation and inhibition of myogenic differentiation. The inhibitory effects of TNF‐α on myogenic differentiation were reversible, indicating that the effects of the cytokine were not due to nonspecific toxicity. Treatment of differentiated myotubes with TNF‐α did not result in a striking loss of muscle‐specific proteins, which shows that myogenesis was selectively affected in the myoblast stage by TNF‐α. An important finding was that NF‐ΚB was activated to the same extent in differentiating and differentiated cells, illustrating that once myocytes have differentiated they become refractory to the effects of NF‐ΚB activation. These results demonstrate that inflammatory cytokines may contribute to muscle wasting through the inhibition of myogenic differentiation via a NF‐κB‐dependent pathway.—Langen, R. C. J., Schols, A. M. W. J., Kelders, M. C. J. M., Wouters, E. F. M., Janssen‐Heininger, Y. M. W. Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor‐KB. FASEB J. 15, 1169–1180 (2001)