Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor-κB.

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-κB (NF-κB) and interfered with the expression of muscle proteins in differentiating myoblasts. Introduction of a mutant form of inhibitory protein κBα (IκBα) restored myogenic differentiation in myoblasts treated with TNF-α or interleukin 1β. Conversely, activation of NF-κB by 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-κB.