Inhibition of muscle insulin-like growth factor I expression by tumor necrosis factor-α

Abstract

The role of TNF-α in muscle catabolism is well established, but little is known about the mechanisms of its catabolic action. One possibility could be that TNF-α impairs the production of local growth factors like IGF-I. The aim of this study was to investigate whether TNF-α can directly inhibit IGF-I gene and protein expression in muscle. First, we investigated whether the acute inflammation induced by endotoxin injection changes IGF-I and TNF-α mRNA in rat tibialis anterior muscle. Endotoxin rapidly increased TNF-α mRNA (7-fold at 1 h, P < 0.001) and later decreased IGF-I mRNA (−73% at 12 h, P < 0.001). Furthermore, in a model of C 2 C 12 myotubes, TNF-α strongly inhibited IGF-I mRNA and protein (−73 and −47% after 72 h, P < 0.001 and P < 0.01, respectively). Other proinflammatory cytokines failed to inhibit IGF-I mRNA. The effect of TNF-α on IGF-I mRNA was not mediated by nitric oxide, and the activation of NF-κB was insufficient to inhibit IGF-I expression. Taken together, our data suggest that TNF-α induced in muscle after LPS injection can locally inhibit IGF-I expression. The inhibition of muscle IGF-I production could contribute to the catabolic effect of TNF-α.