Catabolic situations lead to protein loss considered to be mediated by release of pro-inflammatory cytokines. Because these situations are accompanied by a decrease in IGF-I, we investigated whether the muscle atrophy caused by TNF-a/IFN-g might be reversed by exogenous IGF-I. C₂C₁₂ myotubes were exposed to TNF-a/IFN-g (5 ng/ml each) w/ or w/o IGF-I (50 nM). TNF/IFN reduce myotube diameter by 23% (P<0.001). This atrophy was accompanied by a reduction in fast myosin heavy chains (MHCf) (­50%, P<0.001) and in MyoD, a transcription factor crucial for MHCf transcription (–91%, P<0.001). Furthermore, TNF/IFN increased mRNA of Atrogin-1 (two-fold, P<0.001), an ubiquitin-ligase reported to accelerate the degradation of MyoD, and abolished mRNA of IGF-I (­99%, P<0.001). In an attempt to reverse this atrophy, myotubes exposed to TNF/IFN were co-incubated with IGF-I. Despite the presence of TNF/IFN, IGF-I retained its ability to phosphorylate Akt (IGF-I: 13-fold and IGF-I+cytokines: 16-fold, P<0.001) and FOXO3a (IGF-I: 2.5-fold and IGF-I+cytokines: 3.3-fold, respectively P<0.05 and P<0.01) leading to inhibition of Atrogin-1 mRNA (IGF-I: ­53% and IGF-I+cytokines: ­39%, respectively P<0.001 and P<0.01). In contrast, IGF-I failed to blunt the reduction in MyoD and in MHCf induced by TNF/IFN. Moreover, IGF-I-stimulated protein accumulation (+45%, P<0.001) and increase in myotube diameter (+14%, P<0.001) were dramatically attenuated by TNF/IFN (respectively ­9% and –19%, both P<0.001). Our data show that IGF-I does not reverse the muscle atrophy induced by TNF-a/IFN-g despite intact inhibition of Atrogin-1 through the Akt-FOXO pathway. Moreover, our study suggests that others factors that decrease of IGF-I are responsible for the muscle atrophy induced by pro-inflammatory cytokines.