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IGF-I does not prevent myotube atrophy caused by proinflammatory cytokines despite activation of Akt/Foxo and GSK-3 pathways and inhibition of atrogin-1 mRNA

Divisions of ¹Diabetology and Nutrition and ²Cardiology, Université catholique de Louvain, Brussels, Belgium

Submitted 21 February 2006 ; accepted in final form 14 August 2006

Myofibrillar protein loss occurring in catabolic situations is considered to be mediated by the release of proinflammatory cytokines and associated with a decrease in circulating and muscle levels of insulin-like growth factor I (IGF-I). In this paper, we investigated whether the C₂C₁₂ myotube atrophy caused in vitro by TNF-/IFN- cytokines might be reversed by exogenous IGF-I. Our results showed that, despite the presence of TNF-/IFN-, IGF-I retained its full ability to induce the phosphorylation of Akt, Foxo3a, and GSK-3 (respectively, 16-fold, 9-fold, and 2-fold) together with a decrease in atrogin-1 mRNA (–39%, P < 0.001). Although this ubiquitin ligase has been reported to accelerate the degradation of MyoD, a myogenic transcription factor driving the transcription of myosin heavy chain (MHC), IGF-I failed to blunt the reduction of MyoD and MHC caused by TNF-/IFN-. Moreover, IGF-I only very slightly attenuated the myotube atrophy induced by TNF-/IFN- (TNF-/IFN- 15.48 µm alone vs. TNF-/IFN-/IGF-I 16.97 µm, P < 0.001). In conclusion, our data show that IGF-I does not reverse the myotube atrophy induced by TNF-/IFN- despite the phosphorylation of Foxo and GSK-3 and the downregulation of atrogin-1 mRNA. Our study suggests therefore that factors other than IGF-I decrease are responsible for the muscle atrophy caused by proinflammatory cytokines.

growth factors; ubiquitin-proteasome system; tumor necrosis factor-; transduction pathway; muscle atrophy; glycogen synthase kinase-3

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