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pathways and inhibition of Atrogin-1 mRNA
1 Diabetology and Nutrition, Universite catholique de Louvain, Brussels, Belgium
* To whom correspondence should be addressed. E-mail: thissen{at}diab.ucl.ac.be.
Myofibrillar protein loss occurring in catabolic situations is considered to be mediated by the release of proinflammatory cytokines and associated to 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 GSK3
(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 GSK3 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.
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