Résumé :
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Objective: Abrogation of activin-receptor signaling such as myostatin blockade stimulates skeletal muscle growth and is regarded as a potential therapeutic strategy against muscle wasting in muscular dystrophies. We previously explored the myostatin knockout mouse, an animal model to study abrogated activin-receptor signaling and had found a myofiber conversion from oxidative to glycolytic phenotype. As the PPAR signaling pathway is thought to play a role in the determination of fiber type we hypothesized that myostatin signals via PPAR transcriptional regulators of oxidative metabolism,Methods: We investigated C2C12 myoblasts after 24 h in the presence or absence of myostatin at different concentrations with regard to their PPARalpha, beta/delta and gamma mRNA expression. Vice versa we investigated C2C12 myoblasts in the presence of Bezafibrate (general PPAR agonist) and Pioglitazone (PPARalpha agonist) for their myostatin mRNA expression. Likewise we investigated muscle from wild-type and myostatin knockout mice for expression of PPARalpha, beta/delta and gamma mRNA.Results: Here we show that absence of myostatin strongly decreases transcription of PPAR PPARalpha, beta/delta and gamma mRNA in skeletal muscle from myostatin knockout mice. In order to differentiate whether changes in PPAR expression are secondary to fiber type conversion or a direct effect of myostatin, we studied PPAR expression in C2C12 myoblasts and myotubes, which do not develop specific fiber types. Treatment with recombinant myostatin rapidly increased expression of PPARgamma and PPARbeta/delta in proliferating and differentiating C2C12 myoblasts following myostatin exposure. Pioglitazone, a selective PPARalpha agonist decreased transcription of myostatin as well as PPARalpha mRNAs. Conclusion: These results suggest that myostatin promotes high oxidative metabolism in skeletal muscle via the PPAR signaling pathway. Myostatin induced PPAR expression while PPAR inhibited myostatin expression. This demonstrates that myostatin controls its own expression via a PPAR mediated negative feedback loop. In line with these results are findings of decreased mitochondrial respiration, increased muscle fatigability, and loss in endurance exercise capacity (see also poster by Etienne Mouisel) in myostatin knockout mice. Our results indicate that potential side effects of myostatin blocking therapies on muscle metabolism could be prevented by increasing PPAR activity using PPAR agonists, a strategy that we will explore in future work.
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