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Identification et analyse fonctionnelle de nouveaux gènes impliqués dans la myogénèse chez la drosophile : et mise en évidence d'une transition métabolique nécessaire à la différenciation musculaire

Abstract : A large number of genes involved in myogenesis has been described, but several gaps in comprehension of mechanisms giving rise to functional muscles are still remaining. To fill in these gaps, we selected conserved uncharacterized genes expressed in muscular compartments in drosophila and zebrafish and tested their functions by RNAi knockdown. We found that most of the candidate genes have a role in different steps of embryonic myogenesis in drosophila and interestingly more than a half of them are involved in metabolism. One of these candidates, Pglym78, encodes a glycolytic enzyme and gives rise to late muscle differentiation defects after knockdown in drosophila. Glycolysis is a major metabolic process providing energy and components for biomass synthesis to rapidly growing/proliferating cells such as cancer cells but its role in embryonic development remains unknown. Here we show that starting from midembryogenesis, drosophila Pglym78 and almost all the glycolytic genes display muscle specific expression and that, consistent with this, an important increase in glycolytic activity appears since embryonic stage 14, suggesting that glycolysis can play a role in late steps of myogenesis. This possibility is supported by the fact that attenuation of Pglym78 and other glycolytic genes results in affected muscle differentiation. As shown in Pglm78 knockdown embryos these phenotypes are due to myoblasts fusion arrest and formation of significantly smaller muscle fibres.In order to understand how glycolysis controls myogenesis, we analysed the insulin pathway known to control glycolytic activity and to positively regulate muscle growth by stimulating protein synthesis. Interestingly, inhibition of insulin pathway in differentiating embryonic drosophila muscles leads to the reduced activity of PyK and to phenotypes that are reminiscent of those of glycolytic genes such as fusion arrest and formation of smaller fibres. Thus, our data reveal that metabolic switch to glycolysis positively regulated by insulin pathway is required to support increased biomass synthesis in syncytial muscle cells, revealing direct link between metabolism and development.
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Vanessa Tixier. Identification et analyse fonctionnelle de nouveaux gènes impliqués dans la myogénèse chez la drosophile : et mise en évidence d'une transition métabolique nécessaire à la différenciation musculaire. Médecine humaine et pathologie. Université d'Auvergne - Clermont-Ferrand I, 2011. Français. ⟨NNT : 2011CLF1MM19⟩. ⟨tel-02073617⟩

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