Résumé :
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Myostatin (MSTN), a member of the TGF-beta superfamily, is a negative regulator of skeletal muscle mass. Inactivating mutations of the MSTN gene are responsible for the development of a hypermuscular phenotype in mice (McPherron et al., 1997) and cattle (Grobet et al., 1997). The main objective of this study was to identify molecular targets of MSTN action involved in the regulation of muscle mass. The proteomic profiles of Quadriceps muscles of 5-week-old MSTN-null mice (McPherron et al., 1997) and their controls were analysed using two dimensional electrophoresis (4-7 pH gradient, SAM test, FDR<5%) (Meunier et al., 2005) and the transcriptomic analysis (SAM test, FDR<5%) was carried out using myochips (West Genopole). The data were further analysed with bioinformatics tools (Genomatix, DAVID and String) Comparison of the protein profiles (20 up and 18 down-regulated proteins spots) confirmed that MSTN inactivation caused a glycolytic shift of the muscles (MyBP, MyHCII, H-FABP) and a differential abundance of survival/mortality factors (DJ-1 and TCTP/HSP9A) Comparison of the transcriptomic profiles (192 up and 245 down- regulated genes) revealed up-regulation of genes involved in insulin/IGF and protein kinase beta signalling, carbohydrate metabolism, and apoptosis/differentiation. Genes belonging to the canonical Wnt and calcium signalling pathways were down-regulated. In conclusion, these data showed a differential expression of genes and proteins related to the muscle energy metabolism and cell survival/apoptosis pathway (e.g. DJ-1, PINK1 and TCTP/HSP9A, GSK-3beta). This last finding suggests that MSTN may be a modulator of cell survival, growth and differentiation through the regulation of GSK-3beta activity and downstream signalling pathways; this action may implicate DJ-1 a regulator of the PI3K pathway Our results allowed the identification of molecular networks that may be MSTN targets underpinning hypertrophy. The expected applications will be notably in clinical domains concerning the treatment of muscular dystrophy and muscle wasting associated with aging.
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