Résumé :
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MicroRNAs are recognized as important regulators of gene expression in the differentiation commitment of several cell types and have been shown to occupy very high hierarchical positions in the cascade of regulatory events controlling cell specification. Proper muscle tissue development and function were also described to depend on the controlled expression of specific families of miRNAs; in several cases it has been also shown that their ectopic expression can direct cells towards specific differentiation programmes. We discovered that altered levels of miRNAs are present in Duchenne Muscular Dystrophy. Taking advantage of a controlled rescue of dystrophin synthesis through exon skipping in mdx mice, we discovered that molecular circuitries, important for muscle differentiation and tissue integrity, such as oxidative stress and fibrosis, are directly controlled by dystrophin through NO signalling and epigenetic modulation of miRNA expression. We also identified a miRNA (miR-31), highly expressed in Duchenne muscles, that represses dystrophin expression by targeting its 3'UTR. In human DMD myoblasts treated with exon skipping, we demonstrated that miR-31 inhibition increases dystrophin rescue. These results indicate that interfering with miR-31 activity can provide an ameliorating strategy for those DMD therapies aimed at efficiently recover dystrophin synthesis.
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