Résumé :
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Communication n° 439. Duchenne Muscular Dystrophy (DMD) is a lethal disease characterized by progressive muscle weakness and wasting. Despite the sustained presence of satellite cells in their skeletal muscles, muscle regeneration is inefficient in DMD patients and unable to compensate for the continuous loss of muscle fibers. We set out to identify the molecular switches responsible for the defective regeneration in DMD patients. To this end, we compared the gene expression profiles of differentiating human primary myoblast cultures derived from healthy individuals to those of DMD patients (3 per group). In the proliferative phase, 7 genes are differentially expressed (p<0.05 after Bonferroni correction), confirming morphological differences described. The majority of these genes show differential expression over the whole time course. Among these, the bone morphogenetic protein 4 (BMP4) is consistently higher expressed in DMD cultures. Through addition of recombinant BMP4, we show that BMP4 impairs fusion and differentiation of myoblasts. DMD myoblasts are significantly more sensitive towards BMP4, probably due to the higher endogenous levels of the protein. More evidence for impaired myogenesis in DMD cells comes from a group of genes, including membrane metallo-endopeptidase and adlican (involved in cell adhesion and cell-cell signaling), that are upregulated in normal myogenesis, but not induced in DMD cells. A last difference, observed in the later stages of differentiation, is the significant decline in expression of sarcomeric genes in the absence of the dystrophin protein, probably contributing to sarcomeric instability. Taken together, we present evidence that inefficient muscle regeneration, caused by impaired differentiation and impaired maintenance of the DMD myotubes, contributes to the severe phenotype of DMD patients.
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