Promoteur de thèse: Prof.Sylvain Gabriele
Résumé de la dissertation :
Skeletal muscles are the most abundant muscles of the human body and ensure the maintenance and movement of the body. Disruption of the contractile activity of skeletal muscles is associated with a progressive muscle degeneration and weakness, as observed for instance in sarcopenia and Duchenne muscular dystrophy (DMD). Skeletal muscle fibers are formed by the fusion of mononucleated myoblasts into long linear myotubes, which differentiate and reorganize into multinucleated myofibers that assemble in bundles to form skeletal muscles. This fundamental process requires the elongation of myoblasts into a bipolar shape, although a complete understanding of the mechanisms governing skeletal muscle fusion is lacking. To address this question, we consider cell aspect ratio, actomyosin contractility and the Hippo pathway member YAP as potential regulators of the fusion of myoblasts into myotubes. Using fibronectin micropatterns of different geometries and traction force microscopy, we investigated how myoblast elongation affects actomyosin contractility. Our findings indicate that cell elongation enhances actomyosin contractility in myoblasts, which regulate their actin network to their spreading area. Interestingly, we found that the contractility of cell pairs increased after their fusion and raise on elongated morphologies. Furthermore, our findings indicate that myoblast elongation modulates nuclear orientation and triggers cytoplasmic localization of YAP, increasing evidence that YAP is a key regulator of mechanotransduction in myoblasts. Taken together, our findings support a mechanical model where actomyosin contractility scales with myoblast elongation and enhances the differentiation of myoblasts into myotubes through YAP nuclear export.