Résumé :
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Communication n° 497. SRF is a transcriptional factor involved in both cell growth and muscle-specific gene expression. Our previous data obtained in cultured muscle cells showed that SRF is needed for myoblasts differentiation. Classical disruption of the SRF gene in mice leads to an early embryonic death. Thus, to investigate the role of SRF in the developing skeletal muscle, we used the Cre/loxP technology and generated mice with a skeletal muscle-targeted inactivation of the SRF gene. Mice harboring SRF "floxed" alleles were crossed with HSA-Cre transgenic mice expressing the Cre recombinase under the control of the human skeletal apha-actin gene promoter. 30% of the mutant mice lacking SRF in skeletal muscle fibers died during the perinatal period. Surviving mutant mice rapidly displayed a growth retardation that accentuates with age, a drastically reduced muscle mass and signs of scoliosis that are consistent with muscle weakness. The smaller size of adult mutant muscles was due to a severe myofiber hypotrophy, suggesting an impaired postnatal growth. A significantly reduced myonuclear number could be observed in mutant myofibers. Following cardiotoxin injection, SRF depleted myofibers failed to regenerate, although satellite cells were normally present. Taken together, these results suggest that myofibers lacking SRF are defective for recruiting satellite cells for postnatal growth as for regeneration. At the molecular level, the expression of several known muscular SRF target genes such as skeletal a-actin and creatine kinase M was strongly down-regulated whereas Myogenin, MyoD and MRF4 were highly expressed indicating the immaturity of the adult mutant muscles. Therefore, SRF is essential for the maturation and growth of skeletal muscle fibers as for maintaining the myogenic program. The role of the SRF gene at different steps of myogenesis and during skeletal regeneration will be further investigated with the help of an inducible skeletal-muscle Cre targeted transgenic mice.
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