Résumé :
|
In skeletal muscle, the _1 S subunit of the DHPR calcium channel functions both as the L-type Ca2+ channel and the voltage sensor for excitation-contraction coupling. We have combined optimized U7snRNA and gene transfer to achieve long-lasting down regulation of _1 S in adult skeletal muscle (Pii-Rouxel et al, The EMBO Journal (2010) 29, 643-654). Treated muscles underwent massive atrophy resulting from the _1 S subunit knockdown. Moreover, this functional inhibition of the _1 S subunit also uncovered an unexpected crucial role in controlling mass and in maintaining morphological organization of the adult skeletal muscle. Knowing that knocking myostatin improves muscle mass, we have investigated the effects of myostatin inhibition in the context of muscular atrophy by using both a vector encoding the myostatin-propeptide and the knockout myostatin mouse model. Results showed that interfering with the myostatin pathway protects from muscle atrophic profile and maintains tetanic force. This confirms that myostatin inhibition could be relevant for opposing the progression of muscle degeneration and thus offers a promising therapeutic strategy for muscular dystrophy. Finally, we are currently investigating if the signaling pathways triggered by myostatin and the _1 S subunit could be connected and participate together to the control of the muscle homeostasis.
|