NEXT GENERATION SEQUENCING AND EXPERIMENTAL MYOLOGY: P.381Muscle satellite cells and impaired late stage regeneration in different murine models of muscular dystrophies

Abstract

Satellite cells (SCs) are the main stem cells of the muscle, responsible for its regenerative capacity after injury. In muscular dystrophies, SCs are constantly activated, but a failure of the regenerative process results in muscle degeneration and weakness. We studied muscle SCs in three mouse dystrophic strains: DMDmdx, Largemyd, DMDmdx/Largemyd, to evaluate SCs behavior in muscles with different degrees of degeneration. The dystrophic muscles from the three strains showed similar results, retaining satellite cells pool, expressing PAX7, an important muscle factor for self-renewal of the SCs pool. In addition, a high proportion of proliferating cells was observed by the analysis of cell cycle markers. Expression analysis demonstrated that the cascade of regeneration genes was also activated in all the dystrophic muscles, with high levels of MYOD and Myogenin. The ability to form new fibers was also preserved, with the presence of a significant number of new fibers expressing dMHC. However, these new fibers show incomplete maturation characteristics, such as small size and no variation in fiber caliber, which could be determinant for its dysfunction. On the other hand, muscle degeneration was intense, with significant more connective tissue infiltration in dystrophic mice. We concluded that dystrophic muscles, independently of the degree of degeneration, retain the pool of satellite cells with proliferating capacity and ready to respond to regenerating stimuli. However, the maturation of these new fibers is incomplete and do not prevent the degeneration of the muscle. Effort to improve late muscle regeneration should better contribute to therapeutic approaches.