Strategies to improve muscle repair and the outcome of cell mediated therapies in muscular dystrophy

The goal of this project was to establish whether lack of PKCΘ in dystrophic muscle preserves regenerative ability of resident cell populations and improves the survival and the ability of transplanted stem cells to generate new muscle fibers and correct the genetic defect of the recipient. Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation. Moreover, the constant cycles of degeneration and regeneration and the hostile microenvironment affect the satellite cells function and exhaust their regenerative capacity. Previous work done in our laboratory showed that lack of PKC in mdx mice, the mouse model of DMD, improves muscle maintenance, regeneration and performance and reduces muscle inflammation. The observed phenotype was primarily due to lack of PKCΘ in hemopoietic cells, as demonstrated by BM transplantation experiments. Indeed, PKCΘ plays a unique role in T cell activation, and represents an attractive molecular target for the treatment of immune disorders. Current results obtained in the laboratory show that lack of PKC in mdx prevents early lymphocytes recruitment in muscle, altering the inflammatory response (Lozanoska-Ochser et al. ms in prep). In the present study, I show that the lack of PKC in mdx mouse boosts muscle regeneration even at advanced stages of the disease and prevents fibrosis. This phenotype is associated to a both increased maintenance of the satellite cells pool, through up-regulation of the Notch pathway, and increased myogenic and pro-myogenic activity of FAPs. Fibroadipogenic progenits (FAPs), a population of muscle interstitial cells, are known to either contribute to muscle regeneration or to fibroadipogenic degeneration generating myofibroblasts and adipose cells, depending on the environmental stimuli. Moreover, I show in this study that lack of PKC in dystrophic muscle prolongs survival of transplanted mesoangioblasts (MABs) within muscle, compared to mdx, and favours their ability to form myofibers. Together, these results suggest that lack of PKC in dystrophic muscle makes a more favourable environment for both endogenous and exogenous cell populations to contribute to muscle maintenance and repair. This phenotype is probably dependent on alterations in the immune response. The underlying mechanisms are under investigation and may contribute to the identification of additional molecular/ cellular target to ameliorate the disease and to improve cell mediated therapeutic strategies.