TARGETING INTRACELLULAR SIGNALING PATHWAYS THAT CONTROL MUSCLE GROWTH AND FIBER TYPE AS A THERAPEUTIC STRATEGY FOR MUSCULAR DYSTROPHIES. FOCUS ON AKT-FOXO AND CALCINEURIN-NFAT SIGNALING

Gene therapy and/or cell therapy will possibly provide the cure for muscular dystrophies, however there are difficult problems to be solved before the clinical application of these treatments becomes a reality. Therefore it seems justified to explore alternative therapeutic approaches to reduce degeneration and promote regeneration in dystrophic muscles. For example, a beneficial effect was recently observed by stimulating muscle growth in the dystrophic mdx mouse, an animal model of Duchenne Muscular Dystrophy, either by over-expressing positive regulators of muscle growth, such as the insulin-like growth factor 1 (IGF-1), or by removing negative regulators of muscle growth, such as myostatin. However, a progress in this direction requires a better understanding of the signaling pathways that control muscle growth, such as the kinase Akt that mediates the effect of IGF-1, and its effectors, in particular the transcription factors of the FOXO family. The proposed project aims to define the role of the Akt-FOXO pathway in normal skeletal muscles, to determine whether FOXO is involved in muscle wasting and whether blocking FOXO signaling may alleviate the distrophic pathology in different mouse models of muscular dystrophy. A fiber type shift from the glycolytic/fast to the oxidative/slow profile induced by calcineurin has been also been found to mitigate the dystrophic phenotype, probably by promoting the up-regulation of utrophin A, that compensates for the absence of dystrophin. We will therefore characterize the role of calcineurin and its effectors, in particular the transcription factors of the NFAT family, in muscle growth and fiber type specification and to determine whether over-expression of activated forms of NFAT may be beneficial for muscular dystrophy. In conclusion, the final aim of this project is to identify potential targets of novel therapeutical strategies for preventing the progression of muscle wasting in muscular dystrophies.