ROLE OF NECDIN IN THE DIFFERENTIATION AND REGENERATION OF THE SKELETAL MUSCLE: MECHANISM OF ACTION AND APPLICATION TO THE CELL THERAPY OF MUSCULAR DYSTROPHY

In muscular dystrophy, muscle regeneration is impaired. During regeneration new myofibers are generated to replace the damaged ones thanks to the action of the satellite cells. Understanding the mechanisms regulating muscle regeneration and satellite cells differentiation is crucial, since any new insights leading to the improvement of the regeneration and decreased loss of muscle mass could have a therapeutic application in Duchenne muscular dystrophy, for which no resolutive therapy is yet available. Necdin is a protein expressed in satellite cells, and preliminary data showed that is involved in muscle regeneration: we observed that mice overexpressing necdin in the muscle show an increased and accelerated capacity to regenerate myofibers, with respect to controls, and their satellite cells differentiate more efficiently and are more resistant to cell death. To get more insights into the mechanisms of Necdin action, we will study the muscle phenotype of mice overexpressing necdin and mice lacking necdin, performing morphological and biochemical analysis on the whole muscle and on isolated satellite cells. We have also evidences suggesting that necdin may be used to enhance the therapeutic potential of the stem cell therapy of the dystrophic muscle, using mesoangioblast stem cells: mesoangioblast overexpressing necdin showed an improved capacity to differentiate in skeletal muscle in vitro. We will perform experiments where mesoangioblasts from necdin overexpressing mice are injected in a murine model of muscular dystrophy, the alpha-sarcoglycan deficient mouse. We will carry out morphological and biochemical analysis and functional tests to assess whether these modified stem cells are more efficient in ameliorating the dystrophic phenotype of the mouse. Expected results Achievement of new important knowledge on the mechanisms regulating muscle regeneration. Improvement of the stem cell therapy with the ultimate goal of making it successfull in humans.