ROLE OF IGF-1 ON MUSCLE REGENERATION AND NEUROMUSCULAR DISEASES

One of the most severe characteristics of muscular dystrophy is the progressive loss of muscle tissue due to chronic degeneration of muscle and to the exhaustion of satellite cells that replace damaged fibers. In this context, the persistent protein degradation observed in neuromuscular diseases reflects a pathological muscle catabolism, known as muscle wasting. It is, therefore, important to analyze the factors involved in anabolic pathways, such as insulin-like growth factor-1 (IGF-1), in order to promote stabilization and maintenance of muscle proteins. Recently we have demonstrated that the integrity and regenerative capacity of total body skeletal musculature is safely extended by local IGF-1 supplementation into senescence of transgenic mice (MLC/IGF-1). On the basis of our preliminary results we will characterize whether IGF-1 is able to attenuates and/or rescue the skeletal muscle phenotype and function of a dystrophic mouse model. In this study we will use the MLC/IGF-1 transgenic mice, which display hypertrophic phenotype, and the MyoDnull/mdx mice which represents a more appropriate model for muscular dystrophy than the original mdx mutant line, displaying several phenotypic traits typical of the human muscular diseases. The goals of the research project are: 1. To test whether supplemental IGF-1 expression in mature skeletal muscle of MLC/IGF-1 transgenic mice augments their capacity for regeneration; 2. To test the hypothesis that supplemental IGF-1 production restricted exclusively to skeletal muscle tissue may attenuate progressive degeneration in the mouse dystrophic model MyoD-/- x mdx; 3. To develop tissue-engineered skeletal muscle for cell/gene therapy. The achievement of this project will provide information facilitating the design of interventional strategies to reverse or attenuate the degenerative effects of muscular dystrophy.