Active role of skeletal muscle extracellular matrix in muscular dystrophies

Most of the muscular dystrophies (MDs) are due to defects the trans-membrane protein complex called Dystro-GlycanComplex, which is a structural and functional bridge between myofiber contractile apparatus and extracellular matrix(ECM).MD research is focused upon the cellular mechanisms of the pathology and there is a lack of information about howECM molecules can affect MDs, although alteration in ECM composition is acknowledged since fibrosis is an important badoutcome in the patients.Our hypothesis is that alterations in dystrophic muscle ECM directly account for mechanisms whichnegatively affect skeletal muscle homeostasis.The goal of the project is to identify alterations in ECM compromised bymuscular dystrophy and to investigate their effects on cell behavior.Mdx mouse (model for Duchenne Muscular Dystrophy)and Sarcoglycan-β-null mouse (model for Limb Girdle Muscular Dystrophy 2E) will be used.To obtain the ECMs we will takeadvantage of decellularization approach that removes the cellular components while maintaining the molecular and structuralfeatures as closer as possible to the native ECM.In tissue engineering the use of ECM biomaterials demonstrated that ECMplays a fundamental, active role in tissue remodeling by growth factors release and ECM degradation productaction.Molecular alterations in the ECM composition will be investigated by proteomics that assures an accurate andexhaustive characterization.ECM will be used as 3D environment to study its functions in the behavior of primary cellsinvolved in the pathology: myogenic stem cells, endothelial cells, fibro-adipogenic precursors and macrophages.Discoveringhow alterations in dystrophic muscle ECM affect myogenesis, angiogenesis, fibrosis and inflammatory response will be ofparamount importance for a better understanding of MDs.Changing the focus of the research from the cells to the ECM, thisstudy will provide a new point of view and could contribute to identify new therapeutic targets.