Role of autophagy in muscle diseases

Autophagy is a catabolic pathway conserved among all eukaryotes that allows cells to rapidly eliminate large unwanted structures such as aberrant protein aggregates, damaged or superfluous organelles and invading pathogens, both viruses and bacteria. The general mechanism of autophagy is the sequestration of cytoplasmic cargoes into large double-membrane vesicles called autophagosomes, which then fuse with the lysosome liberating the internal vesicle into the interior of this organelle where, together with the cargo, it is degraded by hydrolases. Autophagy is involved in cell proliferation, death, and differentiation, and clearance of damaged cell components by the autophagic/lysosomal pathway is essential for tissue morphogensis and human health. In fact, defects of this degradative system play a role in inflammation, cancer, and neurodegenerative and lysosomal storage disorders. However, little is known about autophagy in genetic myopathies and muscular dystrophies. Recent findings in an animal model for Bethlem myopathy and Ullrich congenital muscular dystrophy, indicate that persistence of abnormal organelles and spontaneous cell death, two key features of these muscle pathologies, strictly depend on autophagy defects and that reactivation of autophagy is able to restore muscle survival and ameliorate the dystrophic phenotype. Here we propose a multitask and multidisciplinary project aimed at 1) studying this interesting biological process in physiological and pathological conditions in animal and cellular models; 2) identifying novel therapeutical strategies and a class of novel molecules able to interfere with autophagy in muscle inherited diseases and other neuromuscular disorders; 3) isolating autophagic defects in patients affected by muscular dystrophies and other neuromuscular disorders.