Extracellular adenosine-triphosphate (e-ATP) and purinergic signalling in the pathogenesis of alpha-sarcoglycan deficient muscular dystrophy (LGMD2D)

This project is aimed to study a pathophysiological mechanism of a negleted type of Limb girdle muscular dystrophy, LGMD2D, due to α-sarcoglycan deficiency. This disorder is characterized by progressive weakness and degeneration of skeletal muscle, loss of ambulation, and difficulties in breathing and often premature death. Pathological features of muscle biopsies from these patients show myofiber degeneration and necrosis, reactive inflammatory response and endomysial fibrosis. We will througly characterize the release and function of extracellular ATP (eATP) in the muscular dysytrophy caused by α-sarcoglycan (α-SG) deficiency. The role of eATP in α-SG defects is very intriguing since α-SG is able to cleave eATP to its intermediate metabolites, thus inactivating its effects on muscle cell purinergic receptors. We will analyze eATP content, release, cleavage and activity in primary myoblasts isolated from muscle tissue of α-SG affected patients and controls. In parallel we will perform the same analysis in primary myoblasts from a mouse model of α-SG deficiency (Sgca-null). Moreover, we will verify the effects of a purinergic antagonist on the dystrophic phenotype displayed by the Sgca-null mouse model. Our hypothesis is that the eATP/purinergic pathway could be altered in α-SG deficient muscle cells and that inhibition of this signaling cascade by using a purinergic receptor antagonist (oxidized ATP) might improve muscle tissue microenvironment, by decreasing inflammatory responses and enhancing muscle cell regeneration. Indeed, oATP has been shown to ameliorate the phenotype of animal models with different inflammatory diseases. The identification of novel molecular mechanisms of myofiber damage in this disease may suggest new therapeutic strategies and corroborate the interest for drugs targeting the inflammatory pathway.