The danger signal extracellular ATP is involved in the immuno-mediated damage of alpha-sarcoglycan deficient muscular dystrophy.

In muscular dystrophies the muscle membrane fragility results in a tissue-specific increase of danger-associated molecules (DAMPs) and infiltration of inflammatory cells. The DAMP extracellular adenosine triphosphate (eATP) released by dying myofibers steadily activates muscle and immune purinergic receptors exerting dual negative effects: a direct damage linked to altered intracellular calcium homeostasis in muscle cells and an indirect toxicity through the "triggering" of the immune response and inhibition of regulatory T cells. Accordingly, pharmacological and genetic inhibition of eATP signaling improves the phenotype in models of chronic inflammatory diseases. In α-sarcoglycanopathy (LGMD2D), eATP effects may be further amplified since α-sarcoglycan extracellular domain binds eATP and displays an ecto-ATPase activity, thus controlling eATP concentration at the cell surface and attenuating the magnitude and/or the duration of eATP-induced signals. Here we show that in vivo blockade of the eATP/P2X purinergic pathway by a broad spectrum P2XR-antagonist delayed the progression of the dystrophic phenotype in α-sarcoglycan null mice. eATP blockade dampened the muscular inflammatory response and enhanced the recruitment of Foxp3+ immunosuppressive regulatory CD4+ T cells. The improvement of the inflammatory features was associated with increased strength, reduced necrosis and limited expression of pro-fibrotic factors, suggesting that pharmacologic purinergic antagonism, altering the innate and adaptive immune component in the muscle infiltrates, might provide a therapeutic approach to slow disease progression in LGMD2D.