Sarcoglycans are Enriched at the Neuromuscular Junction in a Nerve-Dependent Manner

Abstract Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. These diseases are caused by mutations in genes coding for one of the four sarcoglycan transmembrane proteins, which form the sarcoglycan complex (SGC). Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that enrichment of sarcoglycans within the NMJ occurs only after innervation, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans' participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.