Targeting membrane fragility in LGMD R2 through pharmacological autophagy induction

Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic disorders characterized by progressive weakening of the limb-girdle muscles. Among LGMDs, Limb-girdle muscular dystrophy type R2 (LGMDR2) is a rare condition affecting fewer than 1 in 100,000 individuals caused by mutations in the gene encoding dysferlin. Recent in vitro studies have suggested that autophagy flux is impaired in LGMDR2. Based on this evidence, we hypothesized that enhancing autophagy could provide therapeutic benefits for this condition. Autophagy plays a critical role in maintaining muscle integrity by clearing damaged cellular components, thus improving the defective dysferlin-mediated membrane repair mechanism. In this study, we performed a multiparametric screening of seventeen autophagy inducers in immortalized myoblasts derived from LGMDR2 patients to identify novel pharmacological compounds capable of enhancing membrane repair. Among the drugs tested, six were found to effectively stimulate autophagy and improve membrane resistance. Our findings demonstrate that inhibition of the mTOR pathway improves the cellular phenotype and underscore the potential of autophagy activators as a promising therapeutic target for LGMDR2.