High‐throughput screening identifies bazedoxifene as a potential therapeutic for dysferlin‐deficient limb girdle muscular dystrophy

Abstract Background and Purpose Limb‐girdle muscular dystrophy R2 (LGMD R2) is a rare genetic disorder characterised by progressive weakness and wasting of proximal muscles. LGMD R2 is caused by the loss of function of dysferlin, a transmembrane protein crucial for plasma membrane repair in skeletal muscles. This study aimed to identify drugs that could improve the localisation and restore the function of an aggregated mutant form of dysferlin ( DYSF L1341P ). Experimental Approach We developed an in vitro high‐throughput assay to monitor the expression and reallocation of aggregated mutant dysferlin ( DYSF L1341P ) in immortalised myoblasts. After screening 2239 clinically approved drugs and bioactive compounds, the ability of the more promising candidates to improve cell survival following hypo‐osmotic shock was assessed. Their protective effects were evaluated on immortalised myoblasts carrying other dysferlin mutations and on dysferlin‐deficient muscle fibres from Bla/J mice. Key Results We identified two compounds, saracatinib and bazedoxifene, that increase dysferlin content in cells carrying the DYSF L1341P mutation. Both drugs improved cell survival and plasma membrane resistance following osmotic shock. Whereas saracatinib acts specifically on misfolded L1341P dysferlin, bazedoxifene shows an additional protective effect on dysferlin KO immortalised myoblasts and mice muscle fibres. Further analysis revealed that bazedoxifene induces autophagy flux, which may enhance the survival of LGMD R2 myofibres. Conclusion and Implications Our drug screening identified saracatinib and bazedoxifene as potential treatments for LGMD R2, especially for patients with the L1341P mutation. The widespread protective effect of bazedoxifene reveals a new avenue toward genotype‐independent treatment of LGMD R2 patients.