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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 (<jats:italic>DYSF<\/jats:italic><jats:sup>L1341P<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We developed an in vitro high\u2010throughput assay to monitor the expression and reallocation of aggregated mutant dysferlin (<jats:italic>DYSF<\/jats:italic><jats:sup>L1341P<\/jats:sup>) 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\u2010osmotic shock was assessed. Their protective effects were evaluated on immortalised myoblasts carrying other dysferlin mutations and on dysferlin\u2010deficient muscle fibres from Bla\/J mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We identified two compounds, saracatinib and bazedoxifene, that increase dysferlin content in cells carrying the <jats:italic>DYSF<\/jats:italic><jats:sup>L1341P<\/jats:sup> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>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\u2010independent treatment of LGMD R2 patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70017","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T01:27:33Z","timestamp":1742434053000},"page":"2930-2949","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["High\u2010throughput screening identifies bazedoxifene as a potential therapeutic for dysferlin\u2010deficient limb girdle muscular dystrophy"],"prefix":"10.1111","volume":"182","author":[{"given":"Celine","family":"Bruge","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Universit\u00e9 d\u2019Evry, Inserm, IStem, UMR861  Corbeil\u2010Essonnes France"},{"name":"CECS IStem  Corbeil\u2010Essonnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Bourg","sequence":"additional","affiliation":[{"name":"INTEGRARE Genethon, Inserm, Universit\u00e9 d'Evry, Universit\u00e9 Paris\u2010Saclay  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Pellier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Universit\u00e9 d\u2019Evry, Inserm, IStem, UMR861  Corbeil\u2010Essonnes France"},{"name":"CECS IStem  Corbeil\u2010Essonnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johana","family":"Tournois","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Universit\u00e9 d\u2019Evry, Inserm, IStem, UMR861  Corbeil\u2010Essonnes France"},{"name":"CECS IStem  Corbeil\u2010Essonnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Polentes","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Universit\u00e9 d\u2019Evry, Inserm, IStem, UMR861  Corbeil\u2010Essonnes France"},{"name":"CECS IStem  Corbeil\u2010Essonnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Benabides","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Universit\u00e9 d\u2019Evry, Inserm, IStem, UMR861  Corbeil\u2010Essonnes France"},{"name":"CECS IStem  Corbeil\u2010Essonnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noella","family":"Grossi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Universit\u00e9 d\u2019Evry, Inserm, IStem, UMR861  Corbeil\u2010Essonnes France"},{"name":"CECS IStem  Corbeil\u2010Essonnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Bigot","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9 Inserm, Institut de Myologie, Centre de Recherche en Myologie  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Brureau","sequence":"additional","affiliation":[{"name":"INTEGRARE Genethon, Inserm, Universit\u00e9 d'Evry, Universit\u00e9 Paris\u2010Saclay  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Richard","sequence":"additional","affiliation":[{"name":"INTEGRARE Genethon, Inserm, Universit\u00e9 d'Evry, Universit\u00e9 Paris\u2010Saclay  Evry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3374-6274","authenticated-orcid":false,"given":"Xavier","family":"Nissan","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris\u2010Saclay Universit\u00e9 d\u2019Evry, Inserm, IStem, UMR861  Corbeil\u2010Essonnes France"},{"name":"CECS IStem  Corbeil\u2010Essonnes France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,19]]},"reference":[{"issue":"2","key":"e_1_2_12_2_1","first-page":"S1","article-title":"The concise guide to pharmacology 2023\/24: Introduction and other protein targets","volume":"180","author":"Alexander S. 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