Small-molecule activation of lysosomal TRP channels ameliorates Duchenne muscular dystrophy in mouse models.

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ID: 100640
2020
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Abstract
Duchenne muscular dystrophy (DMD) is a devastating disease caused by mutations in dystrophin that compromise sarcolemma integrity. Currently, there is no treatment for DMD. Mutations in transient receptor potential mucolipin 1 (ML1), a lysosomal Ca channel required for lysosomal exocytosis, produce a DMD-like phenotype. Here, we show that transgenic overexpression or pharmacological activation of ML1 in vivo facilitates sarcolemma repair and alleviates the dystrophic phenotypes in both skeletal and cardiac muscles of mice (a mouse model of DMD). Hallmark dystrophic features of DMD, including myofiber necrosis, central nucleation, fibrosis, elevated serum creatine kinase levels, reduced muscle force, impaired motor ability, and dilated cardiomyopathies, were all ameliorated by increasing ML1 activity. ML1-dependent activation of transcription factor EB (TFEB) corrects lysosomal insufficiency to diminish muscle damage. Hence, targeting lysosomal Ca channels may represent a promising approach to treat DMD and related muscle diseases.
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Authors Yu, Lu;Zhang, Xiaoli;Yang, Yexin;Li, Dan;Tang, Kaiyuan;Zhao, Zifan;He, Wanwan;Wang, Ce;Sahoo, Nirakar;Converso-Baran, Kimber;Davis, Carol S;Brooks, Susan V;Bigot, Anne;Calvo, Raul;Martinez, Natalia J;Southall, Noel;Hu, Xin;Marugan, Juan;Ferrer, Marc;Xu, Haoxing;
Journal Science advances
Year 2020
DOI
10.1126/sciadv.aaz2736
URL
Keywords
palmitoylation electrophysiology post-translational modifications myocardium ion channels s-acylation cardiac physiology zdhhc enzymes

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