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

• Published in: Science advances Vol. 6; no. 6; p. eaaz2736
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 07.02.2020; American Association for the Advancement of Science
• Subjects: Biochemistry, Molecular Biology; Cell Biology; Diseases and Disorders; Human health and pathology; Life Sciences; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aaz2736

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.