Small-molecule Activation of Lysosomal TRP Channels Ameliorates Duchenne Muscular Dystrophy in Mouse Models

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2020 Mar 5

PMID 32128386

Citations 31

Authors

Lu Yu

Xiaoli Zhang

Yexin Yang

Dan Li

Kaiyuan Tang

Zifan Zhao

Wanwan He

Ce Wang

Nirakar Sahoo

Kimber Converso-Baran

Carol S Davis

Susan V Brooks

Anne Bigot

Raul Calvo

Natalia J Martinez

Noel Southall

Xin Hu

Juan Marugan

Marc Ferrer

Haoxing Xu

Affiliations

Soon will be listed here.

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.

Citing Articles

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