Document Type
Article
Publication Date
2-2020
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 Ca2+ 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 mdx 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 Ca2+ channels may represent a promising approach to treat DMD and related muscle diseases.
Recommended Citation
Yu, L., Zhang, X., Yang, Y., Li, D., Tang, K., Zhao, Z., He, W., Wang, C., Sahoo, N., Converso-Baran, K., Davis, C. S., Brooks, S. V., Bigot, A., Calvo, R., Martinez, N. J., Southall, N., Hu, X., Marugan, J., Ferrer, M., & Xu, H. (2020). Small-molecule activation of lysosomal TRP channels ameliorates Duchenne muscular dystrophy in mouse models. Science Advances, 6(6), eaaz2736. https://doi.org/10.1126/sciadv.aaz2736
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
Publication Title
Science Advances
DOI
10.1126/sciadv.aaz2736
Comments
© 2020 The Authors. Original published version available at https://doi.org/10.1126/sciadv.aaz2736