Ubiquitination-Targeted Therapies Improve Bmd iPSC Myogenic Cell Engraftment and Dystrophin Expression in vivo

Authors

Muchen Liu
Somik Chatterjee
Jianbo Wu
Zeinab Kashaniasl
Ashok Kumar
Chunru Lin
Radbod Darabi

Language

English

Publication Date

9-11-2025

Journal

Molecular Therapy Methods & Clinical Development

DOI

10.1016/j.omtm.2025.101515

PMID

40677835

PMCID

PMC12268038

PubMedCentral® Posted Date

6-16-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Becker muscular dystrophy (BMD) is caused by in-frame mutations in dystrophin gene, leading to progressive muscle weakness, and cardiac and respiratory complications. Currently, there is no cure. We have recently identified the importance of poly-ubiquitination in regulating dystrophin stability through the binding of lncRNA H19 to the dystrophin C-terminal zinc-finger domain (ZNF), inhibiting TRIM63-mediated poly-ubiquitination. We also demonstrated that BMD mutations lead to conformational changes in ZNF domain, reduced lncRNA H19 binding and increased dystrophin ubiquitination. Here we used BMD iPSCs to investigate the in vitro myogenic potential of BMD myogenic cells, as well as in vitro and in vivo studies to evaluate the therapeutic efficacy of three candidate molecules targeting dystrophin ubiquitination pathway. In vitro assays indicated significant deficiencies in myogenic cell differentiation of BMD iPSCs, including reduced proliferation, cell-cycle arrest, increased apoptosis, senescence, and membrane damage, and impaired myotube formation. In vivo engraftment demonstrated significant improvement in BMD iPSC myogenic cell survival and dystrophin expression in the animals treated with two molecules: a TRIM63 inhibitor and an α-synuclein aggregation inhibitor. These findings provide promising evidence for the potential therapeutic efficacy of these ubiquitination pathway inhibitors to improve muscle progenitor cell survival and dystrophin expression in BMD patients.

Keywords

Becker muscular dystrophy, BMD, iPSCs, ubiquitination, dystrophin

Published Open-Access

yes

Recommended Citation

Liu, Muchen; Chatterjee, Somik; Wu, Jianbo; et al., "Ubiquitination-Targeted Therapies Improve Bmd iPSC Myogenic Cell Engraftment and Dystrophin Expression in vivo" (2025). Faculty, Staff and Student Publications. 6149.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6149