DMD-Null mice exhibit severe muscle weakness, impaired regeneration, and deficient satellite cell function.

Abstract

Duchenne muscular dystrophy (DMD) is a debilitating and fatal X-linked disease affecting 1/5,000 males worldwide that currently has no cure [D. Duan, N. Goemans, S. Takeda, E. Mercuri, A. Aartsma-Rus, <i>Nat. Rev. Dis. Primers</i> <b>7</b>, 1-19 (2021), 10.1038/s41572-021-00248-3]. Vast amounts of research have been conducted on DMD, and one of the most common animal models for DMD studies is the mouse muscular dystrophy (<i>mdx</i>) model [J. W. McGreevy, C. H. Hakim, M. A. McIntosh, D. Duan, <i>DMM Dis. Model. Mech.</i> <b>8</b>, 195-213 (2015), 10.1242/DMM.018424/-/DC1]. Unfortunately, despite its shared genetic etiology, the <i>mdx</i> mouse shows a relatively mild dystrophic phenotype compared to affected humans, limiting its overall utility as a research model (G. Donen, N. Milad, P. Bernatchez, <i>J. Neuromuscul. Dis.</i> <b>10</b>, 1003 (2023), 10.3233/JND-230126]. Notably, <i>mdx</i> mice have a mutation preventing the production of full-length dystrophin but are still able to produce numerous short isoforms of dystrophin. Here, we provide a comprehensive functional characterization of DMD-Null mice, which lack all dystrophin isoforms. Our studies demonstrate that DMD-Null mice show a more severe skeletal muscle phenotype than <i>mdx</i> mice, characterized by profound weakness, decreased exercise tolerance, and impaired muscle regeneration, while utrophin upregulation was similarly observed in DMD-Null and <i>mdx</i> mice. We identify a marked deficit in satellite cell proliferation and myogenic differentiation, accompanied by downregulation of regenerative gene programs. These findings suggest potential contributions of short dystrophin isoforms to muscle stem cell function, and establish DMD-Null mice as a unique model for investigating the pathogenesis of DMD and testing therapeutic interventions targeting satellite cell health and regeneration.