Abstract
Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder that affects males. However, 8% of female carriers are symptomatic and underrepresented in research due to the lack of animal models. We generated a symptomatic mouse model of DMD carriers via injection of mdx (murine DMD) embryonic stem cells (ESCs) into wild-type (WT) blastocysts (mdx/WT chimera). mdx/WT chimeras developed cardiomyopathic features and dystrophic skeletal muscle phenotypes including elevated mononuclear invasion, central nucleation, fibrosis and declined forelimb grip strength. The disease was accompanied by connexin-43 (Cx43) aberrantly enhanced in both cardiac and skeletal muscles and remodeled in the heart. Genetic reduction of Cx43-copy number in mdx/WT-Cx43(+/−) chimeras protected them from both cardiac and skeletal muscle fiber damage. In dystrophic skeletal muscle, Cx43 expression was not seen in the fibers but in adjacent F4/80+ mononuclear cells. Ethidium Bromide uptake in purified F4/80+/CD11b+ mdx macrophages revealed functional activity of Cx43, which was inhibited by administration of Gap19 peptide mimetic, a Cx43 hemichannel-specific inhibitor. Thus, we suggest that Cx43 reduction in symptomatic DMD carrier mice leads to prevention of Cx43 remodeling in the heart and prevention of aberrant Cx43 hemichannel activity in the skeletal muscle macrophages neighboring Cx43 non-expressing fibers.
Highlights
Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder that affects males
We show that Cx43-copy number reduction in mdx/WT-Cx43(+/−) chimeras result in a rescue of DMD pathology in both the heart and the skeletal muscle
These results are aligned with previous studies in the heart, in which normalized Cx43 levels benefit mdx cardiac pathology[16,24]; but are unlike the observations in mdx skeletal muscle, in which normalized Cx43 levels do not benefit skeletal muscle pathology
Summary
Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder that affects males. We generated a symptomatic mouse model of DMD carriers via injection of mdx (murine DMD) embryonic stem cells (ESCs) into wild-type (WT) blastocysts (mdx/WT chimera). Genetic reduction of Cx43-copy number in mdx/WT-Cx43(+/−) chimeras protected them from both cardiac and skeletal muscle fiber damage. We suggest that Cx43 reduction in symptomatic DMD carrier mice leads to prevention of Cx43 remodeling in the heart and prevention of aberrant Cx43 hemichannel activity in the skeletal muscle macrophages neighboring Cx43 non-expressing fibers. We described the generation of a model to study symptomatic DMD carriers that faithfully recapitulates the pathology and symptoms (mdx/WT mouse chimeras)[14]. Mdx/WT chimeras feature patches of dystrophin negative(−) and dystrophin positive(+) cells[14] This mosaic model resembles well-documented dystrophin mosaicism in human female DMD carriers due to randomized X-inactivation[14,15]. We explore a rescue role of Cx43 reduction in both the cardiac and skeletal muscle of mdx/WT chimeras
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