Duchenne muscular dystrophy (DMD) and its associated cardiomyopathy manifest in 8-10% of all female carriers however research remains male-centric. Although underrepresented, symptomatic females face the risk of cardiac, respiratory, and skeletal muscle problems. Basic research and clinical trials exclude female carriers therefore developments in treatment expose females to unknown safety and efficacy issues. The bottleneck is largely due to the absence of a faithful mouse model. To generate a mouse model, we injected
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embryonic stem cells (ESCs) into wild-type (WT) blastocysts (
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/WT chimera). The cardiac and skeletal muscle phenotype recapitulates the same generated as a consequence of x-inactivation in human manifesting female patients. In the heart,
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/WT chimeras develop fibrotic cardiomyopathy. In the skeletal muscle, we found evidence of fibrosis, inflammation and muscle weakness. We found that Connexin-43 (Cx43), the primary gap junctional protein in the heart, was pathologically enhanced and remodeled in
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/WT chimeras. Cx43 was also enhanced in the dystrophic skeletal muscle. Genetic reduction of Cx43-copy number protected
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/WT chimeras from cardiac and skeletal muscle fiber damage. The latter result was unexpected because Cx43 is not expressed in mature muscle fibers. Upon further investigation, Cx43 was localized to the mononuclear cells invading the interstitial space between dystrophic skeletal muscle fibers. Pathologically enhanced activity of Cx43 in
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FACS-macrophages was observed via ethidium bromide uptake and the Cx43 hemichannel peptide mimetic, Gap19, inhibited Cx43 function in a dose-dependent manner. Because an excess of Cx43 has been associated with cell death, we believe that Cx43 reduction in invading
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macrophages benefits the skeletal muscle of understudied DMD carriers, perhaps by a paracrine mechanism involving macrophage-skeletal muscle fiber communication.
Three Cases of Manifesting Female Carriers in Patients with Duchenne Muscular Dystrophy