Selective Connexin43 Inhibition Prevents Isoproterenol-Induced Arrhythmias and Lethality in Muscular Dystrophy Mice

TL;DR

Inhibiting a specific heart protein prevents dangerous heart rhythms and death in mice with a severe muscle disease.

Contribution

Selective inhibition of lateralized connexin43 prevents arrhythmias in muscular dystrophy mouse models.

Findings

Cx43 is mislocalized and overexpressed in DMD mouse and human heart tissues.

Inhibiting lateralized Cx43 prevents arrhythmias and death in mdx mice under stress.

Selective Cx43 inhibition improves ECG outcomes in severe DMD mouse models.

Abstract

Duchenne muscular dystrophy (DMD) is caused by an X-linked mutation that leads to the absence of dystrophin, resulting in life-threatening arrhythmogenesis and associated heart failure. We targeted the gap junction protein connexin43 (Cx43) responsible for maintaining cardiac conduction. In mild mdx and severe mdx:utr mouse models of DMD, and human DMD tissues, Cx43 was found to be pathologically mislocalized to lateral sides of cardiomyocytes. In addition, overall Cx43 protein levels were markedly increased in mouse and human DMD heart tissues examined. Electrocardiography on isoproterenol challenged mice showed that both models developed arrhythmias and died within 24 hours, while wild-type mice were free of pathology. Administering peptide mimetics to inhibit lateralized Cx43 function prior to challenge protected mdx mice from arrhythmogenesis and death, while mdx:utr mice displayed markedly improved ECG scores. These findings suggest that Cx43 lateralization contributes significantly to DMD arrhythmogenesis and that selective inhibition may provide substantial benefit.

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