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

Sci Rep. 2015 Aug 27;5:13490. doi: 10.1038/srep13490.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Arrhythmias, Cardiac / drug therapy*
  • Arrhythmias, Cardiac / pathology
  • Connexin 43 / antagonists & inhibitors*
  • Connexin 43 / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Isoproterenol
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscular Dystrophy, Animal / complications*
  • Muscular Dystrophy, Animal / pathology
  • Muscular Dystrophy, Duchenne / complications*
  • Muscular Dystrophy, Duchenne / pathology
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Connexin 43
  • Peptides
  • Isoproterenol