First published January 7, 2020 - More info
Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested to play a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD), however a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized that hypo-phosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knock-in mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or non-phosphorylatable alanines (mdxS3A). The mdxS3E but not mdxS3A mice were resistant to Cx43 remodeling with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca2+ signaling and a reduction of NOX2/reactive oxygen species (ROS) production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43-remodeling and suggest that targeting Cx43 may be a therapeutic strategy to prevent heart dysfunction and arrhythmias in DMD patients.