[HTML][HTML] Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy

E Himelman, MA Lillo, J Nouet… - The Journal of …, 2020 - Am Soc Clin Investig
E Himelman, MA Lillo, J Nouet, JP Gonzalez, Q Zhao, LH Xie, H Li, T Liu, XHT Wehrens
The Journal of clinical investigation, 2020Am Soc Clin Investig
Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been
suggested as playing 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
hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the …
Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing 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 hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knockin mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or nonphosphorylatable 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 NADPH oxidase 2 (NOX2)/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 for preventing heart dysfunction and arrhythmias in DMD patients.
The Journal of Clinical Investigation