Journal Article

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

Shirokova, Natalia, Liu, Tong, Gonzalez, J. Patrick, Lillo, Mauricio A., Lampe, Paul D., Xie, Lai-Hua, Wehrens, Xander H.T., Fishman, Glenn I., Contreras, Jorge E., Li, Hong, Himelman, Eric, Zhao, Qingshi, Fraidenraich, Diego, Nouet, Julie

2020

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Arrhythmia / Biomedical research / Ca2+/calmodulin-dependent protein kinase II / Calcium (intracellular) / Calcium Signaling / Calcium signalling / Cardiac arrhythmia / Cardiomyocytes / Cardiomyopathies - genetics / Cardiomyopathies - metabolism / Cardiomyopathies - pathology / Cardiomyopathy / Cardiovascular diseases / Colchicine / Connexin 43 / Connexin 43 - genetics / Connexin 43 - metabolism / Coronary artery disease / CRISPR / CYBB protein / Development and progression / Diseases / Duchenne muscular dystrophy / Duchenne's muscular dystrophy / Gene therapy / Gout suppressants / Heart / Heart cells / Heart diseases / Humans / Intracellular signalling / Ischemia / Kinases / Lethality / Localization / Mass spectrometry / Mice / Mice, Inbred mdx / Mice, Transgenic / Microtubules - genetics / Microtubules - metabolism / Mimicry / Muscular dystrophy / Muscular Dystrophy, Duchenne - genetics / Muscular Dystrophy, Duchenne - metabolism / Muscular Dystrophy, Duchenne - pathology / Musculoskeletal system / Myocardial diseases / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / NAD(P)H oxidase / NADPH Oxidase 2 - genetics / NADPH Oxidase 2 - metabolism / Oxidases / Phosphorylation / Polymerization / Prevention / Proteins / Rodents / Scientific imaging / Serine