Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice.

Abstract

Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/-) mice were studied before (4-6 months) and after (10-15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice. Increased connexin 43 protein levels in mdx hearts were not observed in mdx:Cx43(+/-) hearts. Cx43 remodeling in mdx hearts was attenuated in mdx:Cx43(+/-) hearts. At time-point 4-6 months, isolated cardiomyocytes from mdx hearts displayed enhanced ethidium bromide uptake, augmented intracellular calcium signals and increased production of reactive oxygen species. These pathological features were improved in mdx:Cx43(+/-) cardiomyocytes. Isoproterenol-challenged mdx:Cx43(+/-) mice did not show arrhythmias or acute lethality observed in mdx mice. Likewise, isoproterenol-challenged mdx:Cx43(+/-) isolated hearts were also protected from arrhythmogenesis. At time-point 10-15 months, mdx:Cx43(+/-) mice showed decreased cardiac fibrosis and improved ventricular function, relative to mdx mice. These results suggest that normalization of connexin 43 protein levels in mdx mice reduces overall cardiac pathology.

• Authors: J Patrick Gonzalez, Jayalakshmi Ramachandran, Eric Himelman, Myriam A Badr, Chifei Kang, Julie Nouet, Nadezhda Fefelova, Lai-Hua Xie, Natalia Shirokova, Jorge E Contreras, Diego Fraidenraich
• Journal: Neuromuscular disorders : NMD (Neuromuscul Disord) Vol. 28 Issue 4 Pg. 361-372 (04 2018) ISSN: 1873-2364 [Electronic] England
• PMID: 29477453 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Connexin 43
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cardiomyopathies (metabolism, pathology)
• Connexin 43 (metabolism)
• Disease Models, Animal
• Female
• Male
• Mice, Transgenic
• Muscular Dystrophy, Duchenne (metabolism, pathology)
• Myocardium (pathology)
• Myocytes, Cardiac (pathology)