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Low dystrophin levels in heart can delay heart failure in mdx mice

Lookup NU author(s): Dr Ingrid Verhaart

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Duchenne muscular dystrophy is caused by mutations that prevent synthesis of functional dystrophin. All patients develop dilated cardiomyopathy. Promising therapeutic approaches are underway that successfully restore dystrophin expression in skeletal muscle. However, their efficiency in the heart is limited. Improved quality and function of only skeletal muscle potentially accelerate the development of cardiomyopathy. Our study aimed to elucidate which dystrophin levels in the heart are required to prevent or delay cardiomyopathy in mice. Heart function and pathology assessed with magnetic resonance imaging and histopathological analysis were compared between 2, 6 and 10-month-old female mdx-XistΔhs mice, expressing low dystrophin levels (3–15%) in a mosaic manner based on skewed X-inactivation, dystrophin-negative mdx mice, and wild type mice of corresponding genetic backgrounds and gender.With age mdx mice developed dilated cardiomyopathy and hypertrophy, whereas the onset of heart pathology was delayed and function improved in mdx-XistΔhs mice. The ejection fraction, the most severely affected parameter for both ventricles, correlated to dystrophin expression and the percentage of fibrosis. Fibrosis was partly reduced from 9.8% in mdx to 5.4% in 10 month old mdx-XistΔhs mice. These data suggest that mosaic expression of 4–15% dystrophin in the heart is sufficient to delay the onset and ameliorate cardiomyopathy in mice.


Publication metadata

Author(s): van Putten M, van der Pijl EM, Hulsker M, Verhaart IE, Nadarajah VD, van der Weerd L, Aartsma-Rus A

Publication type: Article

Publication status: Published

Journal: Journal of Molecular and Cellular Cardiology

Year: 2014

Volume: 69

Pages: 17-23

Print publication date: 01/04/2014

Online publication date: 29/01/2014

Acceptance date: 21/01/2014

Date deposited: 12/07/2016

ISSN (print): 0022-2828

ISSN (electronic): 1095-8584

Publisher: Elsevier

URL: http://ac.els-cdn.com/S0022282814000297/1-s2.0-S0022282814000297-main.pdf?_tid=339fa8ee-4829-11e6-ad86-00000aacb360&acdnat=1468325427_e05e2e65d9531b19038a95bbbed10621

DOI: 10.1016/j.yjmcc.2014.01.009

PubMed id: 24486194


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