Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model

Abstract Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder caused by loss of dystrophin. This lack also affects cardiac structure and function, and cardiovascular complications are a major cause of death in DMD. Newly developed therapies partially restore dystrophin expressio...

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Autores principales:	Gerard A. Marchal, Maaike van Putten, Arie O. Verkerk, Simona Casini, Kayleigh Putker, Shirley C. M. van Amersfoorth, Annemieke Aartsma-Rus, Elisabeth M. Lodder, Carol Ann Remme
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e66d62ff25c047aab32a8e28fe2c4a19
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spelling	oai:doaj.org-article:e66d62ff25c047aab32a8e28fe2c4a192021-12-02T15:37:58ZLow human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model10.1038/s41598-021-89208-12045-2322https://doaj.org/article/e66d62ff25c047aab32a8e28fe2c4a192021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89208-1https://doaj.org/toc/2045-2322Abstract Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder caused by loss of dystrophin. This lack also affects cardiac structure and function, and cardiovascular complications are a major cause of death in DMD. Newly developed therapies partially restore dystrophin expression. It is unclear whether this will be sufficient to prevent or ameliorate cardiac involvement in DMD. We here establish the cardiac electrophysiological and structural phenotype in young (2–3 months) and aged (6–13 months) dystrophin-deficient mdx mice expressing 100% human dystrophin (hDMD), 0% human dystrophin (hDMDdel52-null) or low levels (~ 5%) of human dystrophin (hDMDdel52-low). Compared to hDMD, young and aged hDMDdel52-null mice displayed conduction slowing and repolarisation abnormalities, while only aged hDMDdel52-null mice displayed increased myocardial fibrosis. Moreover, ventricular cardiomyocytes from young hDMDdel52-null animals displayed decreased sodium current and action potential (AP) upstroke velocity, and prolonged AP duration at 20% and 50% of repolarisation. Hence, cardiac electrical remodelling in hDMDdel52-null mice preceded development of structural alterations. In contrast to hDMDdel52-null, hDMDdel52-low mice showed similar electrophysiological and structural characteristics as hDMD, indicating prevention of the cardiac DMD phenotype by low levels of human dystrophin. Our findings are potentially relevant for the development of therapeutic strategies aimed at restoring dystrophin expression in DMD.Gerard A. MarchalMaaike van PuttenArie O. VerkerkSimona CasiniKayleigh PutkerShirley C. M. van AmersfoorthAnnemieke Aartsma-RusElisabeth M. LodderCarol Ann RemmeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gerard A. Marchal Maaike van Putten Arie O. Verkerk Simona Casini Kayleigh Putker Shirley C. M. van Amersfoorth Annemieke Aartsma-Rus Elisabeth M. Lodder Carol Ann Remme Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model
description	Abstract Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder caused by loss of dystrophin. This lack also affects cardiac structure and function, and cardiovascular complications are a major cause of death in DMD. Newly developed therapies partially restore dystrophin expression. It is unclear whether this will be sufficient to prevent or ameliorate cardiac involvement in DMD. We here establish the cardiac electrophysiological and structural phenotype in young (2–3 months) and aged (6–13 months) dystrophin-deficient mdx mice expressing 100% human dystrophin (hDMD), 0% human dystrophin (hDMDdel52-null) or low levels (~ 5%) of human dystrophin (hDMDdel52-low). Compared to hDMD, young and aged hDMDdel52-null mice displayed conduction slowing and repolarisation abnormalities, while only aged hDMDdel52-null mice displayed increased myocardial fibrosis. Moreover, ventricular cardiomyocytes from young hDMDdel52-null animals displayed decreased sodium current and action potential (AP) upstroke velocity, and prolonged AP duration at 20% and 50% of repolarisation. Hence, cardiac electrical remodelling in hDMDdel52-null mice preceded development of structural alterations. In contrast to hDMDdel52-null, hDMDdel52-low mice showed similar electrophysiological and structural characteristics as hDMD, indicating prevention of the cardiac DMD phenotype by low levels of human dystrophin. Our findings are potentially relevant for the development of therapeutic strategies aimed at restoring dystrophin expression in DMD.
format	article
author	Gerard A. Marchal Maaike van Putten Arie O. Verkerk Simona Casini Kayleigh Putker Shirley C. M. van Amersfoorth Annemieke Aartsma-Rus Elisabeth M. Lodder Carol Ann Remme
author_facet	Gerard A. Marchal Maaike van Putten Arie O. Verkerk Simona Casini Kayleigh Putker Shirley C. M. van Amersfoorth Annemieke Aartsma-Rus Elisabeth M. Lodder Carol Ann Remme
author_sort	Gerard A. Marchal
title	Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model
title_short	Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model
title_full	Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model
title_fullStr	Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model
title_full_unstemmed	Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model
title_sort	low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a duchenne mouse model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e66d62ff25c047aab32a8e28fe2c4a19
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Low human dystrophin levels prevent cardiac electrophysiological and structural remodelling in a Duchenne mouse model

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