iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities

Abstract Cardiac complications such as electrical abnormalities including conduction delays and arrhythmias are the main cause of death in individuals with Myotonic Dystrophy type 1 (DM1). We developed a disease model using iPSC-derived cardiomyocytes (iPSC-CMs) from a healthy individual and two DM1...

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Autores principales:	Hugo Poulin, Aurélie Mercier, Mohammed Djemai, Valérie Pouliot, Isabelle Deschenes, Mohamed Boutjdir, Jack Puymirat, Mohamed Chahine
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/42b8fdf897964013a27497c44ed24efc
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spelling	oai:doaj.org-article:42b8fdf897964013a27497c44ed24efc2021-12-02T10:48:13ZiPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities10.1038/s41598-021-82007-82045-2322https://doaj.org/article/42b8fdf897964013a27497c44ed24efc2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82007-8https://doaj.org/toc/2045-2322Abstract Cardiac complications such as electrical abnormalities including conduction delays and arrhythmias are the main cause of death in individuals with Myotonic Dystrophy type 1 (DM1). We developed a disease model using iPSC-derived cardiomyocytes (iPSC-CMs) from a healthy individual and two DM1 patients with different CTG repeats lengths and clinical history (DM1-1300 and DM1-300). We confirmed the presence of toxic RNA foci and mis-spliced MBNL1/2 transcripts in DM1 iPSC-CMs. In DM1-1300, we identified a switch in the cardiac sodium channel SCN5A from the adult to the neonatal isoform. The down-regulation of adult SCN5A isoforms is consistent with a shift in the sodium current activation to depolarized potentials observed in DM1-1300. L-type calcium current density was higher in iPSC-CMs from DM1-1300, which is correlated with the overexpression of the CaV1.2 transcript and proteins. Importantly, INa and ICaL dysfunctions resulted in prolonged action potentials duration, slower velocities, and decreased overshoots. Optical mapping analysis revealed a slower conduction velocity in DM1-1300 iPSC-CM monolayers. In conclusion, our data revealed two distinct ions channels perturbations in DM1 iPSC-CM from the patient with cardiac dysfunction, one affecting Na+ channels and one affecting Ca2+ channels. Both have an impact on cardiac APs and ultimately on heart conduction.Hugo PoulinAurélie MercierMohammed DjemaiValérie PouliotIsabelle DeschenesMohamed BoutjdirJack PuymiratMohamed ChahineNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hugo Poulin Aurélie Mercier Mohammed Djemai Valérie Pouliot Isabelle Deschenes Mohamed Boutjdir Jack Puymirat Mohamed Chahine iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities
description	Abstract Cardiac complications such as electrical abnormalities including conduction delays and arrhythmias are the main cause of death in individuals with Myotonic Dystrophy type 1 (DM1). We developed a disease model using iPSC-derived cardiomyocytes (iPSC-CMs) from a healthy individual and two DM1 patients with different CTG repeats lengths and clinical history (DM1-1300 and DM1-300). We confirmed the presence of toxic RNA foci and mis-spliced MBNL1/2 transcripts in DM1 iPSC-CMs. In DM1-1300, we identified a switch in the cardiac sodium channel SCN5A from the adult to the neonatal isoform. The down-regulation of adult SCN5A isoforms is consistent with a shift in the sodium current activation to depolarized potentials observed in DM1-1300. L-type calcium current density was higher in iPSC-CMs from DM1-1300, which is correlated with the overexpression of the CaV1.2 transcript and proteins. Importantly, INa and ICaL dysfunctions resulted in prolonged action potentials duration, slower velocities, and decreased overshoots. Optical mapping analysis revealed a slower conduction velocity in DM1-1300 iPSC-CM monolayers. In conclusion, our data revealed two distinct ions channels perturbations in DM1 iPSC-CM from the patient with cardiac dysfunction, one affecting Na+ channels and one affecting Ca2+ channels. Both have an impact on cardiac APs and ultimately on heart conduction.
format	article
author	Hugo Poulin Aurélie Mercier Mohammed Djemai Valérie Pouliot Isabelle Deschenes Mohamed Boutjdir Jack Puymirat Mohamed Chahine
author_facet	Hugo Poulin Aurélie Mercier Mohammed Djemai Valérie Pouliot Isabelle Deschenes Mohamed Boutjdir Jack Puymirat Mohamed Chahine
author_sort	Hugo Poulin
title	iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities
title_short	iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities
title_full	iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities
title_fullStr	iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities
title_full_unstemmed	iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities
title_sort	ipsc-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/42b8fdf897964013a27497c44ed24efc
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iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities

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