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SMN-deficiency disrupts SERCA2 expression and intracellular Ca(2+) signaling in cardiomyocytes from SMA mice and patient-derived iPSCs

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of alpha motor neurons and skeletal muscle atrophy. The disease is caused by mutations of the SMN1 gene that result in reduced functional expression of survival motor neuron (SMN) protein. SMN is ubiquitously expresse...

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Autores principales: Khayrullina, Guzal, Moritz, Kasey E., Schooley, James F., Fatima, Naheed, Viollet, Coralie, McCormack, Nikki M., Smyth, Jeremy T., Doughty, Martin L., Dalgard, Clifton L., Flagg, Thomas P., Burnett, Barrington G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206821/
https://www.ncbi.nlm.nih.gov/pubmed/32384912
http://dx.doi.org/10.1186/s13395-020-00232-7
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author Khayrullina, Guzal
Moritz, Kasey E.
Schooley, James F.
Fatima, Naheed
Viollet, Coralie
McCormack, Nikki M.
Smyth, Jeremy T.
Doughty, Martin L.
Dalgard, Clifton L.
Flagg, Thomas P.
Burnett, Barrington G.
author_facet Khayrullina, Guzal
Moritz, Kasey E.
Schooley, James F.
Fatima, Naheed
Viollet, Coralie
McCormack, Nikki M.
Smyth, Jeremy T.
Doughty, Martin L.
Dalgard, Clifton L.
Flagg, Thomas P.
Burnett, Barrington G.
author_sort Khayrullina, Guzal
collection PubMed
description Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of alpha motor neurons and skeletal muscle atrophy. The disease is caused by mutations of the SMN1 gene that result in reduced functional expression of survival motor neuron (SMN) protein. SMN is ubiquitously expressed, and there have been reports of cardiovascular dysfunction in the most severe SMA patients and animal models of the disease. In this study, we directly assessed the function of cardiomyocytes isolated from a severe SMA model mouse and cardiomyocytes generated from patient-derived IPSCs. Consistent with impaired cardiovascular function at the very early disease stages in mice, heart failure markers such as brain natriuretic peptide were significantly elevated. Functionally, cardiomyocyte relaxation kinetics were markedly slowed and the T(50) for Ca(2+) sequestration increased to 146 ± 4 ms in SMN-deficient cardiomyocytes from 126 ± 4 ms in wild type cells. Reducing SMN levels in cardiomyocytes from control patient IPSCs slowed calcium reuptake similar to SMA patent-derived cardiac cells. Importantly, restoring SMN increased calcium reuptake rate. Taken together, these results indicate that SMN deficiency impairs cardiomyocyte function at least partially through intracellular Ca(2+) cycling dysregulation.
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spelling pubmed-72068212020-05-15 SMN-deficiency disrupts SERCA2 expression and intracellular Ca(2+) signaling in cardiomyocytes from SMA mice and patient-derived iPSCs Khayrullina, Guzal Moritz, Kasey E. Schooley, James F. Fatima, Naheed Viollet, Coralie McCormack, Nikki M. Smyth, Jeremy T. Doughty, Martin L. Dalgard, Clifton L. Flagg, Thomas P. Burnett, Barrington G. Skelet Muscle Research Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of alpha motor neurons and skeletal muscle atrophy. The disease is caused by mutations of the SMN1 gene that result in reduced functional expression of survival motor neuron (SMN) protein. SMN is ubiquitously expressed, and there have been reports of cardiovascular dysfunction in the most severe SMA patients and animal models of the disease. In this study, we directly assessed the function of cardiomyocytes isolated from a severe SMA model mouse and cardiomyocytes generated from patient-derived IPSCs. Consistent with impaired cardiovascular function at the very early disease stages in mice, heart failure markers such as brain natriuretic peptide were significantly elevated. Functionally, cardiomyocyte relaxation kinetics were markedly slowed and the T(50) for Ca(2+) sequestration increased to 146 ± 4 ms in SMN-deficient cardiomyocytes from 126 ± 4 ms in wild type cells. Reducing SMN levels in cardiomyocytes from control patient IPSCs slowed calcium reuptake similar to SMA patent-derived cardiac cells. Importantly, restoring SMN increased calcium reuptake rate. Taken together, these results indicate that SMN deficiency impairs cardiomyocyte function at least partially through intracellular Ca(2+) cycling dysregulation. BioMed Central 2020-05-08 /pmc/articles/PMC7206821/ /pubmed/32384912 http://dx.doi.org/10.1186/s13395-020-00232-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Khayrullina, Guzal
Moritz, Kasey E.
Schooley, James F.
Fatima, Naheed
Viollet, Coralie
McCormack, Nikki M.
Smyth, Jeremy T.
Doughty, Martin L.
Dalgard, Clifton L.
Flagg, Thomas P.
Burnett, Barrington G.
SMN-deficiency disrupts SERCA2 expression and intracellular Ca(2+) signaling in cardiomyocytes from SMA mice and patient-derived iPSCs
title SMN-deficiency disrupts SERCA2 expression and intracellular Ca(2+) signaling in cardiomyocytes from SMA mice and patient-derived iPSCs
title_full SMN-deficiency disrupts SERCA2 expression and intracellular Ca(2+) signaling in cardiomyocytes from SMA mice and patient-derived iPSCs
title_fullStr SMN-deficiency disrupts SERCA2 expression and intracellular Ca(2+) signaling in cardiomyocytes from SMA mice and patient-derived iPSCs
title_full_unstemmed SMN-deficiency disrupts SERCA2 expression and intracellular Ca(2+) signaling in cardiomyocytes from SMA mice and patient-derived iPSCs
title_short SMN-deficiency disrupts SERCA2 expression and intracellular Ca(2+) signaling in cardiomyocytes from SMA mice and patient-derived iPSCs
title_sort smn-deficiency disrupts serca2 expression and intracellular ca(2+) signaling in cardiomyocytes from sma mice and patient-derived ipscs
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206821/
https://www.ncbi.nlm.nih.gov/pubmed/32384912
http://dx.doi.org/10.1186/s13395-020-00232-7
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