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Ageing in Pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology

Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β(−/−)) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on t...

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Autores principales: Edling, Charlotte E., Fazmin, Ibrahim T., Chadda, Karan R., Ahmad, Shiraz, Valli, Haseeb, Grace, Andrew A., Huang, Christopher L.-H., Jeevaratnam, Kamalan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470410/
https://www.ncbi.nlm.nih.gov/pubmed/30914453
http://dx.doi.org/10.1042/BSR20190127
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author Edling, Charlotte E.
Fazmin, Ibrahim T.
Chadda, Karan R.
Ahmad, Shiraz
Valli, Haseeb
Grace, Andrew A.
Huang, Christopher L.-H.
Jeevaratnam, Kamalan
author_facet Edling, Charlotte E.
Fazmin, Ibrahim T.
Chadda, Karan R.
Ahmad, Shiraz
Valli, Haseeb
Grace, Andrew A.
Huang, Christopher L.-H.
Jeevaratnam, Kamalan
author_sort Edling, Charlotte E.
collection PubMed
description Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β(−/−)) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β(−/−) ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β(−/−) genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction.
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spelling pubmed-64704102019-04-26 Ageing in Pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology Edling, Charlotte E. Fazmin, Ibrahim T. Chadda, Karan R. Ahmad, Shiraz Valli, Haseeb Grace, Andrew A. Huang, Christopher L.-H. Jeevaratnam, Kamalan Biosci Rep Research Articles Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β(−/−)) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β(−/−) ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β(−/−) genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction. Portland Press Ltd. 2019-04-17 /pmc/articles/PMC6470410/ /pubmed/30914453 http://dx.doi.org/10.1042/BSR20190127 Text en © 2019 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
Edling, Charlotte E.
Fazmin, Ibrahim T.
Chadda, Karan R.
Ahmad, Shiraz
Valli, Haseeb
Grace, Andrew A.
Huang, Christopher L.-H.
Jeevaratnam, Kamalan
Ageing in Pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
title Ageing in Pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
title_full Ageing in Pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
title_fullStr Ageing in Pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
title_full_unstemmed Ageing in Pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
title_short Ageing in Pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
title_sort ageing in pgc-1β(−/−) mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470410/
https://www.ncbi.nlm.nih.gov/pubmed/30914453
http://dx.doi.org/10.1042/BSR20190127
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