Cargando…

Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome

Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the TAFAZZIN gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA...

Descripción completa

Detalles Bibliográficos
Autores principales: Greenwell, Amanda A., Tabatabaei Dakhili, Seyed Amirhossein, Gopal, Keshav, Saed, Christina T., Chan, Jordan S. F., Kazungu Mugabo, Nick, Zhabyeyev, Pavel, Eaton, Farah, Kruger, Jennifer, Oudit, Gavin Y., Ussher, John R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9537754/
https://www.ncbi.nlm.nih.gov/pubmed/36211560
http://dx.doi.org/10.3389/fcvm.2022.997352
_version_ 1784803272418131968
author Greenwell, Amanda A.
Tabatabaei Dakhili, Seyed Amirhossein
Gopal, Keshav
Saed, Christina T.
Chan, Jordan S. F.
Kazungu Mugabo, Nick
Zhabyeyev, Pavel
Eaton, Farah
Kruger, Jennifer
Oudit, Gavin Y.
Ussher, John R.
author_facet Greenwell, Amanda A.
Tabatabaei Dakhili, Seyed Amirhossein
Gopal, Keshav
Saed, Christina T.
Chan, Jordan S. F.
Kazungu Mugabo, Nick
Zhabyeyev, Pavel
Eaton, Farah
Kruger, Jennifer
Oudit, Gavin Y.
Ussher, John R.
author_sort Greenwell, Amanda A.
collection PubMed
description Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the TAFAZZIN gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA mediated knockdown of Tafazzin (TazKD mice), myocardial glucose oxidation rates were markedly reduced, likely secondary to an impairment in the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. Furthermore, TazKD mice exhibited cardiac hypertrophy with minimal cardiac dysfunction. Because the stimulation of myocardial glucose oxidation has been shown to alleviate diabetic cardiomyopathy and heart failure, we hypothesized that stimulating PDH activity would alleviate the cardiac hypertrophy present in TazKD mice. In order to address our hypothesis, 6-week-old male TazKD mice and their wild-type (WT) littermates were treated with dichloroacetate (DCA; 70 mM in the drinking water), which stimulates PDH activity via inhibiting PDH kinase to prevent inhibitory phosphorylation of PDH. We utilized ultrasound echocardiography to assess cardiac function and left ventricular wall structure in all mice prior to and following 6-weeks of treatment. Consistent with systemic activation of PDH and glucose oxidation, DCA treatment improved glycemia in both TazKD mice and their WT littermates, and decreased PDH phosphorylation equivalently at all 3 of its inhibitory sites (serine 293/300/232). However, DCA treatment had no impact on left ventricular structure, or systolic and diastolic function in TazKD mice. Therefore, it is unlikely that stimulating glucose oxidation is a viable target to improve BTHS-related cardiomyopathy.
format Online
Article
Text
id pubmed-9537754
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-95377542022-10-08 Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome Greenwell, Amanda A. Tabatabaei Dakhili, Seyed Amirhossein Gopal, Keshav Saed, Christina T. Chan, Jordan S. F. Kazungu Mugabo, Nick Zhabyeyev, Pavel Eaton, Farah Kruger, Jennifer Oudit, Gavin Y. Ussher, John R. Front Cardiovasc Med Cardiovascular Medicine Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the TAFAZZIN gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA mediated knockdown of Tafazzin (TazKD mice), myocardial glucose oxidation rates were markedly reduced, likely secondary to an impairment in the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. Furthermore, TazKD mice exhibited cardiac hypertrophy with minimal cardiac dysfunction. Because the stimulation of myocardial glucose oxidation has been shown to alleviate diabetic cardiomyopathy and heart failure, we hypothesized that stimulating PDH activity would alleviate the cardiac hypertrophy present in TazKD mice. In order to address our hypothesis, 6-week-old male TazKD mice and their wild-type (WT) littermates were treated with dichloroacetate (DCA; 70 mM in the drinking water), which stimulates PDH activity via inhibiting PDH kinase to prevent inhibitory phosphorylation of PDH. We utilized ultrasound echocardiography to assess cardiac function and left ventricular wall structure in all mice prior to and following 6-weeks of treatment. Consistent with systemic activation of PDH and glucose oxidation, DCA treatment improved glycemia in both TazKD mice and their WT littermates, and decreased PDH phosphorylation equivalently at all 3 of its inhibitory sites (serine 293/300/232). However, DCA treatment had no impact on left ventricular structure, or systolic and diastolic function in TazKD mice. Therefore, it is unlikely that stimulating glucose oxidation is a viable target to improve BTHS-related cardiomyopathy. Frontiers Media S.A. 2022-09-23 /pmc/articles/PMC9537754/ /pubmed/36211560 http://dx.doi.org/10.3389/fcvm.2022.997352 Text en Copyright © 2022 Greenwell, Tabatabaei Dakhili, Gopal, Saed, Chan, Kazungu Mugabo, Zhabyeyev, Eaton, Kruger, Oudit and Ussher. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Greenwell, Amanda A.
Tabatabaei Dakhili, Seyed Amirhossein
Gopal, Keshav
Saed, Christina T.
Chan, Jordan S. F.
Kazungu Mugabo, Nick
Zhabyeyev, Pavel
Eaton, Farah
Kruger, Jennifer
Oudit, Gavin Y.
Ussher, John R.
Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome
title Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome
title_full Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome
title_fullStr Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome
title_full_unstemmed Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome
title_short Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome
title_sort stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human barth syndrome
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9537754/
https://www.ncbi.nlm.nih.gov/pubmed/36211560
http://dx.doi.org/10.3389/fcvm.2022.997352
work_keys_str_mv AT greenwellamandaa stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT tabatabaeidakhiliseyedamirhossein stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT gopalkeshav stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT saedchristinat stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT chanjordansf stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT kazungumugabonick stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT zhabyeyevpavel stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT eatonfarah stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT krugerjennifer stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT ouditgaviny stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome
AT ussherjohnr stimulatingmyocardialpyruvatedehydrogenaseactivityfailstoalleviatecardiacabnormalitiesinamousemodelofhumanbarthsyndrome