GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation
Abstract Left ventricular diastolic dysfunction is a structural and functional condition that precedes the development of heart failure with preserved ejection fraction (HFpEF). The etiology of diastolic dysfunction includes alterations in fuel substrate metabolism that negatively impact cardiac bio...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-08-01
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| Series: | Physiological Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.14814/phy2.15415 |
| _version_ | 1797397283826827264 |
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| author | Dharendra Thapa Paramesha Bugga Bellina A. S. Mushala Janet R. Manning Michael W. Stoner Brenda McMahon Xuemei Zeng Pamela S. Cantrell Nathan Yates Bingxian Xie Lia R. Edmunds Michael J. Jurczak Iain Scott |
| author_facet | Dharendra Thapa Paramesha Bugga Bellina A. S. Mushala Janet R. Manning Michael W. Stoner Brenda McMahon Xuemei Zeng Pamela S. Cantrell Nathan Yates Bingxian Xie Lia R. Edmunds Michael J. Jurczak Iain Scott |
| author_sort | Dharendra Thapa |
| collection | DOAJ |
| description | Abstract Left ventricular diastolic dysfunction is a structural and functional condition that precedes the development of heart failure with preserved ejection fraction (HFpEF). The etiology of diastolic dysfunction includes alterations in fuel substrate metabolism that negatively impact cardiac bioenergetics, and may precipitate the eventual transition to heart failure. To date, the molecular mechanisms that regulate early changes in fuel metabolism leading to diastolic dysfunction remain unclear. In this report, we use a diet‐induced obesity model in aged mice to show that inhibitory lysine acetylation of the pyruvate dehydrogenase (PDH) complex promotes energetic deficits that may contribute to the development of diastolic dysfunction in mouse hearts. Cardiomyocyte‐specific deletion of the mitochondrial lysine acetylation regulatory protein GCN5L1 prevented hyperacetylation of the PDH complex subunit PDHA1, allowing aged obese mice to continue using pyruvate as a bioenergetic substrate in the heart. Our findings suggest that changes in mitochondrial protein lysine acetylation represent a key metabolic component of diastolic dysfunction that precedes the development of heart failure. |
| first_indexed | 2024-03-09T01:08:39Z |
| format | Article |
| id | doaj.art-6a55ab8d84e5441b8d4eb92811819642 |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-09T01:08:39Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-6a55ab8d84e5441b8d4eb928118196422023-12-11T09:10:41ZengWileyPhysiological Reports2051-817X2022-08-011015n/an/a10.14814/phy2.15415GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidationDharendra Thapa0Paramesha Bugga1Bellina A. S. Mushala2Janet R. Manning3Michael W. Stoner4Brenda McMahon5Xuemei Zeng6Pamela S. Cantrell7Nathan Yates8Bingxian Xie9Lia R. Edmunds10Michael J. Jurczak11Iain Scott12Division of Exercise Physiology West Virginia University School of Medicine Morgantown West Virginia USAVascular Medicine Institute Pittsburgh Pennsylvania USAVascular Medicine Institute Pittsburgh Pennsylvania USAVascular Medicine Institute Pittsburgh Pennsylvania USAVascular Medicine Institute Pittsburgh Pennsylvania USAVascular Medicine Institute Pittsburgh Pennsylvania USABiomedical Mass Spectrometry Center, Schools of the Health Sciences University of Pittsburgh Pittsburgh Pennsylvania USABiomedical Mass Spectrometry Center, Schools of the Health Sciences University of Pittsburgh Pittsburgh Pennsylvania USABiomedical Mass Spectrometry Center, Schools of the Health Sciences University of Pittsburgh Pittsburgh Pennsylvania USACenter for Metabolism and Mitochondrial Medicine, Department of Medicine University of Pittsburgh Pittsburgh Pennsylvania USACenter for Metabolism and Mitochondrial Medicine, Department of Medicine University of Pittsburgh Pittsburgh Pennsylvania USACenter for Metabolism and Mitochondrial Medicine, Department of Medicine University of Pittsburgh Pittsburgh Pennsylvania USAVascular Medicine Institute Pittsburgh Pennsylvania USAAbstract Left ventricular diastolic dysfunction is a structural and functional condition that precedes the development of heart failure with preserved ejection fraction (HFpEF). The etiology of diastolic dysfunction includes alterations in fuel substrate metabolism that negatively impact cardiac bioenergetics, and may precipitate the eventual transition to heart failure. To date, the molecular mechanisms that regulate early changes in fuel metabolism leading to diastolic dysfunction remain unclear. In this report, we use a diet‐induced obesity model in aged mice to show that inhibitory lysine acetylation of the pyruvate dehydrogenase (PDH) complex promotes energetic deficits that may contribute to the development of diastolic dysfunction in mouse hearts. Cardiomyocyte‐specific deletion of the mitochondrial lysine acetylation regulatory protein GCN5L1 prevented hyperacetylation of the PDH complex subunit PDHA1, allowing aged obese mice to continue using pyruvate as a bioenergetic substrate in the heart. Our findings suggest that changes in mitochondrial protein lysine acetylation represent a key metabolic component of diastolic dysfunction that precedes the development of heart failure.https://doi.org/10.14814/phy2.15415acetylationdiastolic dysfunctionheart failuremitochondriapyruvate dehydrogenase |
| spellingShingle | Dharendra Thapa Paramesha Bugga Bellina A. S. Mushala Janet R. Manning Michael W. Stoner Brenda McMahon Xuemei Zeng Pamela S. Cantrell Nathan Yates Bingxian Xie Lia R. Edmunds Michael J. Jurczak Iain Scott GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation Physiological Reports acetylation diastolic dysfunction heart failure mitochondria pyruvate dehydrogenase |
| title | GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation |
| title_full | GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation |
| title_fullStr | GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation |
| title_full_unstemmed | GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation |
| title_short | GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation |
| title_sort | gcn5l1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation |
| topic | acetylation diastolic dysfunction heart failure mitochondria pyruvate dehydrogenase |
| url | https://doi.org/10.14814/phy2.15415 |
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