Open AccessGCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation
Author(s) -
Thapa Dharendra,
Bugga Paramesha,
Mushala Bellina A. S.,
Manning Janet R.,
Stoner Michael W.,
McMahon Brenda,
Zeng Xuemei,
Cantrell Pamela S.,
Yates Nathan,
Xie Bingxian,
Edmunds Lia R.,
Jurczak Michael J.,
Scott Iain
Publication year - 2022
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.15415
Subject(s) - diastole , pyruvate dehydrogenase complex , heart failure , medicine , bioenergetics , ejection fraction , endocrinology , cardiac function curve , acetylation , lysine , mitochondrion , cardiology , biology , biochemistry , enzyme , blood pressure , amino acid , gene
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.