Inhibitory Acetylation of Pyruvate Dehydrogenase Promotes Diastolic Dysfunction in Mice

Thapa, D.; Bugga, P.; Mushala, B. A. S.; Manning, J. R.; Stoner, M. W.; McMahon, B.; Xie, B.; Edmunds, L. R.; Jurczak, M. J.; Scott, I.

doi:10.1101/2021.09.07.459319

bioRxiv · 10.1101/2021.09.07.459319

Inhibitory Acetylation of Pyruvate Dehydrogenase Promotes Diastolic Dysfunction in Mice

Thapa, D.·Bugga, P.·Mushala, B. A. S.·Manning, J. R.·Stoner, M. W.·McMahon, B.·Xie, B.·Edmunds, L. R.·Jurczak, M. J.·Scott, I.

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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 and quantitative acetylproteomics in aged mice to show that inhibitory lysine acetylation of the pyruvate dehydrogenase (PDH) complex promotes energetic deficits and 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.

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Thapa, D., Bugga, P., Mushala, B. A. S., Manning, J. R., Stoner, M. W., McMahon, B., Xie, B., Edmunds, L. R., Jurczak, M. J., Scott, I.. 2021-09-08. Inhibitory Acetylation of Pyruvate Dehydrogenase Promotes Diastolic Dysfunction in Mice. https://doi.org/10.1101/2021.09.07.459319

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