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.
Show 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.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- A Slc5a6 Deficient Mouse Model Reveals a Metabolically Driven Dilated Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention 94%
- Genome-Wide DNA Methylation Profiling of the Failing Human Heart with Mechanical Unloading Identifies LINC00881 as an Essential Regulator of Calcium Handling in the Cardiomyocyte 93%
- Genetic Inhibition of Serum Glucocorticoid Kinase 1 Prevents Obesity-related Atrial Fibrillation 93%
Similar papers in this journal
- SIRT2 inhibition protects against cardiac hypertrophy and heart failure 94%
- A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8 94%
- Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function and prevents sudden arrhythmic death in failing hearts 94%
Similar papers in this journal
- Relative contributions of correcting the diet and voluntary exercise to myocardial recovery in a two-hit murine model of heart failure with preserved ejection fraction. 94%
- S100A1's single cysteine is an indispensable redox-switch for the protection against diastolic calcium leakage in cardiomyocytes 94%
- Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis 93%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.