1. dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.
- Author
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Mhatre, Ketaki N., Murray, Jason D., Flint, Galina, McMillen, Timothy S., Weber, Gerhard, Shakeri, Majid, Tu, An-Yue, Steczina, Sonette, Weiss, Robert, Marcinek, David J., Murry, Charles E., Raftery, Daniel, Tian, Rong, Moussavi-Harami, Farid, and Regnier, Michael
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OXYGEN consumption , *RIBONUCLEOSIDE diphosphate reductase , *TRANSGENIC mice , *HEART metabolism , *OXIDATIVE phosphorylation , *MYOSIN - Abstract
Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ∼1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs. [Display omitted] • Ubiquitylation-resistant variant RRB in a transgenic mice model (TgRRB) elevates dATP in the heart and improves function. • TgRRB-CMs show greater basal oxygen consumption due to changes in myosin state by dATP. • TgRRB-CMs respond to elevated function with higher pools of oxidative metabolites, elevated OXPHOS, FAO, and energy reserve. • Long-term mitochondrial remodeling may occur to accommodate for the higher energy demands of the high functioning TgRRB-CMs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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