dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.

Autor: Mhatre KN; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Murray JD; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Department of Physiology and Biophysics, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Flint G; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., McMillen TS; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA; Center for Translational Muscle Research, University of Washington, Seattle, WA 98109, USA., Weber G; Division of Cardiology, University of Washington, Seattle, WA 98109, USA., Shakeri M; Division of Cardiology, University of Washington, Seattle, WA 98109, USA., Tu AY; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Steczina S; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Weiss R; Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA., Marcinek DJ; Department of Radiology, University of Washington, Seattle, WA, USA., Murry CE; Division of Cardiology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Raftery D; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA; The Mitochondria and Metabolism Center (MMC), University of Washington, Seattle, WA 98109, USA; Center for Translational Muscle Research, University of Washington, Seattle, WA 98109, USA., Tian R; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA; The Mitochondria and Metabolism Center (MMC), University of Washington, Seattle, WA 98109, USA; Center for Translational Muscle Research, University of Washington, Seattle, WA 98109, USA., Moussavi-Harami F; Division of Cardiology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Center for Translational Muscle Research, University of Washington, Seattle, WA 98109, USA. Electronic address: moussavi@uw.edu., Regnier M; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Department of Physiology and Biophysics, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Center for Translational Muscle Research, University of Washington, Seattle, WA 98109, USA. Electronic address: mregnier@uw.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2023 Feb; Vol. 175, pp. 1-12. Date of Electronic Publication: 2022 Dec 05.
DOI: 10.1016/j.yjmcc.2022.11.010
Abstrakt: 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.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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