dATP elevation induces myocardial metabolic remodeling to support improved cardiac function

J Mol Cell Cardiol. 2023 Feb:175:1-12. doi: 10.1016/j.yjmcc.2022.11.010. Epub 2022 Dec 5.

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.

Keywords: Cardiomyocyte metabolism; Contraction; DRX; Mitochondrial remodeling; dATP; myosin activator.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Retracted Publication

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Mice
  • Mice, Transgenic
  • Myocardial Contraction
  • Myocardium* / metabolism
  • Myocytes, Cardiac / metabolism
  • Myosins / metabolism
  • Ribonucleotide Reductases* / metabolism
  • Ribonucleotide Reductases* / pharmacology

Substances

  • Ribonucleotide Reductases
  • Adenosine Triphosphate
  • Myosins