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Intracellular sodium elevation reprograms cardiac metabolism

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  • Dunja Aksentijević

    (School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital
    William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square)

  • Anja Karlstaedt

    (Division of Cardiology, McGovern Medical School The University of Texas Health Science Center at Houston)

  • Marina V. Basalay

    (School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital)

  • Brett A. O’Brien

    (School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital)

  • David Sanchez-Tatay

    (School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital)

  • Seda Eminaga

    (School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital)

  • Alpesh Thakker

    (Institute of Metabolism and Systems Research, College of Medical and Dental Sciences University of Birmingham)

  • Daniel A. Tennant

    (Institute of Metabolism and Systems Research, College of Medical and Dental Sciences University of Birmingham)

  • William Fuller

    (Institute of Cardiovascular and Medical Sciences, University of Glasgow)

  • Thomas R. Eykyn

    (School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital)

  • Heinrich Taegtmeyer

    (Division of Cardiology, McGovern Medical School The University of Texas Health Science Center at Houston)

  • Michael J. Shattock

    (School of Cardiovascular and Medical Sciences, British Heart Foundation Centre of Research Excellence, King’s College London, The Rayne Institute, St Thomas’ Hospital)

Abstract

Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 μM ouabain 100 nM blebbistatin) or chronic myocardial Nai load (PLM3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic ‘fingerprint’. Control (PLMWT), transgenic (PLM3SA), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by 23Na, 31P, 13C NMR followed by 1H-NMR metabolomic profiling. Elevated Nai leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorates the metabolic changes. In silico modelling indicates altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Nai overload or inhibition of Na/Camito may be a new approach to ameliorate metabolic dysregulation in heart failure.

Suggested Citation

  • Dunja Aksentijević & Anja Karlstaedt & Marina V. Basalay & Brett A. O’Brien & David Sanchez-Tatay & Seda Eminaga & Alpesh Thakker & Daniel A. Tennant & William Fuller & Thomas R. Eykyn & Heinrich Taeg, 2020. "Intracellular sodium elevation reprograms cardiac metabolism," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18160-x
    DOI: 10.1038/s41467-020-18160-x
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    Cited by:

    1. Chris G. Faulkes & Thomas R. Eykyn & Jan Lj. Miljkovic & James D. Gilbert & Rebecca L. Charles & Hiran A. Prag & Nikayla Patel & Daniel W. Hart & Michael P. Murphy & Nigel C. Bennett & Dunja Aksentije, 2024. "Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Yu Jin Chung & Zoe Hoare & Friedrich Baark & Chak Shun Yu & Jia Guo & William Fuller & Richard Southworth & Doerthe M. Katschinski & Michael P. Murphy & Thomas R. Eykyn & Michael J. Shattock, 2024. "Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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