Intracellular sodium elevation reprograms cardiac metabolism

Aksentijević, D. et al. (2020) Intracellular sodium elevation reprograms cardiac metabolism. Nature Communications, 11, 4337. (doi: 10.1038/s41467-020-18160-x) (PMID:32859897) (PMCID:PMC7455741)

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.

• Item Type: Articles
• Additional Information: This work was supported by a British Heart Foundation (BHF) Programme Grant (RG/12/4/29426) (M.J.S. and W.F.), KCL BHF Centre of Research Excellence (RE/08/003), the Friede Springer Herz Stiftung (A.K.), the Roderick McDonald Research Fund (15RDM005 to A.K.), the American Heart Association (17POST33660221 to A.K.), NIH (K99-HL141702 to A.K., R01-HL-61483 to H.T.); BHF Intermediate Basic Science Fellowship (FS/16/21/31860) (SE), NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and KCL; the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and Engineering and Physical Sciences Research Council (EPSRC) (WT 088641/Z/09/Z); KCL Comprehensive Cancer Imaging Centre funded by the Cancer Research UK (CRUK) and EPSRC in association with the Medical Research Council (MRC) and the Department of health (DoH). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or DoH. TRE is grateful for support from CRUK and EPSRC in association with MRC and DoH (C1060/A10334).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Fuller, Professor Will
• Authors: Aksentijević, D., Karlstaedt, A., Basalay, M. V., O’Brien, B. A., Sanchez-Tatay, D., Eminaga, S., Thakker, A., Tennant, D. A., Fuller, W., Eykyn, T. R., Taegtmeyer, H., and Shattock, M. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Nature Communications 11: 4337
• Publisher Policy: Reproduced under a Creative Commons License