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Intracellular sodium elevation reprograms cardiac metabolism

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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 Taegtmeyer, Michael Shattock

Original languageEnglish
Article number4337
Number of pages14
JournalNature Communications
Issue number1
Early online date28 Aug 2020
Accepted/In press10 Jul 2020
E-pub ahead of print28 Aug 2020
Published28 Aug 2020


King's Authors


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 Na i load (PLM 3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic ‘fingerprint’. Control (PLM WT), transgenic (PLM 3SA), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by 23Na, 31P, 13C NMR followed by 1H-NMR metabolomic profiling. Elevated Na i 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 Na i overload or inhibition of Na/Ca mito may be a new approach to ameliorate metabolic dysregulation in heart failure.

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