Intracellular sodium elevation reprograms cardiac metabolism

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

doi:10.1038/s41467-020-18160-x

Intracellular sodium elevation reprograms cardiac metabolism

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

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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 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.

Original language	English
Article number	4337
Number of pages	14
Journal	Nature Communications
Volume	11
Issue number	1
Early online date	28 Aug 2020
DOIs	https://doi.org/10.1038/s41467-020-18160-x
Publication status	Published - 28 Aug 2020

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Intracellular sodium elevation reprograms_AKSENTIJEVIC_Acc10Jul2020Epub28Aug2020_GOLD VoR (CC BY)Final published version, 2.02 MBLicence: CC BY

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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 Na i load (PLM 3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic {\textquoteleft}fingerprint{\textquoteright}. 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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AU - Sanchez-Tatay, David

AU - Eminaga, Seda

AU - Thakker, Alpesh

AU - Tennant, Daniel A.

AU - Fuller, William

AU - Eykyn, Thomas R

AU - Taegtmeyer, Heinrich

AU - Shattock, Michael

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Intracellular sodium elevation reprograms cardiac metabolism

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