Journal Article

Intracellular sodium elevation reprograms cardiac metabolism

Tennant, Daniel A., O’Brien, Brett A., Eminaga, Seda, Shattock, Michael J., Taegtmeyer, Heinrich, Aksentijević, Dunja, Karlstaedt, Anja, Sanchez-Tatay, David, Thakker, Alpesh, Fuller, William, Basalay, Marina V., Eykyn, Thomas R.

2020

Overview

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 23 Na, 31 P, 13 C NMR followed by 1 H-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. The failing heart is characterised by both alterations in mitochondrial metabolism and an elevation of cytosolic sodium. Here, the authors use 23 Na NMR and metabolic profiling to show these are related, and that elevation in intracellular Na reprograms cardiac substrate utilisation via effects on mitochondrial Na/Ca exchange.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/58 / 101/6 / 13/1 / 14 / 38/77 / 631/443/319/333/1465 / 631/443/592/75 / 631/45/320 / 631/80/304 / 64 / 64/60 / 64/86 / 96 / Amino acids / Animals / Calcium / Carbohydrate metabolism / Carbohydrates / Cellular Reprogramming - physiology / Congestive heart failure / Cytoplasm - metabolism / Disease Models, Animal / Energy Metabolism / Fatty acids / Fluxes / Gene Knock-In Techniques / Glycolysis / Heart / Heart Failure - metabolism / Humanities and Social Sciences / Hypertrophy / Intermediates / Intracellular / Isolated Heart Preparation / Krebs cycle / Male / Metabolic Diseases - metabolism / Metabolism / Metabolites / Metabolomics / Mice / Mice, Inbred C57BL / Mice, Knockout / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / multidisciplinary / Myocardium - metabolism / Na+/Ca2+ exchanger / NMR / Nuclear magnetic resonance / Ouabain / Rats / Rats, Wistar / Science / Science (multidisciplinary) / Sodium / Sodium - blood / Sodium - metabolism / Sodium-Calcium Exchanger - drug effects / Substrates / Thiazepines - pharmacology / Tricarboxylic acid cycle