Intracellular sodium elevation reprograms cardiac metabolism
| Autor: | Heinrich Taegtmeyer, Seda Eminaga, David Sanchez-Tatay, William Fuller, Michael J. Shattock, Thomas R. Eykyn, Dunja Aksentijevic, Marina Basalay, Alpesh Thakker, Anja Karlstaedt, Brett A. O’Brien, Daniel A. Tennant |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cytoplasm Thiazepines Metabolite General Physics and Astronomy 02 engineering and technology Ouabain Mice chemistry.chemical_compound Glycolysis Gene Knock-In Techniques lcsh:Science Mice Knockout Multidisciplinary Chemistry Heart Cellular Reprogramming 021001 nanoscience & nanotechnology Mitochondria Mechanisms of disease Cardiovascular diseases 0210 nano-technology Intracellular medicine.drug medicine.medical_specialty Science Carbohydrate metabolism Sodium-Calcium Exchanger Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Metabolic Diseases Internal medicine medicine Animals Metabolomics Rats Wistar Heart Failure Myocardium Sodium Isolated Heart Preparation Hypertrophy Energy metabolism General Chemistry Metabolism Rats Mice Inbred C57BL Citric acid cycle Disease Models Animal Cytosol 030104 developmental biology Endocrinology lcsh:Q |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications 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 & Shattock, M 2020, ' Intracellular sodium elevation reprograms cardiac metabolism ', Nature Communications, vol. 11, no. 1, 4337 . https://doi.org/10.1038/s41467-020-18160-x |
| ISSN: | 2041-1723 |
| Popis: | 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. The failing heart is characterised by both alterations in mitochondrial metabolism and an elevation of cytosolic sodium. Here, the authors use 23Na 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. |
| Databáze: | OpenAIRE |
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