Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice

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dc.contributor.authorCortassa, S.
dc.contributor.authorCaceres, V.
dc.contributor.authorTocchetti, C.G.
dc.contributor.authorBernier, M.
dc.contributor.authorde Cabo, R.
dc.contributor.authorPaolocci, N.
dc.contributor.authorSollott, S.J.
dc.contributor.authorAon, M.A.
dc.date.issued2020
dc.description.abstractType-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose, rescuing β-adrenergic-stimulated cardiac excitation– contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic db/db mice subjected to stress given by β-adrenergic stimulation with isoproterenol and high glucose compared to their non-diabetic controls (+/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics–fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart’s central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are 2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced β-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g. polyol) while maintaining the flux through redox-generating pathways together with glucose–FA ‘shared fuelling’ of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload.
dc.description.statementofresponsibilitySonia Cortassa, Viviane Caceres, Carlo G. Tocchetti, Michel Bernier, Rafael de Cabo, Nazareno Paolocci, Steven J. Sollott, and Miguel A. Aon
dc.identifier.citationJournal of Physiology, 2020; 598(7):1393-1415
dc.identifier.doi10.1113/JP276824
dc.identifier.issn0022-3751
dc.identifier.issn1469-7793
dc.identifier.orcidMundy, L. [0000-0002-7874-4232]
dc.identifier.orcidMaddern, G. [0000-0003-2064-181X]
dc.identifier.urihttps://hdl.handle.net/2440/145960
dc.language.isoen
dc.publisherWILEY
dc.rights© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society
dc.source.urihttp://dx.doi.org/10.1113/jp276824
dc.subjectfluxomics; metabolomics; diabetic cardiomyopathy
dc.subject.meshMyocardium
dc.subject.meshHeart
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshDiabetes Mellitus, Experimental
dc.subject.meshDiabetes Mellitus, Type 2
dc.subject.meshGlucose
dc.subject.meshFatty Acids
dc.subject.meshOxidation-Reduction
dc.titleMetabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice
dc.typeJournal article
pubs.publication-statusPublished

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