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

Abstract

Key points Hearts from type 2 diabetic animals display perturbations in excitation–contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and β‐adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic redirection leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to designing novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients. Abstract Type‐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.

Diabetes Increases the Vulnerability of the Cardiac Mitochondrial Network to Criticality

“…Metabolic substrates influence the dynamic behavior of the mitochondrial cardiac network by altering its catabolic pathways and the ROS/redox balance (Kurz et al, 2015). In this regard, recent work showed that in intact heart under glucose excess, acute palmitate addition elicits metabolic remodeling leading to enhanced redox status, which is linked to improved contractility/relaxation in diabetic db/db mice, compared to their non-diabetic controls, when subjected to stress given by β-adrenergic stimulation with isoproterenol (Cortassa et al, 2018). Consequently, the concurrent effects of the abovementioned diabetic conditions increase the likelihood of mitochondrial criticality.…”

Integration of mitochondrial energetics in heart with mathematical modelling

“…Then the methodology was extended to analyse fatty acid catabolic pathways, substrate movements, and ROS generation, to clarify metabolic characteristics in type 1 and type 2 diabetes model animals (Cortassa et al . 2017, 2018). The involvement of both the fatty acid oxidation pathway and the glucose oxidation pathway enables evaluation of the effects of switching substrate utilization, as often occurs under diseased states.…”

Mechanics and energetics in cardiac arrhythmias and heart failure

“…Cortassa et al . (2020) investigated type‐2 diabetes (T2DM) induced metabolic remodelling of glucose, fatty acid and redox pathways that lead to HF. Previous data showed that palmitate or glutathione can preserve mitochondrial energy/redox balance and rescue β‐adrenergic‐stimulated cardiac excitation‐contraction coupling.…”

“…Their findings add to an emerging view on how mutations or defects in structural proteins, possibly involved in mechanotransduction, could affect mitochondria ATP production and DMD-related cardiac cardiomyopathy. Cortassa et al (2020) investigated type-2 diabetes (T2DM) induced metabolic remodelling of glucose, fatty acid and redox pathways that lead to HF. Previous data showed that palmitate or glutathione can preserve mitochondrial energy/redox balance and rescue β-adrenergic-stimulated cardiac excitation-contraction coupling.…”