Increasing Glycolysis Protects Cardiac Function Against High Fat Diet‐Induced Cardiomyopathy

Abstract

The healthy heart has a dynamic capacity to respond and adapt to changes in both nutrient availability and energy demands. This metabolic flexibility is critical for the maintenance of proper tissue function and its disruption has deleterious effects on the heart. For example, a signature characteristic of diabetic cardiomyopathy is metabolic inflexibility whereby the heart increases reliance on fatty acids to meet energetic demands. We hypothesize that increased rates of glycolysis can restore metabolic flexibility and mitigate cardiac dysfunction in the diabetic heart. Our objective was to examine how the heart coordinates changes in metabolic flexibility under normal and pro-glycolytic conditions. Wild type (WT) and transgenic mice with cardiac-specific increased glucose utilization (GlycoHi) were fed a low fat (LFD) or a high fat diet (HFD) for 16 weeks to induce the metabolic inflexibility seen in type 2 diabetes. Metabolic profiles were determined by measuring mitochondrial respiration and targeted quantitative proteomic and metabolomic analysis. Echocardiography was used to assess cardiac function. Heart mitochondria from GlycoHi mice on LFD exhibited increased rates of glucose-substrate supported respiration compared to WT/LFD. Mitochondria of both groups on HFD exhibited increased fatty acid-supported respiration. However, GlycoHi mitochondria showed a decrease in fatty acid reliance compared to WT. Quantitative proteomics data further supported that GlycoHi hearts have resistance to HFD induced metabolic inflexibility. Increasing glycolysis also had beneficial effects on cardiac function. Echocardiography analysis revealed a decrease of diastolic function in WT/HFD that was not seen in GlycoHi/HFD hearts. In this study, mitochondrial function analysis showed a resistance in GlycoHi mitochondria to the HFD induced metabolic changes seen in WT/HFD. Echocardiography analysis suggests cardio-protection against a HFD in GlycoHi hearts. Together these results provide strong evidence that increasing glucose usage in diabetic hearts can be protective against cardiomyopathy.