Increased Cardiac PFK-2 Protects Against High-Fat Diet-Induced Cardiomyopathy and Mediates Beneficial Systemic Metabolic Effects

Abstract. The healthy heart adapts to changes in nutrient availability and energy demands. In metabolic diseases like type 2 diabetes (T2D), increased reliance on fatty acids for energy production contributes to mitochondrial dysfunction and cardiomyopathy. A principal regulator of cardiac metabolism is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2), which is a central driver of glycolysis. We hypothesized that increasing PFK-2 activity could mitigate cardiac dysfunction induced by high fat diet (HFD). Wild type (WT) and cardiac-specific transgenic mice expressing PFK-2 (Glyco^Hi) were fed a low fat or HFD for 16-weeks to induce metabolic dysfunction. Metabolic phenotypes were determined by measuring mitochondrial bioenergetics and performing targeted quantitative proteomic and metabolomic analysis. Increasing cardiac PFK-2 had beneficial effects on cardiac and mitochondrial function. Unexpectedly, Glyco^Hi mice also exhibited sex-dependent systemic protection from HFD, including increased glucose homeostasis. These findings support improving glycolysis via PFK-2 activity can mitigate mitochondrial and functional changes that occur with metabolic syndrome. There are two types of data in this upload, proteomics and metabolomics. The proteomics data are raw files acquired on a tsq quantiva triple quadrupole mass spectrometer in the SRM mode at OMRF. Each file is panel of protein assays. Please contact Mike Kinter with questions. The metabolomics data are more processed data files as described in the paper. Please contact Haiwei Gu with questions.