Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects

Maria F Mendez Garcia; Satoshi Matsuzaki; Albert Batushansky; Ryan Newhardt; Caroline Kinter; Yan Jin; Shivani N Mann; Michael B Stout; Haiwei Gu; Ying Ann Chiao; Michael Kinter; Kenneth M Humphries

doi:10.1016/j.isci.2023.107131

Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects

iScience. 2023 Jun 15;26(7):107131. doi: 10.1016/j.isci.2023.107131. eCollection 2023 Jul 21.

Authors

Maria F Mendez Garcia^{1

2}, Satoshi Matsuzaki¹, Albert Batushansky^{1

3}, Ryan Newhardt¹, Caroline Kinter¹, Yan Jin⁴, Shivani N Mann², Michael B Stout¹, Haiwei Gu⁴, Ying Ann Chiao¹, Michael Kinter¹, Kenneth M Humphries^{1

2}

Affiliations

¹ Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
² Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³ Ilse Katz Institute for Nanoscale Science & Technology, Ben-Gurion University of the Negev, Beer Sheva, Israel.
⁴ Center for Translational Science, Florida International University, Port St. Lucie, FL, USA.

Abstract

A 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.

Keywords: Metabolomics; Molecular biology; Physiology; Proteomics.

Abstract

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