Enhancing cardiac glycolysis causes an increase in PDK4 content in response to short-term high-fat diet

Maria F. Newhardt, LAbert Batushansky, Satoshi Matsuzaki, Zachary T. Young, Melinda West, Ngun Cer Chin, Luke I. Szweda, Michael Kinter, Kenneth M. Humphries

Research output: Contribution to journalArticle

Abstract

The healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Metabolic inflexibility, such as occurs with diabetes, increases cardiac reliance on fatty acids to meet energetic demands, and this results in deleterious effects, including mitochondrial dysfunction, that contribute to pathophysiology. Enhancing glucose usage may mitigate metabolic inflexibility and be advantageous under such conditions. Here, we sought to identify how mitochondrial function and cardiac metabolism are affected in a transgenicmousemodelofenhancedcardiac glycolysis (GlycoHi) basally and following a short-term (7-day) high-fat diet (HFD). GlycoHi mice constitutively express an active form of phosphofructokinase-2, resulting in elevated levels of the PFK-1 allosteric activator fructose 2,6-bisphosphate. We report that basally GlycoHi mitochondria exhibit augmented pyruvatesupported respiration relative to fatty acids. Nevertheless, both WTand GlycoHi mitochondria had a similar shift toward increased rates of fatty acid-supported respiration followingHFD.Metabolic profiling by GC-MS revealed distinct features based on both genotype and diet, with a unique increase in branched-chain amino acids in the GlycoHi HFDgroup. Targeted quantitative proteomics analysis also supported both genotype- and diet-dependent changes in protein expression and uncovered an enhanced expression of pyruvate dehydrogenase kinase 4 (PDK4) in the GlycoHi HFD group. These results support a newly identified mechanism whereby the levels of fructose 2,6-bisphosphate promote mitochondrial PDK4 levels and identify a secondary adaptive response that prevents excessive mitochondrial pyruvate oxidation when glycolysis is sustained after a high-fat dietary challenge.

Original languageEnglish (US)
Pages (from-to)16831-16845
Number of pages15
JournalJournal of Biological Chemistry
Volume294
Issue number45
DOIs
Publication statusPublished - Jan 1 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Newhardt, M. F., Batushansky, LA., Matsuzaki, S., Young, Z. T., West, M., Cer Chin, N., ... Humphries, K. M. (2019). Enhancing cardiac glycolysis causes an increase in PDK4 content in response to short-term high-fat diet. Journal of Biological Chemistry, 294(45), 16831-16845. https://doi.org/10.1074/jbc.RA119.010371