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J Biol Chem. 2019 Sep 27. pii: jbc.RA119.010371. doi: 10.1074/jbc.RA119.010371. [Epub ahead of print]

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

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Oklahoma Medical Research Foundation, United States.
Department of Internal Medicine, Cardiology, UT Southwestern Medical Center, United States.
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, United States.


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 transgenic mouse model of enhanced cardiac glycolysis (GlycoHi) basally and following a short-term (7d) high fat diet (HFD). GlycoHimice 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 pyruvate supported respiration relative to fatty acids. Nevertheless, both wild type and GlycoHi mitochondria had a similar shift towards increased rates of fatty acid supported respiration following HFD. 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 HFD group. 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 GlycoHiHFD group.  These results support a newly identified mechanism whereby the levels of fructose-2,6-bisphosphate promote mitochondrial PDK4 levels and identifies a secondary adaptive response that prevents excessive mitochondrial pyruvate oxidation when glycolysis is sustained after a high fat dietary challenge.


branched chain amino acids; cardiac metabolism; glycolysis; mitochondria; phosphofructokinase; proteomics

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