Anaplerotic Flux Into Citric Acid Cycle 4-Carbon Intermediates is Phenotypically Increased in a Murine Model of Heart Failure
Aslan Turer1, Thomas Gillette1, Shawn Burgess2, Craig Malloy2, and Matthew Merritt3
1Cardiology, UT Southwestern Medical Center, Dallas, TX, United States, 2AIRC, UT Southwestern Medical Center, Dallas, TX, United States, 3Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States
Heart failure (HF) was studied using a murine model of
aortic constriction. Hearts were perfused to steady state using [1,6-13C2]glucose,
[1,3-13C2]acetoacetate, and [U-13C]fatty
acids. Substrate selection for acetyl-CoA production was measured using
isotopomer analysis by carbon-13 NMR. A standard model which includes oxidative
flux as well as pyruvate anaplerosis (YPC) via pyruvate carboxylase
or the malic enzyme was evaluated. Inconsistencies in the fits led to proposal
of a more complicated model that also includes anaplerosis through the
succinyl-CoA pathway (Ys), leading to significantly better
fits. We hypothesize that induction of the Ys anaplerotic pathway is phenotypic of HF.
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