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1 Program in Integrative Cardiac Metabolism, Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine, Chicago, IL, USA
2 Department of Clinical Science, Tufts University School of Veterinary Medicine, North Grafton, MA, USA
3 Department of Molecular and Cellular Physiology, Pennsylvania State University Medical School, Hershey, PA, USA
4 Cardiovascular Institute, Department of Cellular and Molecular Medicine, UMDNH, New Jersey Medical School, Newark, NJ, USA
* To whom correspondence should be addressed. E-mail: dougl{at}uic.edu.
Glycolysis supplements energy synthesis at high cardiac workloads, producing not only ATP, but also cytosolic NADHc and pyruvate for oxidative ATP synthesis. Despite adequate
PO2, speculation exist that not all NADHc is oxidized by the mitochondria (MITO), leading to lactate production. In this study we elucidate the mechanism for limited NADHc oxidation and increased lactate production at high workload, despite adequate myocardial blood flow and
oxygenation. Reducing equivalents from glycolysis enter MITO via exchange of mitochondrial 
-ketoglutarate (KG) for cytosolic malate. This exchange was monitored at baseline and high workloads by comparing 13C enrichment between the products of KG oxidation (succinate) and KG efflux from MITO (glutamate). Following general anesthesia, a left thoracotomy was performed on fourteen dogs and [13C-2] acetate was infused into the LAD for 40 min. Ratepressure-product was 9,035 ± 1,972 mmHg.bpm (n=7) at baseline and 21,659 ± 5,266 (n=7) with dobutamine. 13C enrichment of succinate was 57±10% at baseline and 45±13% at elevated workload (NS), confirming oxidation of [13C-2] acetate. However, cytosolic glutamate
enrichment, a marker of NADHc transfer to MITO, was dramatically reduced at high cardiacm workload (11±1%) versus baseline (50±14%, P<0.05). This reduced exchange of 13C from KG to cytosolic glutamate at high work indicates reduced shuttling of cytosolic reducing equivalents into the MITO. Myocardial tissue lactate increased 78%, countering this reduced oxidation of NADHc. The findings elucidate a contributing mechanism to glycolysis outpacing glucose oxidation in the absence of myocardial ischemia.
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