Mechanistic model of cardiac energy metabolism predicts localization of glycolysis to cytosolic subdomain during ischemia.
A new multidomain mathematical model of cardiac cellular metabolism was developed to simulate metabolic responses to reduced myocardial blood flow. The model is based on mass balances and reaction kinetics that describe transport and metabolic processes of 31 key chemical species in cardiac tissue. The model has three distinct domains (blood, cytosol, and mitochondria) with interdomain transport of chemical species. In addition to distinguishing between cytosol and mitochondria, the model includes a subdomain in the cytosol to account for glycolytic metabolic channeling. Myocardial ischemia was induced by a 60% reduction in coronary blood flow, and model simulations were compared with experimental data from anesthetized pigs. Simulations with a previous model without compartmentation showed a slow activation of glycogen breakdown and delayed lactate production compared with experimental results. The addition of a subdomain for glycolysis resulted in simulations showing faster rates of glycogen breakdown and lactate production that closely matched in vivo experimental data. The dynamics of redox (NADH/NAD+) and phosphorylation (ADP/ATP) states were also simulated. These controllers are coupled to energy transfer reactions and play key regulatory roles in the cytosol and mitochondria. Simulations showed a similar dynamic response of the mitochondrial redox state and the rate of pyruvate oxidation during ischemia. In contrast, the cytosolic redox state displayed a time response similar to that of lactate production. In conclusion, this novel mechanistic model effectively predicted the rapid activation of glycogen breakdown and lactate production at the onset of ischemia and supports the concept of localization of glycolysis to a subdomain of the cytosol.
Zhou
Lufang
L
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106-6011, USA.
Salem
Jennifer E
JE
Saidel
Gerald M
GM
Stanley
William C
WC
Cabrera
Marco E
ME
D003198:Computer Simulation; D003600:Cytosol / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D006019:Glycolysis / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction