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1 Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Center for Modeling Integrated Metabolic System, Cleveland, Oh, USA
2 Pediatrics, Case Western Reserve University, Cleveland, OH, USA; Center for Modeling Integrated Metabolic System, Cleveland, Oh, USA
3 Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA; Center for Modeling Integrated Metabolic System, Cleveland, Oh, USA
4 Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA; Pediatrics, Case Western Reserve University, Cleveland, OH, USA
* To whom correspondence should be addressed. E-mail: mec6{at}cwru.edu.
A new multi-domain 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 inter-domain 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 to experimental data from anesthetized pigs. Simulations with previous model without compartmentation showed a slow activation of glycogen breakdown and delayed lactate production compared to experimental results. The addition of a subdomain for glycolysis to the model 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 similar dynamic response of mitochondrial redox state and the rate of pyruvate oxidation during ischemia. In contrast, 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.
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