Integrated Computational Modeling of Oxygen Transport and Cellular Energetics Explains Observations on In Vivo Cardiac Oxygen Consumption and Energy Metabolites

Abstract

Observations on the relationship between cardiac work rate and the levels of energy metabolites adenosine triphosphate (ATP), adenosine diphosphate (ADP), and phosphocreatine (CrP) have not been satisfactorily explained by theoretical models of cardiac energy metabolism. Specifically, the in vivo stability of ATP, ADP, and CrP levels in response to changes in work and respiratory rate has eluded explanation. Here a previously developed model of mitochondrial oxidative phosphorylation, which was developed based on data obtained from isolated cardiac mitochondria, is integrated with a spatially distributed model of oxygen transport in the myocardium to analyze data obtained from several laboratories over the past two decades. The model includes the components of the respiratory chain, the F 0 F 1 -ATPase, adenine nucleotide translocase, and the mitochondrial phosphate transporter at the mitochondrial level; adenylate kinase, creatine kinase, and ATP consumption in the cytoplasm; and oxygen transport between capillaries, interstitial fluid, and cardiomyocytes. The integrated model is able to reproduce experimental observations on ATP, ADP, CrP, and inorganic phosphate levels in canine hearts over a range of workload and during coronary hypoperfusion and predicts that cytoplasmic inorganic phosphate level is a key regulator of the rate of mitochondrial respiration at workloads for which the rate of cardiac oxygen consumption is less than or equal to approximately 12 lmol per minute per gram of tissue. At work rates corresponding to oxygen consumption higher than 12 lmol min À1 g À1, model predictions deviate from the experimental data, indicating that at high work rates, additional regulatory mechanisms that are not currently incorporated into the model may be important. Nevertheless, the integrated model explains metabolite levels observed at low to moderate workloads and the changes in metabolite levels and tissue oxygenation observed during graded hypoperfusion. These findings suggest that the observed stability of energy metabolites emerges as a property of a properly constructed model of cardiac substrate transport and mitochondrial metabolism. In addition, the validated model provides quantitative predictions of changes in phosphate metabolites during cardiac ischemia.

Oxidative ATP synthesis in skeletal muscle is controlled by substrate feedback

“…The cell is divided into cytoplasmic and mitochondrial compartments; the variables simulated within the compartments are listed in Table 1, with a brief description of the variables and units associated with each variable. The computational model for cellular energetics and oxidative phosphorylation is derived from recently published computational models developed for cardiac mitochondria (4) and cardiomyocytes (5). A complete description of the computational model is provided in the APPENDIX.…”

“…Thus, to maintain the free energy state of the cytoplasmic phosphoenergetic compounds ATP, ADP, and P i , oxidative phosphorylation is modulated to match the rate of ATP utilization during exercise. It has recently been shown through computational model-based analysis of data obtained from 31 P-NMR spectroscopy of working in vivo dog hearts that the primary control mechanism operating in cardiomyocytes is feedback of substrate concentrations for ATP synthesis (5). In other words, changes in the concentrations of the products generated by the utilization of ATP in the cell, ADP and P i , effect changes in the rate at which mitochondria utilize those products to resynthesize ATP (5).…”