Modeling of Oxygen Transport and Cellular Energetics Explains Observations on In Vivo Cardiac Energy Metabolism

Daniel A Beard,Peter Hunter

doi:10.1371/journal.pcbi.0020107

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 F0F1-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 μmol per minute per gram of tissue. At work rates corresponding to oxygen consumption higher than 12 μmol min−1 g−1, 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.

Highlights

Over 30 years ago, Neely et al [1] showed that adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) concentrations are maintained at essentially constant concentrations with changes in cardiac work in the isolated perfused heart
able to explain a set of data
that has persisted unexplained in the literature for two decades

Summary

Introduction

Over 30 years ago, Neely et al [1] showed that adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) concentrations are maintained at essentially constant concentrations with changes in cardiac work in the isolated perfused heart. Balaban et al [2] observed that energetic phosphate concentrations measured in vivo using NMR spectroscopy remain effectively constant over a range of cardiac workloads These observations contradicted earlier models of the control of mitochondrial metabolism, which assumed that the rate of oxidative phosphorylation was regulated primarily by the availability of ADP [3,4]. A credible validated biophysical model of the in vivo regulation of oxidative phosphorylation that explains the observed phenomena has not been established Such a model would provide a theoretical basis for understanding how mitochondrial metabolism is regulated in response to changing ATP turnover rate while maintaining homeostatic concentrations of ATP, ADP, and CrP. Such a model would form the basis of quantitative studies of the regulation of phosphate metabolites oxidative phosphorylation in the failing heart and other pathophysiological situations [6]

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Conclusion