Beard Daniel A
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
PLoS Comput Biol. 2006 Sep 15;2(9):e107. doi: 10.1371/journal.pcbi.0020107. Epub 2006 Jul 10.
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 mumol per minute per gram of tissue. At work rates corresponding to oxygen consumption higher than 12 mumol 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.
关于心脏工作率与能量代谢物三磷酸腺苷（ATP）、二磷酸腺苷（ADP）和磷酸肌酸（CrP）水平之间关系的观察结果，尚未得到心脏能量代谢理论模型的满意解释。具体而言，ATP、ADP和CrP水平在体内对工作和呼吸率变化的稳定性仍未得到解释。在此，一个先前基于从分离的心脏线粒体获得的数据开发的线粒体氧化磷酸化模型，与心肌中氧运输的空间分布模型相结合，以分析过去二十年中从多个实验室获得的数据。该模型在线粒体水平包括呼吸链、F0F1 - ATP酶、腺嘌呤核苷酸转位酶和线粒体磷酸盐转运体的组成部分；细胞质中的腺苷酸激酶、肌酸激酶和ATP消耗；以及毛细血管、组织间液和心肌细胞之间的氧运输。该整合模型能够重现犬心脏在一系列工作负荷下以及冠状动脉灌注不足期间ATP、ADP、CrP和无机磷酸盐水平的实验观察结果，并预测在心脏氧消耗速率小于或等于约每分钟每克组织12微摩尔的工作负荷下，细胞质无机磷酸盐水平是线粒体呼吸速率的关键调节因子。在对应于高于12微摩尔·分钟⁻¹·克⁻¹氧消耗的工作率下，模型预测偏离实验数据，表明在高工作率下，目前未纳入模型的其他调节机制可能很重要。然而，该整合模型解释了在低至中等工作负荷下观察到的代谢物水平以及在分级灌注不足期间观察到的代谢物水平和组织氧合的变化。这些发现表明，观察到的能量代谢物的稳定性是心脏底物运输和线粒体代谢的正确构建模型的一个特性。此外，经过验证的模型提供了心脏缺血期间磷酸盐代谢物变化的定量预测。
