Systems-level computational modeling demonstrates fuel selection switching in high capacity running and low capacity running rats

High capacity and low capacity running rats, HCR and LCR respectively, have been bred to represent two extremes of running endurance and have recently demonstrated disparities in fuel usage during transient aerobic exercise. HCR rats can maintain fatty acid (FA) utilization throughout the course of transient aerobic exercise whereas LCR rats rely predominantly on glucose utilization. We hypothesized that the difference between HCR and LCR fuel utilization could be explained by a difference in mitochondrial density. To test this hypothesis and to investigate mechanisms of fuel selection, we used a constraint-based kinetic analysis of whole-body metabolism to analyze transient exercise data from these rats. Our model analysis used a thermodynamically constrained kinetic framework that accounts for glycolysis, the TCA cycle, and mitochondrial FA transport and oxidation. The model can effectively match the observed relative rates of oxidation of glucose versus FA, as a function of ATP demand. In searching for the minimal differences required to explain metabolic function in HCR versus LCR rats, it was determined that the whole-body metabolic phenotype of LCR, compared to the HCR, could be explained by a ~50% reduction in total mitochondrial activity with an additional 5-fold reduction in mitochondrial FA transport activity. Finally, we postulate that over sustained periods of exercise that LCR can partly overcome the initial deficit in FA catabolic activity by upregulating FA transport and/or oxidation processes.

高耐力与低耐力长跑大鼠（分别记为HCR与LCR）均经过选育以代表长跑耐力的两个极端表型，且近期研究显示二者在一过性有氧运动中的燃料利用模式存在显著差异。HCR大鼠可在一过性有氧运动全程维持脂肪酸（fatty acid, FA）利用，而LCR大鼠则主要依赖葡萄糖供能。本研究推测，HCR与LCR的燃料利用差异可通过线粒体密度差异加以解释。为验证该假说并探究燃料选择的调控机制，本研究采用基于约束条件的全身代谢动力学分析方法，对上述大鼠的一过性运动数据展开分析。本研究的模型分析采用了热力学约束动力学框架，该框架涵盖糖酵解、三羧酸（TCA）循环以及线粒体脂肪酸转运与氧化过程。该模型可有效拟合观测到的葡萄糖与脂肪酸氧化相对速率随ATP需求变化的规律。在寻找可解释HCR与LCR代谢功能差异的最小差异因子时，研究发现：相较于HCR大鼠，LCR大鼠的全身代谢表型可通过总线粒体活性降低约50%、同时线粒体脂肪酸转运活性进一步降低5倍加以阐释。最后，本研究提出假设：在长期运动过程中，LCR大鼠可通过上调脂肪酸转运及/或氧化过程，部分弥补其初始脂肪酸分解活性的缺陷。