Li Yanjun, Dash Ranjan K, Kim Jaeyeon, Saidel Gerald M, Cabrera Marco E
Center for Modeling Integrated Metabolic Systems, Case Western Reserve University, 11100 Euclid Ave., Cleveland, OH 44106-6011, USA.
Am J Physiol Cell Physiol. 2009 Jan;296(1):C25-46. doi: 10.1152/ajpcell.00094.2008. Epub 2008 Oct 1.
Skeletal muscle can maintain ATP concentration constant during the transition from rest to exercise, whereas metabolic reaction rates may increase substantially. Among the key regulatory factors of skeletal muscle energy metabolism during exercise, the dynamics of cytosolic and mitochondrial NADH and NAD+ have not been characterized. To quantify these regulatory factors, we have developed a physiologically based computational model of skeletal muscle energy metabolism. This model integrates transport and reaction fluxes in distinct capillary, cytosolic, and mitochondrial domains and investigates the roles of mitochondrial NADH/NAD+ transport (shuttling) activity and muscle glycogen concentration (stores) during moderate intensity exercise (60% maximal O2 consumption). The underlying hypothesis is that the cytosolic redox state (NADH/NAD+) is much more sensitive to a metabolic disturbance in contracting skeletal muscle than the mitochondrial redox state. This hypothesis was tested by simulating the dynamic metabolic responses of skeletal muscle to exercise while altering the transport rate of reducing equivalents (NADH and NAD+) between cytosol and mitochondria and muscle glycogen stores. Simulations with optimal parameter estimates showed good agreement with the available experimental data from muscle biopsies in human subjects. Compared with these simulations, a 20% increase (or approximately 20% decrease) in mitochondrial NADH/NAD+ shuttling activity led to an approximately 70% decrease (or approximately 3-fold increase) in cytosolic redox state and an approximately 35% decrease (or approximately 25% increase) in muscle lactate level. Doubling (or halving) muscle glycogen concentration resulted in an approximately 50% increase (or approximately 35% decrease) in cytosolic redox state and an approximately 30% increase (or approximately 25% decrease) in muscle lactate concentration. In both cases, changes in mitochondrial redox state were minimal. In conclusion, the model simulations of exercise response are consistent with the hypothesis that mitochondrial NADH/NAD+ shuttling activity and muscle glycogen stores affect primarily the cytosolic redox state. Furthermore, muscle lactate production is regulated primarily by the cytosolic redox state.
在从静息状态转变为运动状态的过程中，骨骼肌能够维持三磷酸腺苷（ATP）浓度恒定，而代谢反应速率可能会大幅增加。在运动期间骨骼肌能量代谢的关键调节因子中，胞质和线粒体中烟酰胺腺嘌呤二核苷酸（NADH）和烟酰胺腺嘌呤二核苷酸（NAD⁺）的动态变化尚未得到描述。为了量化这些调节因子，我们开发了一种基于生理学的骨骼肌能量代谢计算模型。该模型整合了不同毛细血管、胞质和线粒体区域的转运和反应通量，并研究了中等强度运动（最大耗氧量的60%）期间线粒体NADH/NAD⁺转运（穿梭）活性和肌肉糖原浓度（储存量）的作用。潜在的假设是，与线粒体氧化还原状态相比，收缩骨骼肌中的胞质氧化还原状态（NADH/NAD⁺）对代谢紊乱更为敏感。通过模拟骨骼肌对运动的动态代谢反应，同时改变胞质和线粒体之间还原当量（NADH和NAD⁺）的转运速率以及肌肉糖原储存量，对这一假设进行了检验。使用最佳参数估计值进行的模拟与来自人类受试者肌肉活检的现有实验数据显示出良好的一致性。与这些模拟结果相比，线粒体NADH/NAD⁺穿梭活性增加20%（或大约降低20%）导致胞质氧化还原状态降低约70%（或大约增加3倍），肌肉乳酸水平降低约35%（或大约增加25%）。肌肉糖原浓度加倍（或减半）导致胞质氧化还原状态增加约50%（或大约降低35%），肌肉乳酸浓度增加约30%（或大约降低25%）。在这两种情况下，线粒体氧化还原状态的变化都很小。总之，运动反应的模型模拟结果与线粒体NADH/NAD⁺穿梭活性和肌肉糖原储存主要影响胞质氧化还原状态这一假设一致。此外，肌肉乳酸生成主要受胞质氧化还原状态调节。
