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TRANSLATIONAL PHYSIOLOGY

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Departments of Biomedical Engineering,¹ Physiology and Biophysics,² Pediatrics,³ Nutrition,⁴ and the Center for Modeling Integrated Metabolic Systems,⁵ Case Western Reserve University, Cleveland, Ohio

Submitted 29 December 2005 ; accepted in final form 27 March 2006

In response to exercise, the heart increases its metabolic rate severalfold while maintaining energy species (e.g., ATP, ADP, and Pi) concentrations constant; however, the mechanisms that regulate this response are unclear. Limited experimental studies show that the classic regulatory species NADH and NAD⁺ are also maintained nearly constant with increased cardiac power generation, but current measurements lump the cytosol and mitochondria and do not provide dynamic information during the early phase of the transition from low to high work states. In the present study, we modified our previously published computational model of cardiac metabolism by incorporating parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and oxidative phosphorylation, and simulated the metabolic responses of the heart to an abrupt increase in energy expenditure. Model simulations showed that myocardial oxygen consumption, pyruvate oxidation, fatty acids oxidation, and ATP generation were all increased with increased energy expenditure, whereas ATP and ADP remained constant. Both cytosolic and mitochondrial NADH/NAD⁺ increased during the first minutes (by 40% and 20%, respectively) and returned to the resting values by 10–15 min. Furthermore, model simulations showed that an altered substrate selection, induced by either elevated arterial lactate or diabetic conditions, affected cytosolic NADH/NAD⁺ but had minimal effects on the mitochondrial NADH/NAD⁺, myocardial oxygen consumption, or ATP production. In conclusion, these results support the concept of parallel activation of metabolic processes generating reducing equivalents during an abrupt increase in cardiac energy expenditure and suggest there is a transient increase in the mitochondrial NADH/NAD⁺ ratio that is independent of substrate supply.

diabetes; exercise; heart; lactate; mitochondria; modeling

This article has been cited by other articles:

				L. Zhou, M. E. Cabrera, H. Huang, C. L. Yuan, D. K. Monika, N. Sharma, F. Bian, and W. C. Stanley Parallel activation of mitochondrial oxidative metabolism with increased cardiac energy expenditure is not dependent on fatty acid oxidation in pigs J. Physiol., March 15, 2007; 579(3): 811 - 821. [Abstract] [Full Text] [PDF]