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

• Published in: PLoS computational biology Vol. 14; no. 2; p. e1005982
• Main Authors: Moxley, Michael A, Vinnakota, Kalyan C, Bazil, Jason N, Qi, Nathan R, Beard, Daniel A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-02-2018; Public Library of Science (PLoS)
• Subjects: Adenosine Triphosphatases - metabolism; Adenosine Triphosphate - metabolism; Aerobics; Algorithms; Animals; Biochemistry; Biology and Life Sciences; Carbon Dioxide - metabolism; Computer applications; Computer Simulation; Data processing; Engineering and Technology; Enzymes; Exercise intensity; Fatty acid metabolism; Fatty acids; Fatty Acids - metabolism; Fuels; Glucose; Glucose - metabolism; Glycolysis; Medicine and Health Sciences; Metabolism; Mitochondria; Mitochondria - metabolism; Models, Statistical; Muscle, Skeletal - physiology; Musculoskeletal system; Oxidation; Oxidation-Reduction; Oxygen - metabolism; Phenotypes; Physical Conditioning, Animal; Physical fitness; Physical Sciences; Physical training; Physiological aspects; Physiology; Proteomics; Rats; Reduction; Rodents; Running; Running - physiology; Software; Supervision; Thermodynamics; Transport; Tricarboxylic acid cycle; Utilization; Ann Arbor Michigan; United States > US; Michigan
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1005982

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.