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Publication
Systems-level computational modeling demonstrates fuel selection switching in
high capacity running and low capacity running rats.
Authors Moxley MA, Vinnakota KC, Bazil JN, Qi NR, Beard DA
Submitted By Submitted Externally on 4/24/2018
Status Published
Journal PLoS computational biology
Year 2018
Date Published 2/1/2018
Volume : Pages 14 : e1005982
PubMed Reference 29474500
Abstract 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.




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