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1 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
2 Department of Medicine, University of Kuopio, Kuopio, Finland; A. I. Virtanen Institute and Department of Biochemistry and Biotechnology, University of Kuopio, Kuopio, Finland
3 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA; Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, TN, USA
4 Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, TN, USA
5 Department of Medicine, University of Kuopio, Kuopio, Finland
* To whom correspondence should be addressed. E-mail: patrick.fueger{at}vanderbilt.edu.
Muscle glucose uptake (MGU) is distributively controlled by three serial steps: delivery of glucose to the muscle membrane, transport across the muscle membrane, and intracellular phosphorylation to glucose-6-phosphate by hexokinase (HK). During states of high glucose fluxes such as moderate exercise, the HK activity is of increased importance since augmented muscle perfusion increases glucose delivery and increased GLUT4 at the cell membrane increases glucose transport. Since HK II overexpression augments exercise-stimulated MGU, it was hypothesized that a reduction in HK II activity would impair exercise-stimulated MGU and the magnitude of this impairment would be greatest in tissues with the largest glucose requirement. To this end, mice with a HK II partial knockout (HK+/-) were compared to their wild type control (WT) littermates during either sedentary or moderate exercise periods. Rg, an index of glucose metabolism, was measured using [2-3H]deoxyglucose. No differences in glucose metabolism were detected between sedentary groups. The increase in Rg due to exercise was impaired in the highly oxidative heart and soleus muscles of HK+/- compared to WT mice (7 ± 10 vs. 29 ± 9; 8 ± 3 vs. 25 ± 7 µmol.100g-1.min-1, respectively). However, the increase in Rg due to exercise was not altered in the gastrocnemius and superficial vastus lateralis muscles in HK+/- and WT mice (8 ± 2 vs. 12 ± 3; 5 ± 2 vs. 8 ± 2 µmol.100g-1.min-1, respectively). In conclusion, MGU is impaired by reductions in HK activity during exercise, a physiological condition characterized by high glucose flux. This impairment is critically dependent on the tissue's glucose metabolic rate and correlates with tissue oxidative capacity.
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