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1 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
2 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
3 Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: patrick.fueger{at}vanderbilt.edu.
Skeletal muscle glucose uptake (MGU) is determined by glucose delivery, transport, and phosphorylation. The control of MGU can be distributed amongst all three steps and may change in response to different physiological conditions. C57Bl/6J mice overexpressing GLUT4, hexokinase II (HK II), or both were used to determine the barriers to MGU. A carotid artery and jugular vein were catheterized in 4 mo old mice for serial arterial blood sampling and venous infusions, respectively. Experiments were conducted in conscious animals after they had fully recovered from surgery (~7 days) and following a 5 h fast. 2-deoxy[3H]glucose was administered during rest or treadmill exercise to calculate glucose concentration-dependent and - independent indices of MGU (Rg and Kg, respectively). Compared to wild-type controls, GLUT4 overexpressing mice had lowered fasting glycemia (165 ± 6 vs. 115 ± 6 mg/dl) and increased Rg by 230 and 166 % in the gastrocnemius, and superficial vastus lateralis (SVL) muscles, respectively, under sedentary conditions. GLUT4 overexpression was not able to augment exercise-stimulated Rg or blood glucose concentration-independent Kg. Whereas HK II overexpression had no effect on fasting glycemia (170 ± 6 mg/dl) or sedentary Rg, it dramatically increased exercise-stimulated Rg by 82, 60, and 169 % in soleus, gastrocnemius, and SVL muscles, respectively. Combined GLUT4 and HK II overexpression lowered fasting glycemia (106 ± 6 mg/dl), increased plasma NEFAs, and increased sedentary Rg. Combined GLUT4 and HK II overexpression did not further enhance exercise-stimulated Rg compared to HK II overexpressing mice because of the reduced glucose concentration. However, GLUT4 in combination with HK II overexpression resulted in a marked increase in exercise-stimulated Kg. In conclusion, the control of MGU shifts from membrane transport at rest to phosphorylation during exercise in conscious C57Bl/6J mice. Glucose transport is not normally a significant control point for exercise-stimulated MGU. However, when the phosphorylation barrier is lowered by overexpression of HK II, glucose transport becomes a key site of control for regulating MGU during exercise.
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