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J. Biol. Chem., Vol. 279, Issue 49, 50956-50961, December 3, 2004

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Control of Exercise-stimulated Muscle Glucose Uptake by GLUT4 Is Dependent on Glucose Phosphorylation Capacity in the Conscious Mouse^*

Patrick T. Fueger, Holli S. Hess, Kelly A. Posey, Deanna P. Bracy¶, R. Richard Pencek, Maureen J. Charron||, and David H. Wasserman¶

From the Department of Molecular Physiology and Biophysics and the ^¶Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 and the ^||Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461

Previous work suggests that normal GLUT4 content is sufficient for increases in muscle glucose uptake (MGU) during exercise because GLUT4 overexpression does not increase exercise-stimulated MGU. Instead of glucose transport, glucose phosphorylation is a primary limitation of exercise-stimulated MGU. It was hypothesized that a partial ablation of GLUT4 would not impair exercise-stimulated MGU when glucose phosphorylation capacity is normal but would do so when glucose phosphorylation capacity was increased. Thus, C57BL/6J mice with hexokinase II (HKII) overexpression (HK^Tg), a GLUT4 partial knock-out (G4^+/–), or both (HK^Tg + G4^+/–) and wild-type (WT) littermates were implanted with carotid artery and jugular vein catheters for sampling and infusions at 4 months of age. After a 7-day recovery, 5-h fasted mice remained sedentary or ran on a treadmill at 0.6 mph for 30 min (n = 9–12 per group) and received a bolus of 2-deoxy[³H]glucose to provide an index of MGU (R_g). Arterial blood glucose and plasma insulin concentrations were similar in WT, G4^+/–, HK^Tg, and HK^Tg + G4^+/– mice. Sedentary R_g values were the same in all genotypes in all muscles studied, confirming that glucose transport is a significant barrier to basal glucose uptake. Gastrocnemius and soleus R_g were greater in exercising compared with sedentary mice in all genotypes. During exercise, G4^+/– mice had a marked increase in blood glucose that was corrected by the addition of HK II overexpression. Exercise R_g (µmol/100g/min) was not different between WT and G4^+/– mice in the gastrocnemius (24 ± 5 versus 21 ± 2) or the soleus (54 ± 6 versus 70 ± 7). In contrast, the enhanced exercise R_g observed in HK^Tg mice compared with that in WT mice was absent in HK^Tg + G4^+/– mice in both the gastrocnemius (39 ± 7 versus 22 ± 6) and the soleus (98 ± 13 versus 65 ± 13). Thus, glucose transport is not a significant barrier to exercise-stimulated MGU despite a 50% reduction in GLUT4 content when glucose phosphorylation capacity is normal. However, when glucose phosphorylation capacity is increased by HK II overexpression, GLUT4 availability becomes a marked limitation to exercise-stimulated MGU.

Received for publication, July 22, 2004 , and in revised form, September 27, 2004.

^* This work was supported by NIDDK, National Institutes of Health Grants R01 DK-54902, R01 DK-47425, and U24 DK-59637. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address and to whom correspondence should be addressed: Duke University Medical Center, Dept. of Pharmacology and Cancer Biology, 4321 Medical Park Dr., Suite 200, Durham, NC 27704. Tel.: 919-479-2371; Fax: 919-477-0632; E-mail: patrick.fueger{at}duke.edu.

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