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1 Department of Molecular Physiology & Biophysics
2 Mouse Metabolic Phenotyping Center
3 Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
4 Department of Medicine
5 A. I. Virtanen Institute for Molecular Sciences and Department of Biotechnology and Molecular Medicine,University of Kuopio, Kuopio, Finland
Hexokinase (HK) II content is elevated in fatigue resistant muscle fibres and exercise trained muscle. The aim of this study was to determine if exercise capacity is dependent on muscle HK protein content. C57Bl/6 mice with a 50% HK knockout (HK+/–), no genetic manipulation (wild-type, WT) and an 
3-fold HK overexpression (HKTg) were tested. Mice (n
= 12/group) completed both a maximal oxygen consumption 
test and an endurance capacity test (run at 75%
) on an enclosed treadmill equipped to measure gas exchange. Arterial and venous catheters were surgically implanted into separate groups of mice (n
= 9–11/group) in order to measure an index of muscle glucose uptake (Rg) during 30 min of treadmill exercise. Maximum work rate (0.95 ± 0.05, 1.00 ± 0.04 and 1.06 ± 0.07 kg m min–1), 
(137 ± 3, 141 ± 4 and 141 ± 5 ml kg–1 min–1) and maximal respiratory exchange ratio (1.04 ± 0.02, 1.00 ± 0.03 and 1.04 ± 0.04) were similar in HK+/–, WT and HKTg, respectively. Exercise endurance capacity (measured as time to exhaustion) increased as HK content increased (55 ± 11, 77 ± 5 and 98 ± 9 min) and this was related to Rg measured in mice during 30 min of exercise (13 ± 2, 24 ± 5 and 42 ± 5 µmol (100 g)–1 min–1). Muscle glycogen in sedentary HK+/– mice and HK+/– mice following 30 min of exercise were significantly lower than in HKTg and WT mice. However, the net exercise-induced muscle glycogen breakdown was equal in the three genotypes. In summary, HK protein content within the range studied (a) was not associated with a difference in the capacity to perform maximal intensity exercise, (b) was a powerful determinant of the ability to sustain moderate intensity exercise, as reducing HK content impaired endurance and increasing HK content enhanced endurance, and (c) although directly related to exercise endurance, was not a determinant of net muscle glycogen usage during exercise. In conclusion, adaptations that increase HK protein content and/or functional activity such as regular exercise contribute to increased muscular endurance.
(Received 11 February 2005;
accepted after revision 28 April 2005;
first published online 5 May 2005)
Corresponding author P. T. Fueger: Duke University Medical Center, Department of Pharmacology and Cancer Biology, 4321 Medical Park Drive, Suite 200, Durham, NC 27704, USA. Email: patrick.fueger{at}duke.edu
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