Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice

• Published in: American journal of physiology: endocrinology and metabolism 2003-11, Vol.285 (5), p.E958-E963
• Main Authors: Fueger, Patrick T, Heikkinen, Sami, Bracy, Deanna P, Malabanan, Carlo M, Pencek, R. Richard, Laakso, Markku, Wasserman, David H
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - analysis; Body Weight; Deoxyglucose - metabolism; Fasting; Fatty Acids, Nonesterified - blood; Glucose - metabolism; Glycogen - analysis; Glycogen - metabolism; Hexokinase - deficiency; Hexokinase - physiology; Insulin - blood; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Knockout; Muscle, Skeletal - metabolism; Myocardium - chemistry; Oxidation-Reduction; Physical Exertion; Tritium
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00190.2003

1 Department of Molecular Physiology and Biophysics and 2 Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and 3 Department of Medicine and 4 A. I. Virtanen Institute and Department of Biochemistry and Biotechnology, University of Kuopio, Kuopio 70211, Finland Submitted 28 April 2003 ; accepted in final form 8 July 2003 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. Because HK II overexpression augments exercise-stimulated MGU, it was hypothesized that a reduction in HK II activity would impair exercise-stimulated MGU and that 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 with their wild-type control (WT) littermates during either sedentary or moderate exercise periods. R g , an index of glucose metabolism, was measured using 2-deoxy-[ 3 H]glucose. No differences in glucose metabolism were detected between sedentary groups. The increase in R g due to exercise was impaired in the highly oxidative heart and soleus muscles of HK + / – compared with WT mice (7 ± 10 vs. 29 ± 9 and 8 ± 3 vs. 25 ± 7 µmol · 100 g –1 · min –1 , respectively). However, the increase in R g due to exercise was not altered in gastrocnemius and superficial vastus lateralis muscles in HK + / – and WT mice (8 ± 2 vs. 12 ± 3 and 5 ± 2 vs. 8 ± 2 µmol · 100 g –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. muscle glucose uptake; phosphorylation; transport; distributed control; 2-deoxyglucose Address for reprint requests and other correspondence: P. T. Fueger, Dept. of Molecular Physiology and Biophysics, Vanderbilt Univ. School of Medicine, Nashville, TN 37232–0615 (E-mail: patrick.fueger{at}vanderbilt.edu ).