Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice
Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice
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DOI：
10.1152/ajpendo.00190.2003
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发表时间：
2003-11-01
影响因子：
5.1
通讯作者：
Wasserman, DH
中科院分区：
文献类型：
--
作者：
Fueger, PT;Heikkinen, S;Wasserman, DH
肌肉葡萄糖摄取（MGU）受三个连续步骤的分布控制：葡萄糖向肌膜的传递，跨肌膜的运输，以及细胞内己糖激酶（HK）对葡萄糖6-磷酸的磷酸化。在高葡萄糖通量的状态下，如适度运动，HK活性变得更加重要，因为增强的肌肉灌注增加了葡萄糖的输送，而细胞膜上增加的GLUT4增加了葡萄糖的运输。由于HK II过表达增强了运动刺激的MGU，因此假设HK II活性的降低会损害运动刺激的MGU，并且这种损害的程度在葡萄糖需求量最大的组织中最大。为此，在久坐或适度运动期间，将HK II部分敲除（HK+/-）的小鼠与野生型对照（WT）小鼠进行比较。葡萄糖代谢指标R-g用2-脱氧-[H-3]葡萄糖测定。在久坐组之间，葡萄糖代谢没有发现差异。与WT小鼠相比，在高度氧化的HK+/-小鼠心脏和比目鱼肌中，运动引起的Rg增加受到损害（7 +/- 10 vs. 29 +/- 9, 8 +/- 3 vs. 25 +/- 7）。100g (-1)-min（-1）。然而，在HK+/-和WT小鼠的腓肠肌和股外侧浅表肌中，运动引起的Rg增加并没有改变（8 +/- 2 vs. 12 +/- 3, 5 +/- 2 vs. 8 +/- 2）。100克(1)。分钟(1),分别)。综上所述，运动期间HK活动减少会损害MGU，这是一种以高葡萄糖通量为特征的生理状态。这种损伤严重依赖于组织的葡萄糖代谢率，并与组织氧化能力相关。
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-[H-3]glucose. 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 with WT mice (7 +/- 10 vs. 29 +/- 9 and 8 +/- 3 vs. 25 +/- 7 mumol.100 g(-1)-min(-1), respectively). However, the increase in Rg 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 mumol.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.