Hexokinase II-deficient Mice

Heikkinen, Sami; Pietilä, Marko; Halmekytö, Maria; Suppola, Suvikki; Pirinen, Eija; Deeb, Samir S.; Jänne, Juhani; Laakso, Markku

doi:10.1074/jbc.274.32.22517

Cited by 59 publications

(25 citation statements)

References 49 publications

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“…Although there are no data in humans with type 1 diabetes, studies done in obese and type 2 diabetic patients have shown similar findings (5,24,25). Mice with a heterozygous knockout of hexokinase II have a 50% decrease in hexokinase II mRNA and a corresponding 50% decrease in muscle glucose uptake, suggesting that hexokinase II may serve as a rate-limiting step for glucose uptake in the muscle (26). The second irreversible and rate-limiting step in glycolysis is the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate and is catalyzed by phosphofructokinase-1 (PFK-1).…”

Section: Resultsmentioning

confidence: 56%

Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice

Yechoor

Patti

Saccone

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

143

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Metabolic abnormalities underlying diabetes are primarily the result of the lack of adequate insulin action and the associated changes in protein phosphorylation and gene expression. To define the full set of alterations in gene expression in skeletal muscle caused by diabetes and the loss of insulin action, we have used Affymetrix oligonucleotide microarrays and streptozotocindiabetic mice. Of the genes studied, 235 were identified as changed in diabetes, with 129 genes up-regulated and 106 down-regulated. Analysis revealed a coordinated regulation at key steps in glucose and lipid metabolism, mitochondrial electron transport, transcriptional regulation, and protein trafficking. mRNAs for all of the enzymes of the fatty acid ␤-oxidation pathway were increased, whereas those for GLUT4, hexokinase II, the E1 component of the pyruvate dehydrogenase complex, and subunits of all four complexes of the mitochondrial electron transport chain were all coordinately down-regulated. Only about half of the alterations in gene expression in diabetic mice could be corrected toward normal after 3 days of insulin treatment and euglycemia. These data point to as of yet undefined mechanisms for highly coordinated regulation of gene expression by insulin and potential new targets for therapy of diabetes mellitus.

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Section: Resultsmentioning

confidence: 56%

Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice

Yechoor

Patti

Saccone

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

143

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“…An alternative approach is to increase the resistance to a step by genetically lowering the concentration or functional activity of those same proteins and determine whether such a manipulation reduces MGU. This was done for glucose phosphorylation by partially knocking out HK II (25,26), and it was demonstrated that glucose phosphorylation is a primary site of resistance to MGU during exercise, because partial HK II knock-out mice had impaired glucose influx in oxidative muscles (26). Here we show that a partial GLUT4 ablation in C57BL/6J mice impaired neither sedentary nor exercise-stimulated MGU in any of the muscles studied at 4 months of age.…”

Section: Discussionmentioning

confidence: 84%

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

Fueger

Hess

Posey

et al. 2004

Journal of Biological Chemistry

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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[ 3 H]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 (mol/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.Muscle glucose uptake (MGU) 1 can be separated into three sequential steps, i.e. delivery of glucose from the blood to the muscle, transport across the sarcolemma by a GLUT, and irreversible phosphorylation to glucose-6-phosphate by an HK isozyme. Each of these steps can serve as a barrier to MGU and, thus, are important in regulating glucose influx. During resting conditions, the transport step exerts the most control in regulating MGU, as GLUT1 (1-4) or GLUT4 (5, 6) overexpression augments basal MGU. Previous work suggests that normal GLUT4 content is sufficient for increases in MGU during exercise, because GLUT4 overexpression alone does not further increase exercise-stimulated MGU (7). Instead of glucose transport, glucose phosphorylation is a primary limitation of exercise-stimulated MGU (7-9). Heterozygous GLUT4 knock-out mice serve as a useful ...

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“…The HK +/- mice were first described by Heikkinen et al [12] and have a partial deletion to the HKII gene; the HK tg mice contain a HKII transgene composed of the human HKII cDNA driven by the rat muscle creatine kinase promoter [2]. HK +/- and HK tg were initially bred with wild-type C57Bl/6 mice (Jackson Laboratories) and subsequently by wild-type offspring, which were used for this investigation.…”

Section: Methodsmentioning

confidence: 99%

“…To study alterations in the level of HK, we make use of two different HKII genotypes: the C57Bl/6 mice with a partial deletion of HKII [12; HK +/- ] as well as mice overexpressing HKII (HK tg ) [2]. These mice are reported to have a 50% decrease (HK +/- ) and a 350% increase (HK tg ) in HKII content relative to wild-type (WT) gastrocnemius muscles [8].…”

Section: Introductionmentioning

confidence: 99%

Partial hexokinase II knockout results in acute ischemia–reperfusion damage in skeletal muscle of male, but not female, mice

Smeele

Eerbeek

Koeman

et al. 2010

Pflugers Arch - Eur J Physiol

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Cellular studies have demonstrated a protective role of mitochondrial hexokinase against oxidative insults. It is unknown whether HK protective effects translate to the in vivo condition. In the present study, we hypothesize that HK affects acute ischemia–reperfusion injury in skeletal muscle of the intact animal. Male and female heterozygote knockout HKII (HK+/-), heterozygote overexpressed HKII (HKtg), and their wild-type (WT) C57Bl/6 littermates mice were examined. In anesthetized animals, the left gastrocnemius medialis (GM) muscle was connected to a force transducer and continuously stimulated (1-Hz twitches) during 60 min ischemia and 90 min reperfusion. Cell survival (%LDH) was defined by the amount of cytosolic lactate dehydrogenase (LDH) activity still present in the reperfused GM relative to the contralateral (non-ischemic) GM. Mitochondrial HK activity was 72.6 ± 7.5, 15.7 ± 1.7, and 8.8 ± 0.9 mU/mg protein in male mice, and 72.7 ± 3.7, 11.2 ± 1.4, and 5.9 ± 1.1 mU/mg in female mice for HKtg, WT, and HK+/-, respectively. Tetanic force recovery amounted to 33 ± 7% for male and 17 ± 4% for female mice and was similar for HKtg, WT, and HK+/-. However, cell survival was decreased (p = 0.014) in male HK+/- (82 ± 4%LDH) as compared with WT (98 ± 5%LDH) and HKtg (97 ± 4%LDH). No effects of HKII on cell survival was observed in female mice (92 ± 2% LDH). In conclusion, in this mild model of acute in vivo ischemia–reperfusion injury, a partial knockout of HKII was associated with increased cell death in male mice. The data suggest for the first time that HKII mediates skeletal muscle ischemia–reperfusion injury in the intact male animal.

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Hexokinase II-deficient Mice

Cited by 59 publications

References 49 publications

Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice

Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice

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

Partial hexokinase II knockout results in acute ischemia–reperfusion damage in skeletal muscle of male, but not female, mice

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