Regulation of cell surface GLUT4 in skeletal muscle of transgenic mice

Brozinick, Joseph T.; McCoid, Scott C.; Reynolds, Thomas H.; Wilson, C M; Stevenson, R. W.; Cushman, Samuel W.; Gibbs, E. Michael

doi:10.1042/bj3210075

Cited by 23 publications

(37 citation statements)

References 30 publications

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“…First, transgenic complementation of GLUT4 in EDL muscle from male and female GLUT4-null mice led to a significant increase in muscle glycogen levels. This finding is in agreement with several reports whereby increased muscle glycogen levels have been noted in GLUT4 transgenic mice (29,32,33,42) and suggests that enhanced glucose flux, presumably because of increased expression of GLUT4, leads to greater glycogen storage in skeletal muscle. Our finding that glycogen content in soleus muscle of male GLUT4-null mice was 45% lower than control levels supports this concept.…”

Section: Figsupporting

confidence: 83%

“…Furthermore, transgenic complementation of GLUT4 was sufficient to fully restore hypoxia-induced glucose transport in EDL muscle from MLC-GLUT4-null. In vitro exposure of isolated skeletal muscle to hypoxia, followed by re-oxygenation, is known to increase glucose transport (8,14,15,33,40,41) and GLUT4 recruitment to the cell surface (8,14). Because hypoxia appears to be a relevant model for exercise-stimulated glucose transport (8), our results suggest that GLUT4 is the only downstream effector of the muscle contraction/hypoxia pathway to glucose transport.…”

mentioning

confidence: 67%

“…Several groups have shown that GLUT4 overexpression in skeletal muscle leads to enhanced basal and insulin-stimulated glucose uptake (29 -31), and this is attributed to increased glucose transport in skeletal muscle (32,33). However, recent studies with GLUT4-overexpressing transgenic mice were not able to provide a clear link between increased GLUT4 content and enhanced hypoxia-stimulated glucose uptake (33).…”

mentioning

confidence: 99%

“…However, recent studies with GLUT4-overexpressing transgenic mice were not able to provide a clear link between increased GLUT4 content and enhanced hypoxia-stimulated glucose uptake (33). Thus, overexpressed GLUT4 may be targeted to an insulin-sensitive, rather than a muscle contraction/hypoxia-sensitive pool.…”

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confidence: 99%

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Restoration of Hypoxia-stimulated Glucose Uptake in GLUT4-deficient Muscles by Muscle-specific GLUT4 Transgenic Complementation

Zierath

Tsao

Stenbit

et al. 1998

Journal of Biological Chemistry

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To investigate whether GLUT4 is required for exercise/hypoxia-induced glucose uptake, we assessed glucose uptake under hypoxia and normoxia in extensor digitorum longus (EDL) and soleus muscles from GLUT4-deficient mice. In EDL and soleus from wild type control mice, hypoxia increased 2-deoxyglucose uptake 2-3-fold. Conversely, hypoxia did not alter 2-deoxyglucose uptake in either EDL or soleus from either male or female GLUT4-null mice. Next we introduced the fasttwitch skeletal muscle-specific MLC-GLUT4 transgene into GLUT4-null mice to determine whether changes in the metabolic milieu accounted for the lack of hypoxiamediated glucose transport. Transgenic complementation of GLUT4 in EDL was sufficient to restore hypoxiamediated glucose uptake. Soleus muscles from MLC-GLUT4-null mice were transgene-negative, and hypoxiastimulated 2-deoxyglucose uptake was not restored. Although ablation of GLUT4 in EDL did not affect normoxic glycogen levels, restoration of GLUT4 to EDL led to an increase in glycogen under hypoxic conditions. Male GLUT4-null soleus displayed reduced normoxic glycogen stores, but female null soleus contained significantly more glycogen under normoxia and hypoxia. Reduced normoxic levels of ATP and phosphocreatine were measured in male GLUT4-null soleus but not in EDL. However, transgenic complementation of GLUT4 prevented the decrease in hypoxic ATP and phosphocreatine levels noted in male GLUT4-null and control EDL.In conclusion, we have demonstrated that GLUT4 plays an essential role in the regulation of muscle glucose uptake in response to hypoxia. Because hypoxia is a useful model for exercise, our results suggest that stimulation of glucose transport in response to exercise in skeletal muscle is totally dependent upon GLUT4. Furthermore, the compensatory glucose transport system that exists in GLUT4-null soleus muscle is not sensitive to hypoxia/muscle contraction.

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Section: Figsupporting

confidence: 83%

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confidence: 67%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Restoration of Hypoxia-stimulated Glucose Uptake in GLUT4-deficient Muscles by Muscle-specific GLUT4 Transgenic Complementation

Zierath

Tsao

Stenbit

et al. 1998

Journal of Biological Chemistry

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“…Previous studies have shown that insulin and exercise-contraction recruit different GLUT4 storage compartments in skeletal muscle through distinct signaling pathways (1, 11, 20, 29-31, 39, 50). Since hypoxia in vitro is a commonly used model for exercise-stimulated glucose transport (6,7,21,52), the isolated soleus muscles were also made hypoxic and assayed for glucose transport activity. Even though hypoxia was a weaker activator of glucose uptake than insulin, identical responses were obtained in both wild-type and VAMP3 null mice.…”

Section: Vol 21 2001 Targeted Disruption Of the Vamp3 Gene 1575mentioning

confidence: 99%

VAMP3 Null Mice Display Normal Constitutive, Insulin- and Exercise-Regulated Vesicle Trafficking

Yang¹,

Mora²,

Ryder³

et al. 2001

Molecular and Cellular Biology

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To investigate the physiological function of the VAMP3 vesicle SNARE (v-SNARE) isoform in the regulation of GLUT4 vesicle trafficking, we generated homozygotic VAMP3 null mice by targeted gene disruption. The VAMP3 null mice had typical growth rate and weight gain, with normal maintenance of fasting serum glucose and insulin levels. Analysis of glucose disposal and insulin sensitivity demonstrated normal insulin and glucose tolerance, with no evidence for insulin resistance. Insulin stimulation of glucose uptake in isolated primary adipocytes was essentially the same for the wild-type and VAMP3 null mice. Similarly, insulin-, hypoxia-, and exercise-stimulated glucose uptake in isolated skeletal muscle did not differ significantly. In addition, other general membrane trafficking events including phagocytosis, pinocytosis, and transferrin receptor recycling were also found to be unaffected in the VAMP3 null mice. Taken together, these data demonstrate that VAMP3 function is not necessary for either regulated GLUT4 translocation or general constitutive membrane recycling.Insulin increases glucose uptake in adipose and striated muscle tissues primarily by recruiting the GLUT4 glucose transporter protein to the cell surface (37). In the basal noninsulin-stimulated state, the majority of GLUT4 resides in one or more intracellular compartments (44,45). Upon addition of insulin, the signaling cascade triggered by the insulin receptor leads to rapid translocation of the GLUT4 transporter to the plasma membrane, thereby increasing the number of transporters at the cell surface and the rate of glucose uptake (12,27,38,41).The process of GLUT4 translocation shares important features with the exocytosis of synaptic vesicles during neurotransmitter release. For example, the plasma membrane docking and fusion of GLUT4 vesicles appears to require the t-SNARE protein isoforms syntaxin 4 and SNAP23 (9,37,48). GLUT4 vesicles contain the v-SNARE-interacting partners VAMP2 and VAMP3, both of which translocate to the plasma membrane in parallel with GLUT4 (33,47). Recent studies using various toxins and endosomal ablation techniques have indicated that VAMP2 is the predominant v-SNARE responsible for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes and in the L6 muscle cell line (9,32,33,40). In contrast, guanosine-5Ј-O-(3-thiotriphosphate) (GTP␥S)-stimulated GLUT4 translocation was found to be dependent on VAMP3, thereby suggesting the presence of two independently regulated pools of GLUT4 storage compartments (35). In this regard, skeletal muscle has also been shown to contain two pools of GLUT4 vesicles, one that responds to insulin and another that is responsive to exercise and contraction (1,11,39).In addition, the skeletal muscle exercise-contraction subpopulation utilizes a signaling pathway independent of the phosphatidylinositol (PI) 3-kinase (30, 31, 50). Similarly, GTP␥S stimulation in adipocytes is also independent of the PI 3-kinase, suggesting that the GTP␥S and exercise-contraction pathways may util...

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