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Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Exercise acutely stimulates muscle glucose transport and also brings about an adaptive increase in the capacity of muscle for glucose uptake by inducing increases in GLUT-4 and hexokinase.1 Recent studies have provided evidence that activation of AMP protein kinase (AMPK) is involved in the stimulation of glucose transport by exercise. The purpose of this study was to determine whether activation of AMPK is also involved in mediating the adaptive increases in GLUT-4 and hexokinase. To this end, we examined the effect of incubating rat epitrochlearis muscles in culture medium for 18 h in the presence or absence of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which enters cells and is converted to the AMP analog ZMP, thus activating AMPK. Exposure of muscles to 0.5 mM AICAR in vitro for 18 h resulted in an ~50% increase in GLUT-4 protein and an ~80% increase in hexokinase. This finding provides strong evidence in support of the hypothesis that the activation of AMPK that occurs in muscle during exercise is involved in mediating the adaptive increases in GLUT-4 and hexokinase.
AMP kinase; exercise; gene expression; skeletal muscle; tissue culture; 5-aminoimidazole-4-carboxamide ribonucleoside
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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EXERCISE CAN INDUCE EXTENSIVE changes in skeletal muscle phenotype (2, 8, 17). Despite considerable research, the signaling mechanisms that mediate the adaptations induced by exercise have not been identified. A major reason for this is that exercise simultaneously perturbs numerous aspects of muscle cell homeostasis, including changes in concentrations of high-energy phosphates (~P), Ca2+, and glycolytic and lipolytic intermediates, as well as activation of numerous enzymes. Therefore, it seems necessary to use a system in which the various perturbations induced by exercise can be studied individually. To this end, we evaluated the use of isolated rat epitrochlearis muscles in tissue culture.
A major acute effect of exercise is to lower the concentration of creatine phosphate and raise the concentrations of creatine and AMP in muscle. These changes in ~P levels result in activation of AMP-activated protein kinase (AMPK) (23). Recent studies have provided evidence that activation of AMPK is the mechanism by which exercise induces translocation of the GLUT-4 isoform of the glucose transporter into the sarcolemma and stimulates glucose transport (6, 11, 12, 19). Phosphorylation of transcription factors by protein kinases is a mechanism by which gene expression is regulated. Therefore, it seemed possible that, in addition to stimulating GLUT-4 translocation, activation of AMPK could also mediate the increase in GLUT-4 expression induced by exercise. GLUT-4 and hexokinase levels appear to be regulated in parallel (3, 13, 17); therefore, it appeared likely that if 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) induces an increase in GLUT-4 there would also be an increase in hexokinase. To evaluate this possibility, we treated epitrochlearis muscles with AICAR, which is taken up by cells and converted to the AMP analog ZMP, resulting in activation of AMPK (5, 12, 21, 23).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. This research was approved by the Animal Studies Committee of Washington University. Male Wistar rats weighing ~100 g were obtained from Charles River and maintained on a diet of Purina chow and water ad libitum. Food was removed at 6:00 PM the day before an experiment. Rats were anesthetized with pentobarbital sodium (5 mg/100 g body wt) given intraperitoneally, and the epitrochlearis muscles were removed.
In preliminary experiments to test and validate the in vitro muscle incubation system, rats were exercised with a swimming protocol, described previously (17), that consisted of swimming for two 3-h-long periods separated by a 45-min rest period. The exercised rats and nonexercised controls were anesthetized immediately after the exercise, and their epitrochlearis muscles were used for 18-h in vitro incubations.Treatment of muscles.
Epitrochlearis muscles weighing ~20 mg were incubated for 18 h in
glass vials in a shaking incubator maintained at 35°C. In one
series of experiments, muscles of rats exercised by swimming were
compared with muscles of sedentary animals. In other experiments, muscles of sedentary rats were incubated in the presence or absence of
0.5 mM AICAR (Sigma Chemical). Some muscles were mounted on Plexiglas
clamps to keep them at resting length. The vials, containing 2 ml of
medium, were gassed continuously with 95% O2-5%
CO2 throughout the incubation. The incubation medium
consisted of MEM alpha (GIBCO BRL 12000-063), 10% fetal bovine
serum (GIBCO BRL), 50 µU/ml purified pork insulin (Ilectin II, Eli
Lilly), 100 µU/ml penicillin and 100 µg/ml streptomycin, and 0.25 µg/ml fungizone. In some experiments, triiodothyronine (1 µg/ml)
and hydrocortisone (50 ng/ml) were added to the incubation medium. The
medium was sterilized by filtration through 0.2-µm Millipore filters.
The medium was replaced with fresh medium after 6 and 12 h of
incubation. After the 18-h incubation, the muscles were washed in 2 ml
of PBS for 10 min, blotted, clamp frozen, and stored at 
80°C
until they were used for measurement of GLUT-4 and hexokinase.
Measurement of muscle GLUT-4 protein. The GLUT-4 glucose transporter protein content of epitrochlearis muscles was determined by Western blotting with a rabbit polyclonal antibody, directed at the COOH terminus of GLUT-4, as described previously (4). The GLUT-4 antibody was kindly given to us by Mike Mueckler (Washington University, St. Louis, MO).
Hexokinase measurement. Aliquots of the epitrochlearis muscle homogenates used for Western blot analysis of GLUT-4 were used for measurement of hexokinase activity by the method of Uyeda and Racker (22).
Statistics. Results are expressed as means ± SE. Statistically significant differences were determined with Student's t-test or one-way ANOVA, as appropriate.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Muscle GLUT-4 after exercise.
As shown in Fig. 1, there was a 60%
increase in GLUT-4 protein in muscles that were incubated in tissue
culture medium in vitro for 18 h after removal from rats that swam for
6 h. This significant increase shows that muscles incubated in vitro
can undergo an adaptive response of GLUT-4 to exercise similar to that
seen in vivo (17).
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Increase in muscle GLUT-4 in response to AICAR in vitro.
As shown in Fig. 2, muscles incubated in
culture medium with 0.5 mM AICAR for 18 h showed an ~50% increase in
GLUT-4. It seemed possible that keeping muscles at resting length by
attaching them to a muscle holder might enhance this adaptive response.
However, the muscles held on clamps did not show an enhanced response. Addition of the hormones triiodothyronine and hydrocortisone at concentrations sometimes used in tissue culture (20) also had no effect
on the AICAR-induced increase in GLUT-4.
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AICAR induces an increase in hexokinase.
Exposure to 0.5 mM AICAR for 18 h also induced a significant increase
in hexokinase in epitrochlearis muscles that averaged ~80% (Fig.
3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study show that in vitro exposure of muscles to AICAR, at a concentration shown to activate AMPK in muscle (12), induces significant increases in GLUT-4 protein and hexokinase within 18 h. The adaptive increases of muscle GLUT-4 and hexokinase in response to exercise are also evident within 1 day, indicating that these proteins have short half-lives (16, 17). Neufer and Dohm (14) showed that the exercise-induced increase in GLUT-4 is mediated at the transcriptional level. Furthermore, O'Doherty et al. (15) found that the increase in muscle hexokinase in response to exercise is also due to increased transcription.
It has been our working hypothesis that some component of the perturbation of ~P concentration in exercising muscle provides the initial signal that leads to the biochemical adaptations induced by exercise. Recent studies have provided evidence that activation of AMPK, presumably by the decrease in creatine phosphate and the increase in AMP in muscle during exercise, is involved in the translocation of GLUT-4 to the cell surface and increase in glucose transport activity (6, 11, 12). Because phosphorylation of transcription factors by protein kinases is a common mechanism for regulation of gene expression, it seemed possible that AMPK might also be involved in the exercise-induced increases in GLUT-4 and hexokinase expression. The present results showing that treatment of muscles in vitro with AICAR induces increases in GLUT-4 and hexokinase strongly support this possibility, as AICAR is taken up by cells and converted to the AMP analog ZMP, which activates AMPK (5, 12, 21, 23). It is interesting in this context that AMPK is the mammalian analog of SNF1, a kinase involved in the transcriptional regulation of genes by glucose, i.e., energy availability, in yeast (5).
While this paper was in preparation, we learned of a study in which AICAR given to rats by subcutaneous injection for 5 days resulted in a large increase in muscle GLUT-4 protein concentration (10). The present results are consistent with this finding, and they provide the additional important information that this adaptation is due to a direct effect of AICAR on skeletal muscle, rather than to nonspecific humoral or other systemic effects.
GLUT-4 and hexokinase function in tandem, with GLUT-4 mediating glucose transport across the sarcolemma and hexokinase phosphorylating the glucose as it enters the cytosol. Glucose transport is normally the rate-limiting step for glucose uptake and glycogen synthesis in skeletal muscle (9). Perhaps the increase in hexokinase functions to prevent phosphorylation from becoming limiting when glucose uptake is enhanced as the result of the increase in GLUT-4. We have proposed the hypothesis that the role of the adaptive increases in GLUT-4 and hexokinase induced by exercise is to increase the rate of muscle glycogen repletion after exercise (17). There is considerable experimental support for this hypothesis (3, 7, 13, 17). The rapid increases in GLUT-4 and hexokinase may also play a role in explaining the significant enhancement of insulin action on glucose disposal that can occur in response to a few days of exercise training (1, 18).
In conclusion, the results of this study and that by Winder's group (10) are important in that they represent initial steps toward discovery of the mechanisms that mediate the adaptive responses of muscle to exercise. They also may point the way to an improved treatment of insulin resistance and Type 2 diabetes.
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ACKNOWLEDGEMENTS |
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We thank May Chen for excellent technical assistance and Victoria Reckamp for expert help with preparation of the manuscript.
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FOOTNOTES |
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This research was supported by National Institute on Aging Grant AG-00425. E. O. Ojuka was supported by Institutional National Research Service Award AG-00078.
1 Original submission in response to a special call for papers on "Molecular and Cellular Basis of Exercise Adaptations."
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. O. Holloszy, Washington Univ. School of Medicine, Division of Geriatrics and Gerontology, 4566 Scott Ave., Campus Box 8113, St. Louis, MO 63110 (E-mail: jhollosz{at}imgate.wustl.edu).
Received 2 November 1999; accepted in final form 16 December 1999.
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RESULTS
DISCUSSION
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E. Tomas, A. Zorzano, and N. B. Ruderman Exercise Effects on Muscle Insulin Signaling and Action: Exercise and insulin signaling: a historical perspective J Appl Physiol, August 1, 2002; 93(2): 765 - 772. [Abstract] [Full Text] [PDF]
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J. R. Zierath Exercise Effects of Muscle Insulin Signaling and Action: Invited Review: Exercise training-induced changes in insulin signaling in skeletal muscle J Appl Physiol, August 1, 2002; 93(2): 773 - 781. [Abstract] [Full Text] [PDF]
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G. L. Dohm Exercise Effects on Muscle Insulin Signaling and Action: Invited Review: Regulation of skeletal muscle GLUT-4 expression by exercise J Appl Physiol, August 1, 2002; 93(2): 782 - 787. [Abstract] [Full Text] [PDF]
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K. Sakamoto and L. J. Goodyear Exercise Effects on Muscle Insulin Signaling and Action: Invited Review: Intracellular signaling in contracting skeletal muscle J Appl Physiol, July 1, 2002; 93(1): 369 - 383. [Abstract] [Full Text] [PDF]
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E. S. Buhl, N. Jessen, R. Pold, T. Ledet, A. Flyvbjerg, S. B. Pedersen, O. Pedersen, O. Schmitz, and S. Lund Long-Term AICAR Administration Reduces Metabolic Disturbances and Lowers Blood Pressure in Rats Displaying Features of the Insulin Resistance Syndrome Diabetes, July 1, 2002; 51(7): 2199 - 2206. [Abstract] [Full Text] [PDF]
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W. G. Aschenbach, M. F. Hirshman, N. Fujii, K. Sakamoto, K. F. Howlett, and L. J. Goodyear Effect of AICAR Treatment on Glycogen Metabolism in Skeletal Muscle Diabetes, March 1, 2002; 51(3): 567 - 573. [Abstract] [Full Text] [PDF]
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J. F.P. Wojtaszewski, S. B. Jorgensen, Y. Hellsten, D. G. Hardie, and E. A. Richter Glycogen-Dependent Effects of 5-Aminoimidazole-4-Carboxamide (AICA)-Riboside on AMP-Activated Protein Kinase and Glycogen Synthase Activities in RatSkeletal Muscle Diabetes, February 1, 2002; 51(2): 284 - 292. [Abstract] [Full Text] [PDF]
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J. S. Fisher, J. Gao, D.-H. Han, J. O. Holloszy, and L. A. Nolte Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E18 - E23. [Abstract] [Full Text] [PDF]
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R. Bergeron, J. M. Ren, K. S. Cadman, I. K. Moore, P. Perret, M. Pypaert, L. H. Young, C. F. Semenkovich, and G. I. Shulman Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1340 - E1346. [Abstract] [Full Text] [PDF]
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S. R. Paulsen, D. S. Rubink, and W. W. Winder AMP-activated protein kinase activation prevents denervation-induced decline in gastrocnemius GLUT-4 J Appl Physiol, November 1, 2001; 91(5): 2102 - 2108. [Abstract] [Full Text] [PDF]
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W. W. Winder Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle J Appl Physiol, September 1, 2001; 91(3): 1017 - 1028. [Abstract] [Full Text] [PDF]
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D. Zheng, P. S. MacLean, S. C. Pohnert, J. B. Knight, A. L. Olson, W. W. Winder, and G. L. Dohm Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase J Appl Physiol, September 1, 2001; 91(3): 1073 - 1083. [Abstract] [Full Text] [PDF]
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N. Musi, N. Fujii, M. F. Hirshman, I. Ekberg, S. Fröberg, O. Ljungqvist, A. Thorell, and L. J. Goodyear AMP-Activated Protein Kinase (AMPK) Is Activated in Muscle of Subjects With Type 2 Diabetes During Exercise Diabetes, May 1, 2001; 50(5): 921 - 927. [Abstract] [Full Text]
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E. S. Buhl, N. Jessen, O. Schmitz, S. B. Pedersen, O. Pedersen, G. D. Holman, and S. Lund Chronic Treatment With 5-Aminoimidazole-4-Carboxamide-1-{beta}-D-Ribofuranoside Increases Insulin-Stimulated Glucose Uptake and GLUT4 Translocation in Rat Skeletal Muscles in a Fiber Type--Specific Manner Diabetes, January 1, 2001; 50(1): 12 - 17. [Abstract] [Full Text]
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W. W. Winder, B. F. Holmes, D. S. Rubink, E. B. Jensen, M. Chen, and J. O. Holloszy Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle J Appl Physiol, June 1, 2000; 88(6): 2219 - 2226. [Abstract] [Full Text] [PDF]
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E. O. Ojuka, T. E. Jones, L. A. Nolte, M. Chen, B. R. Wamhoff, M. Sturek, and J. O. Holloszy Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca2+ Am J Physiol Endocrinol Metab, May 1, 2002; 282(5): E1008 - E1013. [Abstract] [Full Text] [PDF]
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P < 0.01 vs.
control.
