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Department of Zoology, Brigham Young University, Provo, Utah 84602; and Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Muscle contraction causes an increase in activity of
5'-AMP-activated protein kinase (AMPK). This study was designed
to determine whether chronic chemical activation of AMPK will increase
mitochondrial enzymes, GLUT-4, and hexokinase in different types of
skeletal muscle of resting rats. In acute studies, rats were
subcutaneously injected with either
5-aminoimidazole-4-carboxamide-1-
-D-ribofuranoside (AICAR; 1 mg/g body wt) in 0.9% NaCl or with 0.9% NaCl alone and were
then anesthetized for collection and freezing of tissues. AMPK activity
increased in the superficial, white region of the quadriceps and in
soleus muscles but not in the deep, red region of the quadriceps
muscle. Acetyl-CoA carboxylase (ACC) activity, a target for AMPK,
decreased in all three muscle types in response to AICAR injection but
was lowest in the white quadriceps. In rats given daily, 1 mg/g body
wt, subcutaneous injections of AICAR for 4 wk, activities of citrate
synthase, succinate dehydrogenase, and malate dehydrogenase were
increased in white quadriceps and soleus but not in red quadriceps.
Cytochrome c and 
-aminolevulinic acid synthase levels were
increased in white, but not red, quadriceps. Carnitine
palmitoyl-transferase and hydroxy-acyl-CoA dehydrogenase were not
significantly increased. Hexokinase was markedly increased in all three
muscles, and GLUT-4 was increased in red and white quadriceps. These
results suggest that chronic AMPK activation may mediate the effects of
muscle contraction on some, but not all, biochemical adaptations of
muscle to endurance exercise training.
-aminolevulinate synthase; carnitine palmitoyl transferase; citrate synthase; citric acid cycle enzymes; endurance training; GLUT-4; muscle mitochondria
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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BIOCHEMICAL ADAPTATIONS OF skeletal muscle to endurance
exercise have been extensively studied, beginning with a report in 1967 that showed an increase in mitochondrial oxidative enzyme activities in
response to 3 mo of endurance training in rats (3, 4, 14-16).
However, the mechanisms that couple chronic muscle contractions with an
increase in mitochondrial enzymes have been elusive (3). Previous
studies (3) have provided some evidence that the energy charge of the
cell is somehow involved. When creatine and creatine phosphate (CP) are
depleted in the muscle by giving rats -guanidinopropionic acid in
their food for 6 wk, CP is replaced by -guanidinopropionic acid
phosphate, ATP concentration is decreased, and levels of mitochondrial
enzymes, GLUT-4, and hexokinase are increased (31, 34). Chronic
exposure of muscle cells to hypoxia results in an increase in
mitochondrial enzyme content (cf. Ref. 3), and thyroid hormone
treatment of rats also produces an increase in muscle mitochondria
(39).
5'-AMP activated protein kinase (AMPK) has recently been implicated as being important as a metabolic master switch in the muscle, controlling both fat metabolism and glucose uptake (38). This enzyme is controlled by both allosteric and covalent mechanisms. It is activated allosterically by an increase in 5'-AMP and inhibited by ATP and CP (8, 9, 38). Phosphorylation of AMPK by an upstream kinase (AMPKK), also activated by 5'-AMP, results in activation of AMPK. A large amplification of activity can result from maximal stimulation by both mechanisms (8, 9, 38). AMPK activity increases in the muscles of rats running on a treadmill and in response to electrical stimulation (32, 37, 38).
5-Aminoimidazole-4-carboxamide-1--D-ribofuranoside
(AICAR) is an analog of adenosine that is taken up by muscle and
phosphorylated to form
5-aminoimidazole-4-carboxamide-1--D-ribofuranosyl-5'-monophosphate (ZMP) that also activates AMPK (9, 25, 38). Therefore, AICAR treatment can be used to mimic the effects of exercise on AMPK
activity. This approach has been used previously to determine the
effects of AMPK activation in perfused muscle, incubated muscle, and
intact, sedentary rats (2, 11, 18, 23, 25). Evidence has been reported
for AMPK involvement in the control of fatty acid oxidation and in the
insulin-like effect of muscle contraction on glucose transport (11, 23,
25, 38).
More recently, evidence was obtained for the involvement of AMPK in coupling the effect of muscle contraction with some of the adaptations to exercise training. Daily injections of AICAR in resting rats were found to increase GLUT-4 and hexokinase activity in gastrocnemius and epitrochlearis muscles, similar to the activity found after a few days of endurance exercise training (18). Incubation of epitrochlearis muscle with AICAR resulted in significant increases in GLUT-4 and hexokinase during an 18-h period (28). The present study was designed to determine whether chronic activation of AMPK with AICAR would produce mitochondrial adaptations similar to those induced by exercise training. Because of the longer half-lives of the mitochondrial enzymes, a prolonged treatment was deemed necessary. We were also interested in determining whether the adaptations in GLUT-4 and hexokinase seen after 5 days of treatment (18) would persist or be enhanced by a prolonged AICAR treatment. Fiber type-specific responses were also studied.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Treatment of rats. All procedures were approved by the Institutional Animal Care and Use Committee of Brigham Young University. Male Sprague-Dawley rats (Sasco, Wilmington, MA) were housed in individual cages in a temperature- (22-25°C) and light-controlled (12:12-h light-dark cycle) room and were given Harlan Teklad rodent diet (Madison, WI) and water ad libitum. All rats were handled daily for at least 5 days before the beginning of treatment to accustom them to the experimental procedures.
Acute studies. The purpose of these studies was to determine whether AMPK activity was acutely increased in muscle by AICAR treatment. Three days before the experiment, jugular cathethers were installed and exteriorized on the back of the neck to allow rapid anesthesia of the rat and blood and tissue collection. Rats were then subcutaneously injected with AICAR (1 mg/g body wt) in sterile 0.9% NaCl or were given 0.9% NaCl (n = 6 animals per group). One hour after the subcutaneous injection, rats were anesthetized by intravenous injection of pentobarbital sodium (4.8 mg/100 g body wt). The superficial white and the deep red regions of the quadriceps muscles and the soleus muscles were quickly removed with stainless steel clamps and frozen at liquid nitrogen temperature.
Resuspended ammonium sulfate precipitates of tissue homogenates were analyzed for AMPK activity and acetyl-CoA carboxylase (ACC) activity, as described previously (25, 37). This measurement of AMPK only detects increases in AMPK activity that survive ammonium sulfate precipitation of the muscle homogenate (i.e., increases due to phosphorylation) and does not provide information concerning allosteric control by AMP, CP, and ATP. ACC activity at 0.2 mM citrate provided some indication of the in vivo activity of AMPK because ACC is a target for phosphorylation of AMPK. ACC activity was previously reported to decrease in response to phosphorylation by AMPK (37). The acute experiment was also repeated on rats treated with AICAR or saline for 4 wk to determine whether the responses of AMPK and ACC to AICAR persisted for the entire treatment period. In both experiments, ATP and CP were measured on neutralized perchloric acid extracts of muscle.Chronic studies.
To determine the effect of chronic injections of AICAR on muscle enzyme
activities or expression and on muscle GLUT-4, rats were given daily
subcutaneous injections, between 8 and 10 AM, of AICAR (1 mg/g body wt)
or saline vehicle for 28 ± 1 successive days. Beginning
with the first injection, saline-injected controls were pair-fed with
AICAR-injected rats. Rats were anesthetized by intraperitoneal
injection of pentobarbital sodium 22-25 h after the last AICAR
injection, and the white and red regions of the quadriceps and the
soleus muscles were removed and frozen, as described previously.
Muscles were kept frozen at 
70°C until analyzed. Liver,
heart, kidney, and fat pads were also weighed.
Analytical methods. Muscles from rats killed 1 h after injection of AICAR or saline were analyzed for AMPK (25, 37), ACC at 0.2 mM citrate (25, 37), ATP and CP (13), and ZMP (25).
To determine the chronic effects of AICAR injection, muscles were analyzed for glycogen (10), GLUT-4, hexokinase, lactate dehydrogenase, and several mitochondrial enzymes. GLUT-4 was quantitated by Western blotting, as described previously (18), using GLUT-4 polyclonal antibody RaIRGT (Biogenesis, Sandown, NH) and horseradish peroxidase-conjugated anti-rabbit IgG (Amersham Life Science, Arlington Heights, IL).-Aminolevulinic acid synthase was determined using
Western blotting techniques as described by Li et al. (24). For
determination of cytochrome c, muscles were homogenized in 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic
acid, 1 mM EDTA, and 250 mM sucrose (hydroxyethyl starch buffer).
Homogenates were centrifuged at 700 g for 10 min, and aliquots
of the supernatant containing 100 µg of protein were solubilized in
Laemmli sample buffer, subjected to SDS-polyacrylamide gel
electrophoresis (15% resolving gel), and then transferred to
nitrocellulose. Cytochrome c was detected by incubating the
nitrocellulose blots with a rabbit polyclonal antibody against rabbit
heart cytochrome c (Alpha Diagnostics International, San
Antonio, TX) followed by horseradish peroxidase-conjugated anti-rabbit
IgG. Antibody-bound GLUT-4, -aminolevulinic acid synthase, and
cytochrome c were visualized using enhanced chemiluminescence. Protein bands were quantified by densitometry.
For enzyme activity measurements, 10% homogenates were made from the
respective muscles in 175 mM KCl, 10 mM GSH, and 2 mM EDTA, pH 7.4. This homogenate was frozen and thawed three times and mixed thoroughly
before enzymatic measurements. For succinate dehydrogenase and lactate
dehydrogenase assays, an aliquot of the homogenate was centrifuged at
700 g for 10 min at 4°C. The remainder of the assays were
performed on aliquots and dilutions of the mixed whole homogenate.
Assays were performed by the following methods: citrate synthase (35),
succinate dehydrogenase (21), the mitochondrial fraction of malate
dehydrogenase (33), hexokinase (36), lactate dehydrogenase (29),
carnitine palmitoyl transferase (1, 26), and hydroxyacyl-CoA
dehydrogenase (22).
Differences between the saline-injected control rats and AICAR-injected
rats were determined using Student's t-test. Values are
expressed as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Acute studies.
A single injection of AICAR in rats not previously treated with AICAR
resulted in significant increases in AMPK activity in white quadriceps
and soleus muscle but not in red quadriceps muscles (Table
1) 60 min after the injection. In these
same muscle extracts, the activity of ACC at 0.2 mM citrate was
markedly decreased in all three muscle types. In the AICAR-injected
rats, white quadriceps exhibited the lowest activity of ACC (44% and
61% of that seen in soleus and red quadriceps, respectively; P < 0.05).
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Chronic studies.
Food intake and body weight of rats injected with either saline or
AICAR in saline for 4 wk is shown in Fig.
1. No statistically significant differences
were noted between AICAR- and saline-injected rats. Final body and
organ weights are shown in Table 2. No
statistically significant differences were noted in muscle, heart, or
kidney weights, but the liver showed significant hypertropy in the
AICAR-treated animals. There was also a significant decrease in fat pad
weight in the AICAR-treated rats.
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-aminolevulinic acid synthase, as determined by
Western blot, and cytocrome c were significantly increased in
white, but not red, quadriceps (Fig. 2).
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1 · min1
in AICAR-injected rats. This represented a 48% increase and was highly
significant (P < 0.001). A significant increase also occurred in the red region of the quadriceps in response to AICAR [47.0 ± 2.8 (controls) vs. 57.4 ± 2.5 µmol · g1 · min1
(AICAR-injected); (P < 0.025)].
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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One of the key adaptations to endurance exercise training is the increase in mitochondrial oxidative enzymes of the muscles involved in exercise (3, 4, 14-16). Previous studies have indicated that skeletal muscle enzymes of the citric acid cycle, of the electron transport chain, and also of fatty acid oxidation all increase in response to an endurance training program or to chronic electrical stimulation (3, 4, 14-16). The physiological consequence of this adaptation is an increase in the capacity to oxidize pyruvate and fatty acids and to generate ATP. The insulin-sensitive glucose transporter GLUT-4 and hexokinase tend to adapt in the same direction as the mitochondrial oxidative enzymes (3, 5, 7, 12, 17, 19, 20, 27, 30, 31).
Although these adaptations are well-characterized, little is known
about the mechanisms coupling muscle contractile activity to the
increase in expression of these proteins in muscle (see Refs. 3, 4). A
recent study provides evidence that AMPK may be involved in some of
these adaptations: activation of muscle AMPK by injecting rats with
AICAR for 5 successive days resulted in significant increases in GLUT-4
and hexokinase activities of epitrochlearis and gastrocnemius muscles
(18). The present results show that this adaptative response is
maintained, but not further enhanced, during 28 days of AICAR
injection. It has also been shown that incubation of epitrochlearis
muscle with AICAR for 18 h results in increases in GLUT-4 and
hexokinase, providing additional evidence of AMPK involvement in
control of muscle gene expression (28). AMPK activity has been shown to
increase in skeletal muscle of rats running on treadmills and in
electrically stimulated muscle (32, 37, 38). These observations suggest that AMPK activation may be involved in mediating the effect of exercise on at least some biochemical adaptations of muscle (see Fig.
6).
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The current study was undertaken to determine whether mitochondrial adaptations would also be mediated by chronic AMPK activation. We previously observed that ZMP is increased in muscle 15 min after a subcutaneous injection of AICAR and remains elevated for at least 2 h after the injection (18). In the present study, we found that AMPK activity was increased in white quadriceps and soleus, but not in red quadriceps, 60 min after the AICAR injection. It should be emphasized that AMPK can be activated by phosphorylation by AMPKK and also by allosteric mechanisms (Fig. 6). The AMPK activity that we measured in muscle extracts provides an indirect measure of the phosphorylation state of AMPK. However, both AMPKK and AMPK are also allosterically activated by the free AMP concentration that has been shown to increase in the muscle in response to contraction (cf. Ref. 38). In addition, AMPK is inhibited allosterically by CP, making the decline in CP during muscle contraction an important signal for allowing activation of this enzyme (cf. Refs. 9, 38). These allosteric effects are lost during preparation of the AMPK extracts and, therefore, cannot be detected with the AMPK assay. However, it is possible to obtain an estimation of the in vivo activation of AMPK by measuring the effects of the phosphorylation of one of its known target proteins.
Purified muscle ACC has been shown to be phosphorylated in vitro by AMPK (37). This also results in an increase in the activation constant for citrate and a decrease in the maximal velocity of the purified ACC (37). Similar changes in kinetic properties of ACC are observed in muscles of rats running on treadmills and in electrically stimulated muscle (32, 37, 38). Phosphorylation by AMPK results in marked decreases in activity of ACC at physiological concentrations of citrate of ~0.2 mM; therefore, measurement of ACC activity at 0.2 mM citrate provides information regarding the true activity of AMPK in vivo. In the present study, injection of AICAR resulted in decreases in ACC activity in all three muscle types, but the greatest decrease occurred in the white portion of the quadriceps. The decrease in ACC activity provides evidence that AMPK activity was stimulated in all three muscle types in response to AICAR. In the chronically treated animals and in the red quadriceps before chronic treatment, AMPK was apparently activated by predominately allosteric mechanisms (i.e., ZMP effects on AMPK) and not by phosphorylation of AMPK by AMPKK.
Citrate synthase, cytochrome c, -aminolevulinate synthase,
and malate dehydrogenase were all significantly increased in the white
region of the quadriceps muscle in response to 4 wk of AICAR injections. -Aminolevulinate synthase activity was previously reported to increase within 16 h of a prolonged bout of exercise (see
Ref. 15); however, preliminary experiments on the effect of a single
injection of AICAR 16 h before tissue collection have produced negative
results (unpublished data). Hexokinase activity increased in response
to AICAR in all muscle types. Interestingly, neither of the enzymes
involved in fatty acid oxidation that we measured increased in response
to AICAR injection. The fact that some enzymes appear to respond and
others do not provides evidence that more than one signal is
responsible for the concerted rise in mitochondrial oxidative enzyme
activity in response to endurance training. It should be noted that
AICAR injection does not precisely mimic the effects of contraction on
this control system. The decline in CP accompanying contraction may be
a critical component of the signal, and muscle CP was not significantly
changed in red quadriceps in response to AICAR. A previous
study (Winder, unpublished data) demonstrated that the time course of
the decline in gastrocnemius ACC activity during electrical stimulation
correlates more closely with the decline in CP than with the measured
AMPK activity. The increase in cytosolic calcium during
excitation-contraction coupling and the rise in plasma fatty acids that
accompanies prolonged exercise bouts may also be important in inducing
the increase in mitochondrial enzymes. These effects of exercise are
not mimicked by AICAR injections.
Evidence has recently been presented for the role of calcium and
protein kinase C in inducing increases in cytochrome c gene expression (6). An increase in cytochrome c gene expression was
observed in myotube culture by treatment with a calcium ionophore (6).
The ionophore-induced response was increased by enhancing expression of
calcium-sensitive 
and 2 protein kinase C isoforms but not of the calcium-insensitive -isoform. It is unclear at this
time how the putative AMPK-induced pathway is related to the
calcium-triggered pathway. It is also possible that the AMPK pathway is
activated with this calcium ionophore. AMPK activity was not
quantitated in that study.
It is unclear, at this time, why the white quadriceps muscle responded with an increase in mitochondrial enzymes and the red quadriceps did not. One possible interpretation is that AMPK activation is not responsible for the mitochondrial adaptations. It is also possible that the phosphorylated species of AMPK is responsible for triggering increased rates of synthesis of mitochondrial enzymes. If the decline in ACC activity is a true measure of in vivo AMPK activity, we may conclude that AMPK is activated allosterically in red quadriceps by AICAR injection, but the phosphorylation state of AMPK is unchanged with respect to controls. It is also important to consider the total daily signal rather than the isolated effects of AICAR. The total daily contractile activity would certainly be expected to be greater in red quadriceps and in soleus fibers than in fibers of the white quadriceps.
In addition, the AMPK response to AICAR appeared to be downregulated by the end of the 4-wk treatment period. No significant increase was observed in AMPK activity in any of the muscle types 1 h after injection of AICAR in the chronically treated rats. However, the decrease in ACC activity at 0.2 mM citrate was similar to that seen in rats at the beginning of the 4-wk treatment regimen. The reason for this downregulation response is not clear. We did note significant liver hypertrophy, increasing the probability of more rapid metabolism of the AICAR after the daily injections. However, 1 h after the chronically treated rats were injected with AICAR, the ZMP concentration was elevated in all three muscle fiber types to levels in the same range as observed previously (18). There is also the possibility that expression of the AMPK or AMPKK genes changes in response to chronic activation.
When it was apparent that the response of AMPK to AICAR was diminishing over the course of the 4-wk chronic study and that the magnitude of the adaptation appeared to be less than that seen in response to 2 h/day of endurance training (a twofold increase), it seemed important to determine whether an intermittent pattern of AICAR injection would prevent downregulation, allowing the true response of a mitochondrial marker enzyme to AMPK activation to be observed. Previous studies clearly demonstrated that training adaptations occur in rats run only 5 days/wk, 2 h/day, representing an intermittent stimulus (14). The fact that a significant increase in citrate synthase was observed in red quadriceps in response to 2 wk of intermittent treatment with AICAR suggests the possibility that, in the 4-wk chronic-injection study, the mitochondrial enzymes may have increased early in the treatment but, because of downregulation, subsided in red quadriceps as the treatment was extended to 4 wk.
The marked decrease in fat pad size is of considerable interest in terms of treatment of Type 2 diabetes and obesity using AMPK activators. The chronic AMPK activation is accompanied by ACC inactivation and a consequent decline in malonyl-CoA (see Ref. 18). The decline in malonyl-CoA would allow an increased influx of fatty acids into the mitochondria and an increase in fatty acid oxidation. AICAR-treated rats were pair-fed so that they ate the same amount of food and gained weight at the same rate as controls, but the size of the fat pads was still markedly decreased. These results provide an additional rationale for the development of more potent AMPK activators to treat Type 2 diabetes and obesity, but the large amount of AICAR required to induce these adaptations makes it an unlikely candidate for use in human patients for these purposes.
In summary, chronic AMPK activation using AICAR injections in resting
rats results in significant increases in -aminolevulinic synthase,
cytochrome c, citrate synthase, and malate dehydrogenase in
white, but not red, quadriceps. Hexokinase activity was significantly increased in both quadriceps muscle types and in soleus muscles. GLUT-4
was increased in both red and white quadriceps, and a trend toward an
increase was noted in soleus. The extent of AMPK activation appeared to
be greatest in the white quadriceps, as evidenced by AMPK activity
measurements in the presence of maximally effective AMP concentrations
and by the extent of reduction in ACC activity (an AMPK target). These
results suggest that the activation of AMPK that accompanies muscle
contraction during daily bouts of training may play a role in mediating
some of the biochemical adaptations that are induced in skeletal muscle
by endurance exercise. The data also suggest that not all muscular
adaptations to training are mediated by activation of AMPK.
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ACKNOWLEDGEMENTS |
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This research was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-41438 to W. W. Winder and by National Institute on Aging Grant AG-00425 to J. O. Holloszy.
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FOOTNOTES |
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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: W. W. Winder, Dept. of Zoology, Brigham Young Univ., Provo, UT 84602 (E-mail: william_winder{at}byu.edu).
Received 16 December 1999; accepted in final form 28 January 2000.
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RESULTS
DISCUSSION
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 J. V. Swinnen, A. Beckers, K. Brusselmans, S. Organe, J. Segers, L. Timmermans, F. Vanderhoydonc, L. Deboel, R. Derua, E. Waelkens, et al. Mimicry of a Cellular Low Energy Status Blocks Tumor Cell Anabolism and Suppresses the Malignant Phenotype Cancer Res., March 15, 2005; 65(6): 2441 - 2448. [Abstract] [Full Text] [PDF]
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E. B. Taylor, D. Hurst, L. J. Greenwood, J. D. Lamb, T. D. Cline, S. N. Sudweeks, and W. W. Winder Endurance training increases LKB1 and MO25 protein but not AMP-activated protein kinase kinase activity in skeletal muscle Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1082 - E1089. [Abstract] [Full Text] [PDF]
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T. Akimoto, T. J. Ribar, R. S. Williams, and Z. Yan Skeletal muscle adaptation in response to voluntary running in Ca2+/calmodulin-dependent protein kinase IV-deficient mice Am J Physiol Cell Physiol, November 1, 2004; 287(5): C1311 - C1319. [Abstract] [Full Text] [PDF]
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 G. R. Steinberg, A. C. Smith, B. J. W. van Denderen, Z. Chen, S. Murthy, D. J. Campbell, G. J. F. Heigenhauser, D. J. Dyck, and B. E. Kemp AMP-Activated Protein Kinase Is Not Down-Regulated in Human Skeletal Muscle of Obese Females J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4575 - 4580. [Abstract] [Full Text] [PDF]
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J. A. Villena, B. Viollet, F. Andreelli, A. Kahn, S. Vaulont, and H. S. Sul Induced Adiposity and Adipocyte Hypertrophy in Mice Lacking the AMP-Activated Protein Kinase-{alpha}2 Subunit Diabetes, September 1, 2004; 53(9): 2242 - 2249. [Abstract] [Full Text] [PDF]
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D. Nagata, R. Takeda, M. Sata, H. Satonaka, E. Suzuki, T. Nagano, and Y. Hirata AMP-Activated Protein Kinase Inhibits Angiotensin II-Stimulated Vascular Smooth Muscle Cell Proliferation Circulation, July 27, 2004; 110(4): 444 - 451. [Abstract] [Full Text] [PDF]
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E.-K. Kim, I. Miller, S. Aja, L. E. Landree, M. Pinn, J. McFadden, F. P. Kuhajda, T. H. Moran, and G. V. Ronnett C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase J. Biol. Chem., May 7, 2004; 279(19): 19970 - 19976. [Abstract] [Full Text] [PDF]
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S. A. Clark, Z.-P. Chen, K. T. Murphy, R. J. Aughey, M. J. McKenna, B. E. Kemp, and J. A. Hawley Intensified exercise training does not alter AMPK signaling in human skeletal muscle Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E737 - E743. [Abstract] [Full Text] [PDF]
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U. Andersson, K. Filipsson, C. R. Abbott, A. Woods, K. Smith, S. R. Bloom, D. Carling, and C. J. Small AMP-activated Protein Kinase Plays a Role in the Control of Food Intake J. Biol. Chem., March 26, 2004; 279(13): 12005 - 12008. [Abstract] [Full Text] [PDF]
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C. Frosig, S. B. Jorgensen, D. G. Hardie, E. A. Richter, and J. F. P. Wojtaszewski 5'-AMP-activated protein kinase activity and protein expression are regulated by endurance training in human skeletal muscle Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E411 - E417. [Abstract] [Full Text]
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S. Terada and I. Tabata Effects of acute bouts of running and swimming exercise on PGC-1{alpha} protein expression in rat epitrochlearis and soleus muscle Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E208 - E216. [Abstract] [Full Text] [PDF]
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S. B. Jorgensen, B. Viollet, F. Andreelli, C. Frosig, J. B. Birk, P. Schjerling, S. Vaulont, E. A. Richter, and J. F. P. Wojtaszewski Knockout of the {alpha}2 but Not {alpha}1 5'-AMP-activated Protein Kinase Isoform Abolishes 5-Aminoimidazole-4-carboxamide-1-{beta}-4-ribofuranosidebut Not Contraction-induced Glucose Uptake in Skeletal Muscle J. Biol. Chem., January 9, 2004; 279(2): 1070 - 1079. [Abstract] [Full Text] [PDF]
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J. Norrbom, C. J. Sundberg, H. Ameln, W. E. Kraus, E. Jansson, and T. Gustafsson PGC-1{alpha} mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle J Appl Physiol, January 1, 2004; 96(1): 189 - 194. [Abstract] [Full Text] [PDF]
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N. B. Ruderman, A. K. Saha, and E. W. Kraegen Minireview: Malonyl CoA, AMP-Activated Protein Kinase, and Adiposity Endocrinology, December 1, 2003; 144(12): 5166 - 5171. [Abstract] [Full Text] [PDF]
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M. Suwa, H. Nakano, and S. Kumagai Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles J Appl Physiol, September 1, 2003; 95(3): 960 - 968. [Abstract] [Full Text] [PDF]
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K. BAAR, Z. SONG, C. F. SEMENKOVICH, T. E. JONES, D.-H. HAN, L. A. NOLTE, E. O. OJUKA, M. CHEN, and J. O. HOLLOSZY Skeletal muscle overexpression of nuclear respiratory factor 1 increases glucose transport capacity FASEB J, September 1, 2003; 17(12): 1666 - 1673. [Abstract] [Full Text] [PDF]
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C. T Putman, M. Kiricsi, J. Pearcey, I. M MacLean, J. A Bamford, G. K Murdoch, W. T Dixon, and D. Pette AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions J. Physiol., August 15, 2003; 551(1): 169 - 178. [Abstract] [Full Text] [PDF]
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S. I. Itani, A. K. Saha, T. G. Kurowski, H. R. Coffin, K. Tornheim, and N. B. Ruderman Glucose Autoregulates Its Uptake in Skeletal Muscle: Involvement of AMP-Activated Protein Kinase Diabetes, July 1, 2003; 52(7): 1635 - 1640. [Abstract] [Full Text] [PDF]
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E. O. OJUKA, T. E. JONES, D.-H. HAN, M. CHEN, and J. O. HOLLOSZY Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle FASEB J, April 1, 2003; 17(6): 675 - 681. [Abstract] [Full Text] [PDF]
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N. Jessen, R. Pold, E. S. Buhl, L. S. Jensen, O. Schmitz, and S. Lund Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles J Appl Physiol, April 1, 2003; 94(4): 1373 - 1379. [Abstract] [Full Text] [PDF]
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S. L. McGee, K. F. Howlett, R. L. Starkie, D. Cameron-Smith, B. E. Kemp, and M. Hargreaves Exercise Increases Nuclear AMPK {alpha}2 in Human Skeletal Muscle Diabetes, April 1, 2003; 52(4): 926 - 928. [Abstract] [Full Text] [PDF]
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K. Hojlund, K. Wrzesinski, P. M. Larsen, S. J. Fey, P. Roepstorff, A. Handberg, F. Dela, J. Vinten, J. G. McCormack, C. Reynet, et al. Proteome Analysis Reveals Phosphorylation of ATP Synthase beta -Subunit in Human Skeletal Muscle and Proteins with Potential Roles in Type 2 Diabetes J. Biol. Chem., March 14, 2003; 278(12): 10436 - 10442. [Abstract] [Full Text] [PDF]
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J. N. Nielsen, K. J. W. Mustard, D. A. Graham, H. Yu, C. S. MacDonald, H. Pilegaard, L. J. Goodyear, D. G. Hardie, E. A. Richter, and J. F. P. Wojtaszewski 5'-AMP-activated protein kinase activity and subunit expression in exercise-trained human skeletal muscle J Appl Physiol, February 1, 2003; 94(2): 631 - 641. [Abstract] [Full Text] [PDF]
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M. Yu, N. K Stepto, A. V Chibalin, L. G D Fryer, D. Carling, A. Krook, J. A Hawley, and J. R Zierath Metabolic and mitogenic signal transduction in human skeletal muscle after intense cycling exercise J. Physiol., January 15, 2003; 546(2): 327 - 335. [Abstract] [Full Text] [PDF]
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T. Daniel and D. Carling Functional Analysis of Mutations in the gamma 2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome J. Biol. Chem., December 20, 2002; 277(52): 51017 - 51024. [Abstract] [Full Text] [PDF]
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H. Zong, J. M. Ren, L. H. Young, M. Pypaert, J. Mu, M. J. Birnbaum, and G. I. Shulman AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation PNAS, December 10, 2002; 99(25): 15983 - 15987. [Abstract] [Full Text] [PDF]
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E. Tomas, T.-S. Tsao, A. K. Saha, H. E. Murrey, C. c. Zhang, S. I. Itani, H. F. Lodish, and N. B. Ruderman Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation PNAS, December 10, 2002; 99(25): 16309 - 16313. [Abstract] [Full Text] [PDF]
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J. Stoppani, A. L. Hildebrandt, K. Sakamoto, D. Cameron-Smith, L. J. Goodyear, and P. D. Neufer AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1239 - E1248. [Abstract] [Full Text] [PDF]
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E. O. Ojuka, T. E. Jones, D.-H. Han, M. Chen, B. R. Wamhoff, M. Sturek, and J. O. Holloszy Intermittent increases in cytosolic Ca2+ stimulate mitochondrial biogenesis in muscle cells Am J Physiol Endocrinol Metab, November 1, 2002; 283(5): E1040 - E1045. [Abstract] [Full Text] [PDF]
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M. A. Iglesias, J.-M. Ye, G. Frangioudakis, A. K. Saha, E. Tomas, N. B. Ruderman, G. J. Cooney, and E. W. Kraegen AICAR Administration Causes an Apparent Enhancement of Muscle and Liver Insulin Action in Insulin-Resistant High-Fat-Fed Rats Diabetes, October 1, 2002; 51(10): 2886 - 2894. [Abstract] [Full Text] [PDF]
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B. R. Barnes, J. W. Ryder, T. L. Steiler, L. G.D. Fryer, D. Carling, and J. R. Zierath Isoform-Specific Regulation of 5' AMP-Activated Protein Kinase in Skeletal Muscle From Obese Zucker (fa/fa) Rats in Response to Contraction Diabetes, September 1, 2002; 51(9): 2703 - 2708. [Abstract] [Full Text] [PDF]
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H. Park, V. K. Kaushik, S. Constant, M. Prentki, E. Przybytkowski, N. B. Ruderman, and A. K. Saha Coordinate Regulation of Malonyl-CoA Decarboxylase, sn-Glycerol-3-phosphate Acyltransferase, and Acetyl-CoA Carboxylase by AMP-activated Protein Kinase in Rat Tissues in Response to Exercise J. Biol. Chem., August 30, 2002; 277(36): 32571 - 32577. [Abstract] [Full Text] [PDF]
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