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1Institute of Health Science, Kyushu University, Kasuga, Fukuoka 816-8580; and 2Department of Human Development, Nakamura Gakuen University, Jonan-ku, Fukuoka 814-0198, Japan
Submitted 7 April 2003 ; accepted in final form 24 May 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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-D-ribofuranoside
(AICAR) for 14 successive days. AICAR treatment caused a significant decrease
in the percentage of type IIB fibers and the concomitant increase in the
percentage of type IIX fibers in extensor digitorum longus (EDL) muscle. The
capillary density and the capillary-to-fiber ratio were not altered by AICAR.
AICAR treatment increased the glycolytic and oxidative enzyme activities but
not the antioxidant enzyme activities. The AICAR treatment increased the
uncoupling protein 3 (UCP3) level in EDL and the peroxisome
proliferator-activated receptor-
coactivator-1
protein level in
the soleus and EDL muscles, whereas the myogenin level was not altered by
AICAR. These results seem to imply that the chronic activation of AMPK alters
such muscle histochemical and metabolic characteristics.
5'-AMP-activated protein kinase; antioxidant capacity; mitochondrial enzymes; muscle fiber type composition; peroxisome proliferator-activated receptor-
coactivator-1; 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside; uncoupling protein 3
Recently, the activation of 5'-AMP-activated protein kinase (AMPK) by
the injection of
5-aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR) or
-guanidinopropionic acid feeding showed an increase in fatty acid
oxidation (31), glucose uptake
(31), mitochondrial biogenesis
(2,
58), hexokinase (HK) activity
(20,
53), mitochondrial enzyme
activities (53), glucose
transporter 4 (GLUT-4) protein
(20), and uncoupling protein 3
(UCP3) (57). AMPK was
activated by muscle contraction such as exercise
(14,
52) and electrical stimulation
(22) by depression of
ATP-to-AMP ratio. It is thus hypothesized that such skeletal muscle
adaptations to endurance exercise training occur at least in part through the
AMPK pathway.
Peroxisome proliferator-activated receptor- coactivator 1
(PGC-1) is a transcriptional coactivator that interacts with several nuclear
transcriptional factors (40).
PGC-1 promoted GLUT-4 expression
(32), mitochondrial biogenesis
(30,
56), and fiber type
transformation (30) in
skeletal muscle cells. PGC-1 mRNA expression was enhanced by AICAR
(46). Acute endurance exercise
increased skeletal muscle PGC-1 mRNA
(1,
36,
46) and protein
(1) levels. Endurance exercise
training also increased skeletal muscle PGC-1 mRNA
(36). On the basis of these
data, it is hypothesized that some skeletal muscle adaptations due to
endurance exercise training such as an increase in the oxidative enzyme
activities and fiber type transformation are induced by the activation of AMPK
and the consequent increase in the PGC-1 expression. However, a study to
determine whether such skeletal muscle adaptations are related to the chronic
activation of AMPK and increased PGC-1 protein content has yet to be
conducted. Therefore, one purpose of the present study was to determine
whether the chronic injection of AICAR influences the PGC-1 protein content,
muscle histochemical characteristics including the fiber composition and
capillary density, and metabolic enzyme activities in rat slow- and
fast-twitch skeletal muscles.
Endurance exercise training enhances skeletal muscle antioxidant enzyme activities (37). In addition, acute exercise and AICAR increase skeletal muscle UCP3 (57), which is a possible regulator of free radical production (49). These reports raise the possibility that the activation of AMPK also enhances antioxidant systems. However, very few studies concerning the relationship between AMPK and antioxidant systems have so far been conducted (43, 57). Another purpose of the present study was to test the hypothesis that the chronic activation of AMPK by AICAR increases the skeletal muscle UCP3 content and antioxidant enzyme activities.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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140 g were used for this experiment. All rats were handled daily for at
least 6 days before beginning the treatment regimen. All rats were housed two
to three per cage (42 x 25 x 20 cm deep) in a temperature- (22
± 2°C) and humidity-controlled (60 ± 5%) room with a 12-h
light (0700 to 1900) and 12-h dark (1900 to 0700) cycle. Food and water were
provided ad libitum. All experimental procedures were approved by the
University Committee for the Use of Animals in Research and were in strict
accordance with the American Physiological Society Guiding Principles in the
Care and Use of Animals. The rats were divided into control (n = 9)
or AICAR (n = 7) groups. The rats of the control and AICAR groups
were given daily subcutaneous injections of saline vehicle and AICAR (Toronto
Research Chemicals, North York, ON, Canada) (1 mg/g body wt) in saline,
respectively. This dose of AICAR certainly enhanced the skeletal muscle AMPK
activity at 60 and 120 min after injection
(20,
23,
43,
53). Such procedures were
performed between 0800 and 1000 for 14 successive days. The nonfasted rats
were anesthetized 24 h after the last injection, with pentobarbital
sodium (60 mg/kg body wt ip). The soleus and extensor digitorum longus (EDL)
muscles of both legs were rapidly dissected. The muscles of the right leg were
used for an enzyme assay and those of the left leg were used for
histochemistry and Western blotting. The abdominal fat pads (perirenal,
epididymal, and mesenteric) were also excised and weighed. Muscle histochemistry. Skeletal muscle fibers were roughly categorized as type I, IIA, and IIB fibers (6). An analysis of single muscle fibers demonstrated that the histochemically defined type I, IIA, and IIB fibers expressed myosin heavy chains 1, 2a, and 2b, respectively (47). Furthermore, an additional myosin heavy chain 2x, which is also called 2d, has been identified (29, 47). In addition, the type IIC fibers that coexpress type 1 and type 2a myosin heavy chain proteins were also observed (42, 47). In this study, the muscle fibers were categorized as type I, IIC, IIA, IIX, and IIB fibers. The rank order of maximum contraction velocity in rat skeletal muscle fibers was I < IIA < IIX < IIB (15). Muscle transverse sections (7 µm) were cut from each muscle by using a cryostat maintained at -20°C, and the sections were then mounted on a cover glass. Myosin adenosine triphosphatase (ATPase) was determined by using the previously described procedures (44). In brief, consecutive serial sections were processed by using three different pretreatments, preincubation at pH 4.3, 4.6, and 10.4. The muscle fibers were identified as type I, IIC, IIA, IIX, and IIB fibers on the basis of the myosin ATPase staining intensity. Each section was photographed by use of an Axioskop 2 plus microscope (Carl Zeiss, Hallbergmoos, Germany) mounted with an Axiocam HRm CCD camera (Carl Zeiss), and then each fiber was identified and counted by use of a hand counter. Next, the muscle fiber composition was determined by evaluating all countable fibers in both muscles. A remaining transverse section was stained to determine the succinate dehydrogenase activity (33).
To visualize the capillaries, another cross-section (7 µm) was also cut. The section was fixed with 100 mM phosphate buffer containing 4% formaldehyde for 4 min at room temperature and then myosin ATPase (preincubation at pH 10.3) was demonstrated as described previously (45). The stained sections were photographed, and then the artifact-free three 0.147-mm2 areas in each section were analyzed to determine the capillary density (capillaries/mm2), capillary-to-fiber ratio (capillaries/fibers), and fiber density (fibers/mm2).
Enzyme assay. The frozen muscle samples were homogenized 1:20
(wt/vol) in 175 mM KCl, 10 mM GSH, 2 mM EDTA, and 0.1% Triton X-100, pH 7.4.
Enzyme activities were measured spectrophometrically. All enzymatic assays
were carried out at 30°C by using saturating concentrations of substrates
and cofactors as determined in preliminary analyses. Citrate synthase (CS;
tricarboxylic acid cycle) and carnitine palmitoyltransferase (CPT; transport
of fatty acids to mitochondria) activities were measured at 412 nm to detect
the transfer of sulfhydryl groups to 5,5'-dithiobis(2-nitrobenzonic
acid) (DTNB). HK (mobilization of blood glucose), pyruvate kinase (PK;
glycolysis), lactate dehydrogenase (LDH; anaerobic glycolysis), malate
dehydrogenase (MDH; tricarboxylic acid cycle), -hydroxyacyl CoA
dehydrogenase (HAD; -oxidation of fatty acids), glutathione peroxidase
(GPX; antioxidant system), and glutathione reductase (GR; antioxidant system)
activities were measured at 340 nm by following the production or
disappearance of NADH or NADPH.
For the HK (EC 2.7.1.1 [EC] ) assay, 100 mM Tris·HCl, 0.4 mM NADP, 5 mM MgCl2, 700 U/ml glucose-6-phosphate dehydrogenase, 1 mM glucose, and 5 mM ATP, pH 7.0, were used.
For the PK (EC 2.7.1.40 [EC] ) assay, 50 mM Tris·HCl, 0.1 mM KCl, 10 mM MgCl2, 0.28 mM NADH, 1.5 mM ADP, 6 U/ml LDH, and 5 mM phosphoenolpyruvate, pH 7.6, were used.
For the LDH (EC 1.1.1.27 [EC] ) assay, 50 mM Tris·HCl, 0.28 mM NADH, and 2.4 mM pyruvic acid, pH 7.6, were used.
For the MDH (EC 1.1.1.37 [EC] ) assay, 50 mM Tris·HCl, 0.28 mM NADH, and 0.5 mM oxalacetate, pH 7.6, were used.
For the CS (EC 4.1.3.7 [EC] ) assay, 100 mM Tris·HCl, 0.1 mM DTNB, 0.3 mM acetyl-CoA, 3.33 mM K2HPO4, and 0.5 mM oxalacetate, pH 8.0, were used.
For the CPT (EC 2.3.1.21 [EC] ) assay, 75 mM Tris·HCl, 0.2 mM DTNB, 1.5 mM EDTA, 2 mM L-carnitine, 0.05 mM palmitoyl-CoA, pH 8.0, were used.
For the HAD (EC 1.1.1.35 [EC] ) assay, 100 mM Tris·HCl, 0.28 mM NADH, 5 mM EDTA, and 0.1 mM acetoacetyl-CoA, pH 6.9, were used.
For the GPX (EC 1.11.1.9 [EC] ) assay, 100 mM Tris·HCl, 0.5 mM EDTA, 2 mM GSH, 0.2 mM NADPH, 1 U/ml GR, and 0.07 mM t-butyl hydroperoxide, pH 8.0, were used.
For the GR (EC 1.6.4.2 [EC] ) assay, 50 mM phosphate buffer, 1 mM EDTA, 1 mM GSSG, 0.2 mM NADPH, and 0.1% BSA, pH 7.6, were used.
Primary antibodies. Affinity-purified rabbit polyclonal antibody to UCP3 (AB3046, Chemicon International, Temecula, CA), PGC-1 (H-300, Santa Cruz Biotechnology, Santa Cruz, CA), and myogenin (M-225, Santa Cruz Biotechnology) were used in this study.
Gel electrophoresis and Western blotting. The tissue specimens from each muscle were homogenized (1:10) in 50 mM Tris·HCl pH 7.4, 5 mM EDTA, 10 µg/ml PMSF, 0.5 µg/ml leupeptin, 0.2 µg/ml aprotinin, 0.1% Triton X-100, 0.2% NP-40, 0.05% mercaptoethanol, and 1 mM Na3VO4 for 30 s. The homogenate was centrifuged at 15,000 g (4°C) for 25 min. The supernatant was removed, and its protein concentration was determined by use of a protein determination kit (Protein Assay II, 500-0006, Bio-Rad, Richmond, CA). Sodium dodecyl sulfate-polyacrylamide gel (12.5% for UCP3 and myogenin and 7.5% for PGC-1) electrophoresis (SDS-PAGE) was performed. The proteins separated by SDS-PAGE were transferred onto the polyvinylidene difluoride membrane electrophoretically. The membrane was incubated with a blocking buffer of casein solution (SP-5020, Vector Laboratories, Burlingame, CA) for 30 min. The membrane was reacted with the primary antibodies for 1 h and then incubated with biotinylated anti-rabbit IgG (1:800 dilution, Vector Laboratories) for 30 min. The membrane was incubated for 30 min with the avidin and biotinylated horseradish peroxidase macromolecular complex technique (PK-6100, Vector Laboratories) and then was visualized with diaminobenzidine and H2O2. The band densities were determined by use of the NIH Image 1.62 software (National Institutes of Health, Bethesda, MD).
Statistical analysis. To compare the body weight between the treatment groups, the two-way repeated-measures ANOVA (rat group x day) was used. To compare the other variables, the unpaired t-test was used. A value of P < 0.05 was considered to be significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Histochemical analyses. In the EDL muscle, from the myosin ATPase stained sections (Fig. 2A, a and b), the intermediately stained type IIB fibers appear to decrease in the AICAR group. In addition, in the succinate dehydrogenase-stained sections (Fig. 2A, c and d), the intensely stained oxidative fibers seem to increase in the AICAR group. As shown in Fig. 2B, the percentage of type IIB fibers in AICAR was significantly lower than in control (26.9 ± 2.7 and 36.1 ± 2.4%, respectively, P = 0.024), and the percentage of IIX fibers in AICAR was significantly higher than in control (49.0 ± 2.6 and 40.9 ± 2.1%, respectively, P = 0.030). In the soleus muscle, as shown in Fig. 2B, no significant differences were observed in fiber composition of either fiber type. No type IIX or IIB fibers were observed in the soleus muscle.
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The capillary density, capillary-to-fiber ratio, and fiber density (an index of fiber size) are indicated in Table 1. No significant differences were observed regarding the capillary network between the groups.
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Enzyme activities. Table 2 indicates the muscle enzyme activities. HK, PK, CS, MDH, and HAD activities in the AICAR group was significantly greater than control (P < 0.05) in both the soleus and EDL muscles. On the other hand, the LDH, CPT, GPX, and GR activities in AICAR were not significantly different from control in either the soleus or EDL muscles.
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Western blotting. Figure 3A shows representative Western blot detections of UCP3 in the EDL muscle of rats from both groups. Compared with control, UCP3 was markedly increased in the EDL muscle of the AICAR group. The densitometric data (Fig. 3B) indicated that UCP3 protein level in AICAR was significantly higher than in control (1.96 ± 0.28 and 1.00 ± 0.19, respectively, P = 0.010). In the soleus muscle, UCP3 was undetected.
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Figure 4A shows representative Western blot detections of PGC-1 in the soleus and EDL muscles of the rats from both groups. PGC-1 appeared to markedly increase in both the soleus and EDL muscles of the AICAR group. The densitometric data (Fig. 4B) indicated that the PGC-1 protein level of the soleus and EDL muscles in AICAR were significantly higher than control (2.14 ± 0.32 and 1.00 ± 0.08, P = 0.003 in soleus, and 1.87 ± 0.39 and 1.00 ± 0.07, P = 0.025 in EDL, respectively). We also determined the myogenin protein level because it was a possible regulator of oxidative enzyme activities (21). In Fig. 5, the myogenin content was shown to demonstrate no change after chronic AICAR treatment in the soleus muscle (1.00 ± 0.14 in control and 1.26 ± 0.23 in AICAR, P = 0.33). In the EDL muscle, no myogenin was detected.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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IIX conversion occurred in the early phase of chronic muscle
contraction. On the basis of these data, AICAR treatment appears to mimic the
effect of chronic electrical stimulation and endurance exercise training on
muscle fiber type transformation. The reason why AICAR treatment alters the
muscle fiber composition is unclear at present. One possible mechanism for
this is that increased PGC-1 protein by AICAR alters the fiber type-related
gene expression. PGC-1 coactivated transcriptional factor myocyte enhancer
factor-2 (30,
32) and skeletal muscle fiber
type transformation (30).
Myocyte enhancer factor-2 activated the expression of slow or oxidative muscle
genes (55). The induction of
PGC-1 has been proposed to play an important role in coordinating the
activation of various genes linking to the skeletal muscle fiber
phenotype. It should be noted that the fiber-type transformation from type II to type I fibers was not observed in the present study. Although any evidences of the transformation from type II to type I fibers with AICAR treatment have not yet been observed, our results did not completely negate the potential role of AMPK for such transformation. In the early phase of high-intensity endurance exercise training (26) and chronic electrical stimulation (11), the fiber-type transformation within subtypes of type II fibers was only seen. However, in the later phase, alternation from type II to type I fibers may possibly occur (11, 16, 26). Therefore, it might be possible that AICAR treatment for over 14 days induces the transformation from type II to type I fibers. Further research is needed to examine whether AICAR treatment affects all fiber types.
Acute and chronic AICAR treatment increased the skeletal muscle glucose
uptake (8,
18,
28,
31) and GLUT-4 protein content
(20,
23), respectively. Like
previous studies (20,
53), we demonstrated that the
AICAR treatment increased the skeletal muscle HK activity, which is a possible
determinant of the glucose uptake in skeletal muscle during exercise and
hyper-insulinemic conditions
(17). Interestingly, the
present study also demonstrated that the glycolytic PK activities of the
soleus and EDL muscles were also increased by AICAR. Collectively, these
findings provide evidence that the activation of AMPK by AICAR totally
enhances the glucose metabolism. We demonstrated that chronic AICAR treatment
increased the tricarboxylic acid cycle and -oxidation enzyme activities
in skeletal muscle. Furthermore, a previous study demonstrated that acute
AICAR treatment enhanced fat oxidation through the inhibition of the
acetyl-CoA carboxylase activity and the consequent reduction in the
malomyl-CoA content, which inhibits the transport of fatty acids to the
mitochondria, in skeletal muscle
(31). Collectively, such
evidence suggests that the activation of AMPK may totally enhance the capacity
of energy utilization.
It is noteworthy that the HK activity of EDL was increased 108% by 14
successive days of AICAR treatment, whereas all other enzyme activities
affected by AICAR increased 15-31%. Winder et al.
(53) demonstrated that the 4
wk of AICAR treatment increased GLUT-4 protein content in fast-twitch
quadriceps muscle but not in slow-twitch soleus muscle. In addition, Buhl and
coworkers (7,
8) indicated that chronic AICAR
treatment enhanced GLUT-4 protein expression, insulin-stimulated glucose
uptake, and GLUT-4 translocation in primarily fast-twitch glycolytic muscles.
Collectively, these findings provide evidence that chronic AICAR treatment
improves the capacity of skeletal muscle glucose uptake especially in
fast-twitch glycolytic muscles.
Because PGC-1 and myogenin controlled the mitochondrial biogenesis and oxidative enzyme activities (21, 30, 56), we herein examined their protein content in skeletal muscles. As shown in the results, the PGC-1 protein contents in the rat soleus and EDL muscles increased after chronic AICAR treatment. In addition, a previous study indicated that acute AICAR treatment increased the PGC-1 mRNA expression in rat epitrochlearis muscle (46). Therefore, the activation of AMPK with AICAR should enhance the PGC-1 expression. PGC-1 increased the mRNA expression and transcriptional activity of nuclear respiratory factors 1 and 2 (1, 56), which were transcriptional factors related to mitochondrial function (40). Although the transcriptional activities of nuclear respiratory factors were not determined in this study, on the basis of these data we speculate that the increase in the muscle mitochondrial oxidative enzyme activities with chronic AICAR treatment is at least partially induced by the interaction of PGC-1 and nuclear respiratory factors. On the other hand, myogenin protein was not altered in the soleus muscle by AICAR or undetected in the EDL muscle. Therefore, an upregulation of myogenin by exercise (19, 50) is probably not related to the AMPK pathway.
Both the present study (treatment for 2 wk) and a previous study (treatment
for 4 wk) (53) demonstrated
that chronic AICAR treatment increased the mitochondrial tricarboxylic acid
cycle enzyme activities. In addition, the HAD activity, which catalyzes
mitochondrial -oxidation of fatty acids, was also increased by AICAR in
the present study. On the other hand, Winder et al.
(53) failed to demonstrate
such an increase. They also showed that treatment with AICAR for 2 wk
increased the CS activity in the rat red quadriceps muscle, whereas 4 wk of
such treatment did not. These results raise the possibility that the increase
in the mitochondrial oxidative enzyme activities by AICAR occurs in the early
phase but downregulation occurs if the treatment period is extended. To
resolve the effect of the time course on the AICAR-treated muscle oxidative
enzyme activities, further studies are thus called for.
Although the HAD activity was enhanced by AICAR treatment, this study and
the previous study (53)
demonstrated that CPT activity, which may be the rate-limiting step in fatty
acid uptake and oxidation by mitochondria, was not changed by chronic AICAR
treatment. Because both HAD and CPT are the enzymes of mitochondrial fatty
acid metabolism, our results suggested that CPT was not regulated by the AMPK
pathway. The upregulation of CPT in response to endurance exercise training
(3,
48) has thus been proposed to
depend on the other signaling pathways. It should be noted that such results
did not exactly negate the effect of AICAR treatment on fatty acid uptake by
mitochondria. Merrill et al.
(31) demonstrated that acute
AICAR perfusion to the hindlimb immediately inactivated acetyl-CoA carboxylase
and decreased malonyl-CoA, an inhibitor of CPT, and then the fatty acid
oxidation was increased. In the present study, the muscles were dissected
24 h after the last AICAR injection. It is possible that such an acute
effect is not maintained at least 24 h after injection.
In this study, we demonstrated that chronic AICAR treatment increased the UCP3 protein content in EDL muscle. UCPs inhibited the production of reactive oxygen species in the mitochondria (12, 34, 49). Exercise and hypoxia, which are considered to produce reactive oxygen species, immediately enhanced the skeletal muscle UCP3 protein level as well as AICAR (57). In addition, exercise (14, 52), hypoxia (13), and hydrogen peroxide (10) all activated AMPK. As a result, the increased muscle UCP3 protein by the AMPK pathway thus appears to inhibit the reactive oxygen species production in fast-twitch muscle. On the other hand, this study indicated that the antioxidant enzyme activities, including GPX and GR, were not altered after chronic AICAR treatment in either the soleus or EDL muscles. The increase in the antioxidant enzyme activities by exercise training (37) is thus suggested to be independent of the AMPK pathway. As a result, our original hypothesis was proven to be incorrect. To resolve the underlying process for the increased antioxidant enzyme activities in response to exercise, further experimental studies are called for.
In the EDL muscle, both the UCP3 levels and mitochondrial enzyme activities except for CPT increased after chronic AICAR treatment. These results were consistent with previous reports describing that the UCP3 appeared to increase as a component of the exercise-induced increase in skeletal muscle mitochondria (24). These results seem plausible because the PGC-1 protein, which regulated both mitochondrial biogenesis (30, 56) and expression of UCPs (56), increased with chronic AICAR treatment. In other words, it is speculated that the activation of AMPK increased the PGC-1 protein level, and it consequently increased both mitochondrial enzyme activities and UCP3.
Both this study and a previous one (41) demonstrated that UCP3 protein was not detectable in the control rat slow-twitch soleus muscle. In addition, the rank order of the UCP3 protein content in human skeletal muscle fibers is IIX > IIA > I (39). These results suggest that UCP3 protein preferentially accumulates in fast-twitch muscle fibers. The factors causing a difference in the UCP3 protein content between slow- and fast-twitch muscles remain to be elucidated. One possibility might be the difference in the recruitment of muscles. Because the slow-twitch soleus is an antigravity and postural muscle, it would be recruited to a much greater extent than EDL muscle at least in the sedentary condition. The muscle UCP3 protein content in endurance-trained subjects was lower than in untrained subjects (39), thus suggesting that an increase in the muscle activity results in a decrease in the UCP3 expression. As a result, the UCP3 protein of the soleus muscle dramatically decreased until reaching an undetectable level.
In summary, we herein demonstrated that chronic AICAR treatment for 2 wk decreased the percentage of type IIB fibers and increased the percentage of type IIX fibers in EDL muscle. In addition, such treatment also increased the glycolytic and oxidative enzyme activities in the soleus and EDL muscles and the UCP3 protein content in the EDL muscle of rats. It is speculated that at least several such adaptations with AICAR treatment may be due to an increased PGC-1 protein content. On the other hand, the capillary network, antioxidant enzyme activities, and myogenin protein content may be independent of the AMPK pathway.
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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. Section 1734 solely to indicate this fact.
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 S. Jager, C. Handschin, J. St.-Pierre, and B. M. Spiegelman AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1{alpha} PNAS, July 17, 2007; 104(29): 12017 - 12022. [Abstract] [Full Text] [PDF]
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 E. J. Kim, S.-N. Jung, K. H. Son, S. R. Kim, T. Y. Ha, M. G. Park, I. G. Jo, J. G. Park, W. Choe, S.-S. Kim, et al. Antidiabetes and Antiobesity Effect of Cryptotanshinone via Activation of AMP-Activated Protein Kinase Mol. Pharmacol., July 1, 2007; 72(1): 62 - 72. [Abstract] [Full Text] [PDF]
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A. C. Smith, K. L. Mullen, K. A. Junkin, J. Nickerson, A. Chabowski, A. Bonen, and D. J. Dyck Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E172 - E181. [Abstract] [Full Text] [PDF]
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L. M. Rohas, J. St-Pierre, M. Uldry, S. Jager, C. Handschin, and B. M. Spiegelman A fundamental system of cellular energy homeostasis regulated by PGC-1{alpha} PNAS, May 8, 2007; 104(19): 7933 - 7938. [Abstract] [Full Text] [PDF]
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T. E. Jensen, A. J. Rose, S. B. Jorgensen, N. Brandt, P. Schjerling, J. F. P. Wojtaszewski, and E. A. Richter Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1308 - E1317. [Abstract] [Full Text] [PDF]
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J. D. Mulligan, A. A. Gonzalez, A. M. Stewart, H. V. Carey, and K. W. Saupe Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse J. Physiol., April 15, 2007; 580(2): 677 - 684. [Abstract] [Full Text] [PDF]
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 C. A. Stuart, M. E.A. Howell, and D. Yin Overexpression of GLUT5 in Diabetic Muscle Is Reversed by Pioglitazone Diabetes Care, April 1, 2007; 30(4): 925 - 931. [Abstract] [Full Text] [PDF]
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D. Freyssenet Energy sensing and regulation of gene expression in skeletal muscle J Appl Physiol, February 1, 2007; 102(2): 529 - 540. [Abstract] [Full Text] [PDF]
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 K. A. Rasbach and R. G. Schnellmann Signaling of Mitochondrial Biogenesis following Oxidant Injury J. Biol. Chem., January 26, 2007; 282(4): 2355 - 2362. [Abstract] [Full Text] [PDF]
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G. D. Wadley and G. K. McConell Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle J Appl Physiol, January 1, 2007; 102(1): 314 - 320. [Abstract] [Full Text] [PDF]
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M. Suwa, T. Egashira, H. Nakano, H. Sasaki, and S. Kumagai Metformin increases the PGC-1{alpha} protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo J Appl Physiol, December 1, 2006; 101(6): 1685 - 1692. [Abstract] [Full Text] [PDF]
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H.-J. Koh, D. E. Arnolds, N. Fujii, T. T. Tran, M. J. Rogers, N. Jessen, Y. Li, C. W. Liew, R. C. Ho, M. F. Hirshman, et al. Skeletal Muscle-Selective Knockout of LKB1 Increases Insulin Sensitivity, Improves Glucose Homeostasis, and Decreases TRB3 Mol. Cell. Biol., November 15, 2006; 26(22): 8217 - 8227. [Abstract] [Full Text] [PDF]
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 A. G. Smith and G. E. O. Muscat Orphan nuclear receptors: therapeutic opportunities in skeletal muscle Am J Physiol Cell Physiol, August 1, 2006; 291(2): C203 - C217. [Abstract] [Full Text] [PDF]
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C. R. Benton, X.-X. Han, M. Febbraio, T. E. Graham, and A. Bonen Inverse relationship between PGC-1{alpha} protein expression and triacylglycerol accumulation in rodent skeletal muscle J Appl Physiol, February 1, 2006; 100(2): 377 - 383. [Abstract] [Full Text] [PDF]
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S. J. Lessard, Z.-P. Chen, M. J. Watt, M. Hashem, J. J. Reid, M. A. Febbraio, B. E. Kemp, and J. A. Hawley Chronic rosiglitazone treatment restores AMPK{alpha}2 activity in insulin-resistant rat skeletal muscle Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E251 - E257. [Abstract] [Full Text] [PDF]
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E. B. Taylor, J. D. Lamb, R. W. Hurst, D. G. Chesser, W. J. Ellingson, L. J. Greenwood, B. B. Porter, S. T. Herway, and W. W. Winder Endurance training increases skeletal muscle LKB1 and PGC-1{alpha} protein abundance: effects of time and intensity Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E960 - E968. [Abstract] [Full Text] [PDF]
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L. J. Cluberton, S. L. McGee, R. M. Murphy, and M. Hargreaves Effect of carbohydrate ingestion on exercise-induced alterations in metabolic gene expression J Appl Physiol, October 1, 2005; 99(4): 1359 - 1363. [Abstract] [Full Text] [PDF]
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 I. Valle, A. Alvarez-Barrientos, E. Arza, S. Lamas, and M. Monsalve PGC-1{alpha} regulates the mitochondrial antioxidant defense system in vascular endothelial cells Cardiovasc Res, June 1, 2005; 66(3): 562 - 573. [Abstract] [Full Text] [PDF]
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M. A. Maxwell, M. E. Cleasby, A. Harding, A. Stark, G. J. Cooney, and G. E. O. Muscat Nur77 Regulates Lipolysis in Skeletal Muscle Cells: EVIDENCE FOR CROSS-TALK BETWEEN THE {beta}-ADRENERGIC AND AN ORPHAN NUCLEAR HORMONE RECEPTOR PATHWAY J. Biol. Chem., April 1, 2005; 280(13): 12573 - 12584. [Abstract] [Full Text] [PDF]
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R. L. G. S. Oliveira, M. Ueno, C. T. de Souza, M. Pereira-da-Silva, A. L. Gasparetti, R. M. N. Bezzera, L. C. Alberici, A. E. Vercesi, M. J. A. Saad, and L. A. Velloso Cold-induced PGC-1{alpha} expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway Am J Physiol Endocrinol Metab, October 1, 2004; 287(4): E686 - E695. [Abstract] [Full Text] [PDF]
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R. T. Hepple and J. E. Vogell Anatomic capillarization is maintained in relative excess of fiber oxidative capacity in some skeletal muscles of late middle-aged rats J Appl Physiol, June 1, 2004; 96(6): 2257 - 2264. [Abstract] [Full Text] [PDF]
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P. Schrauwen and M. K.C. Hesselink Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes Diabetes, June 1, 2004; 53(6): 1412 - 1417. [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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