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Department of Physiology and Cell Biology, Albany Medical College, Albany, New York 12208
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ABSTRACT |
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Abstract
Introduction
Methods
Results & Discussion
References
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Activities of Akt1, Akt2, and Akt3 kinases and glucose uptake in hindlimb muscles of the rat in vivo were investigated. The rats were studied either after intravenous injection of 0.1 U of insulin or during exercise induced by stimulating calf muscles electrically at 1 contraction/s. Akt kinases were immunoprecipitated from supernatants of muscle homogenates. Glucose uptake by muscles in vivo was assessed by cellular accumulation of 2-deoxy-D-[1,2-3H(N)]glucose. Administration of insulin resulted in rapid activation of Akt1 kinase, with peak activity observed 5 min after insulin injection. Soleus muscle, a slow-twitch muscle, and plantaris muscle, a fast-twitch muscle, differed in their content of Akt1 kinase and in their response to insulin. Soleus muscle exhibited a 105% higher abundance of Akt1 kinase, a 101% higher insulin-stimulated activity of Akt1 kinase, and 83% higher insulin-stimulated 2-deoxyglucose uptake compared with plantaris muscle. Additionally, insulin administration increased the activities of Akt1, Akt2, and Akt3 kinases in calf muscles and caused a sevenfold augmentation in 2-deoxyglucose uptake by these muscles. In contrast, the exercised calf muscles exhibited an increase in Akt1 kinase activity at 5, 15, and 25 min of exercise but no change in activities of Akt2 and Akt3 isoforms, and the 2-deoxyglucose uptake by calf muscles exercised for 25 min was 11-fold higher compared with muscles of resting rats. The data demonstrate that 1) there is a close, direct correlation between the magnitude of insulin-stimulated activity of Akt1 kinase and the level of glucose uptake in muscles with different fiber populations, 2) insulin activates three isoforms of Akt kinase in skeletal muscle, and 3) exercise in vivo is associated with activation of Akt1 but not Akt2 and Akt3 kinases in contracting muscles.
protein kinase B isoforms; soleus muscle; plantaris muscle; slow-twitch muscle; fast-twitch muscle
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results & Discussion
References
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STIMULATION OF GLUCOSE UPTAKE by insulin is initiated
by insulin binding to its disulfide-linked heterotetrameric receptor consisting of two extracellular 
-subunits and two transmembrane 
-subunits. Insulin binding to the -subunit rapidly results in receptor autophosphorylation and activation of an intrinsic tyrosine kinase associated with the -subunit (7). Subsequently, this tyrosine
kinase phosphorylates a number of cellular proteins, most notably
insulin receptor substrates (IRS) on tyrosine residues. This
phosphorylation provides phosphotyrosine-dependent and
sequence-specific contact sites for the regulatory subunit (p85) of
phosphatidylinositol (PI) 3-kinase. Binding of p85 to IRS results in
the activation of the catalytic subunit (p110) of PI 3-kinase (7).
Numerous reports provide evidence for the concept that activation of PI 3-kinase by insulin is required for stimulation of glucose transport (15, 17, 23, 25, 30). Recently, a new enzyme,
3-phosphoinositide-dependent protein kinase-1 (PDK-1), has been added
to the insulin pathway (10). This kinase is only active in the presence
of lipid vesicles containing PI (3-5)
P3 or PI (3, 4)
P2. Because PI (3-5) P3 is the product of PI 3-kinase
action, the PDK-1 is believed to be a signaling component distal to PI
3-kinase. PDK-1 acts by phosphorylating Akt kinase (also called protein
kinase B or RAC kinase) at Thr-308 (2). Studies indicate that full
activation of Akt kinase requires phosphorylation of Thr-308 and
Ser-473. Because PDK-1 phosphorylates Akt kinase only on Thr-308, an
additional, so far unknown, kinase that would phosphorylate Ser-473 is
believed to participate in the regulation of Akt kinase activity.
Available evidence suggests that Akt kinase, a serine kinase, cannot
phosphorylate itself on Ser-473 (1). A role for Akt kinase in mediating
the insulin-induced stimulation of glucose uptake is suggested by the
observation that the transfection of a constitutively active Akt kinase
into 3T3-L1 adipocytes or primary rat adipocytes mimics the effect of
insulin by promoting translocation of GLUT-4 to the plasma membrane and
glucose uptake (11, 19, 26). The number of steps between the activation
of Akt kinase and the translocation of GLUT-4 is unknown. Several
reports indicate that Akt kinase can be also activated by a
mechanism(s) independent of the PI 3-kinase pathway (21, 22, 24). Three
mammalian isoforms of Akt kinase, Akt1 (9), Akt2 (8), and Akt3 (20),
which differ in amino acid composition, have been identified.
In humans, skeletal muscle represents ~40% of body weight and is responsible for 80% of postprandial glucose disposal (4, 14). Skeletal muscle appears to have two distinct pathways for stimulation of glucose transport: one is activated by insulin, and the other is activated by muscle contractions and hypoxia. Available evidence suggests that the stimulatory actions of exercise and hypoxia are mediated by an increase in cytoplasmic Ca2+ levels (6, 18). We set out to investigate the role of Akt kinase in stimulation of glucose uptake by skeletal muscle to answer the following questions: 1) What isoforms of Akt kinase are activated by insulin, and is the magnitude of Akt kinase activation proportional to different levels of insulin-stimulated glucose uptake observed in muscles with different fiber populations? and 2) Is the augmented glucose uptake by exercising muscles mediated by an isoform of Akt kinase? The subsequent report provides a detailed account of the studies.
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METHODS |
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Top
Abstract
Introduction
Methods
Results & Discussion
References
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Materials.
Anti-human Akt1/protein kinase B (PKB) pleckstrin homology domain
sheep polyclonal IgG, anti-rat Akt2/PKB sheep IgG, anti-rat Akt3/PKB
sheep IgG, horseradish peroxidase (HRP)-conjugated rabbit anti-sheep IgG, cAMP-dependent protein kinase inhibitor peptide, and
Akt/PKB specific substrate peptide were purchased from Upstate Biotechnology (Lake Placid, NY). Protein G-Sepharose (GammaBind G-Sepharose) was from Pharmacia (Piscataway, NJ).
[-32P]ATP and
2-deoxy-D-[1,2-3H(N)]glucose
were from NEN (Boston, MA).
[U-14C]sucrose was
obtained from ICN Pharmaceuticals (Costa Mesa, CA). Microcystin was
from Calbiochem (San Diego, CA). All other chemicals were from Sigma
(St. Louis, MO).
Animals. The experiments were performed on adult male Sprague-Dawley rats weighing 225-240 g. All experimental procedures were approved by the Institutional Animal Care and Use Committee and the institutional veterinarian. The National Institutes of Health Guide for the Care and Use of Laboratory Animals was strictly adhered to. The animals were always fasted overnight (18 h) before the experiment and were anesthetized with pentobarbital sodium (50 mg/kg body wt ip) at the time of the experiment.
To study the effect of insulin, we injected each rat with 0.1 U of insulin in 0.4 ml of 0.1% defatted BSA via the dorsal vein of the penis. Control rats were injected with 0.4 ml of diluent. To study the effect of exercise, calf muscles of one hindlimb of each rat were exercised electrically as described previously (27, 29). Thin needle electrodes were inserted into the calf muscle mass through the skin. The positive electrode was positioned near the proximal insertion, and the negative electrode was placed near the distal insertion of the calf muscles. The muscles were stimulated with a Grass S5 Stimulator (Grass Instruments, Quincy, MA) using 8-V pulses 100 ms in duration at a frequency of 1 pulse/s and were made to work against a 10-g suspended weight. The exercised muscles were compared with resting muscles of nonexercised control rats.2-Deoxyglucose uptake by muscles in vivo. Glucose uptake by skeletal muscles in vivo was assessed by cellular accumulation of 2-deoxyglucose, as described previously (16, 27-29). The anesthetized rats were injected with 10 µCi of 2-deoxy-D-[1,2-3H(N)]glucose and 2 µCi of [U-14C]sucrose with or without 0.1 U of bovine insulin in 0.4 ml/rat of 0.1% defatted BSA via the dorsal vein of the penis. In studies on exercised animals, labeled 2-deoxyglucose and sucrose (without insulin) were injected immediately before the beginning of exercise. In all experiments, the animals were killed by rapid exsanguination 25 min after the administration of labeled substances. Blood was collected, and the indicated muscles were excised from one hindlimb of each rat. Tissue samples and serum were digested separately in tissue solubilizer (Solvable; NEN), and the 3H and 14C radioactivities were determined by liquid scintillation counting. Cellular uptakes of 2-deoxy-D-glucose by muscles were calculated as the difference between the total tissue 3H radioactivity in disintegrations per minute and the amount of 3H radioactivity present in the tissue extracellular ([14C]sucrose) space. The 25-min period was sufficient for full equilibration of labeled sucrose with the extracellular water, because 60-min equilibration did not show a further increase in measured tissue extracellular space (29).
Akt kinase isoforms in skeletal muscles.
The indicated muscles were excised at the desired interval after the
injection of insulin or after the onset of exercise. The muscles were
immediately frozen in liquid nitrogen and then kept at 
85°C
until further use. Each muscle was powdered under liquid nitrogen
within 24 h. The powder was transferred into a polypropylene tube
containing 0.5 ml/100 mg muscle of ice-cold buffer
A. The composition of
buffer
A was 50 mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA, 0.5 mM
Na3VO4,
0.1% 2-mercaptoethanol, 1% Triton X-100, 50 mM NaF, 5 mM sodium
pyrophosphate, 10 mM sodium -glycerol phosphate, 0.1 mM
phenylmethylsulfonyl fluoride, 1 µg/ml aprotinin, 1 µg/ml
pepstatin, 1 µg/ml leupeptin, and 1 µM microcystin. The suspension
was homogenized using three 10-s bursts of a Polytron homogenizer set
at 75% of maximum power. The test tube with the homogenate was kept in
an ice bath during the homogenization. After centrifugation at 13,000 g and 4°C for 15 min, the
supernatant of muscle homogenate was separated, frozen in liquid
nitrogen, and kept at 85°C until further use.
pleckstrin homology domain sheep IgG, anti-rat
Akt2/PKB sheep IgG, and anti-rat Akt3/PKB sheep IgG. Unless
indicated otherwise, all steps were performed on ice and
centrifugations were done at 4°C. Protein G-Sepharose (30 µl of
packed volume) in 250 µl of buffer
A was agitated with 4 µg of the
desired antibody overnight at 4°C. The antibody-protein G-Sepharose
complex was washed three times with
buffer
A and then allowed to react with 500 µg of muscle homogenate supernatant protein (Bradford protein assay)
under constant agitation at 4°C for 90 min. The
enzyme-antibody-protein G-Sepharose complex was washed three times with
buffer
A containing 0.5 M NaCl, two times with buffer
B [50 mM
Tris · HCl, pH 7.5, 0.03% (wt/vol) Brij-35, 0.1 mM
EGTA, and 0.1% 2-mercaptoethanol], and two times with assay dilution buffer (20 mM MOPS, pH 7.2, 25 mM -glycerol phosphate, 5 mM
EGTA, 1 mM sodium orthovanadate, and 1 mM dithiothreitol). The
enzyme-antibody-protein G-Sepharose complex was subsequently incubated
with 40 µl of assay dilution buffer containing 10 µM cAMP-dependent
protein kinase inhibitor peptide, 100 µM Akt/PKB-specific substrate
peptide, 125 µM ATP (with 10 µCi
[-32P]ATP per
reaction mixture), and 19 mM MgCl2
for 10 min at 30°C with continuous shaking. The 40 µl of
supernatant was then transferred into another tube, mixed with 20 µl
of 40% TCA, and incubated at room temperature for 5 min. After mixing,
40 µl of TCA mixture was applied onto a 2 × 2-cm P81
phosphocellulose paper and allowed to bind to it for 30 s before
immersion of the square in 0.75% phosphoric acid. The collected
phosphocellulose squares were washed three times with 0.75% phosphoric
acid and one time with acetone for 5 min per wash with continuous
mixing. The radioactivity of each square was determined by
scintillation counting. Radioactivity of samples that did not contain
Akt kinases (enzyme blank) was subtracted from measured radioactivities.
To determine the abundance of Akt1 kinase, aliquots of muscle
homogenate supernatant were prepared for SDS-PAGE by diluting them in
electrophoresis reducing sample buffer and heating them at 98°C for
4 min. Aliquots corresponding to 10 µg of protein were subjected to
SDS-PAGE using 4% stacking gels and 8% resolving gels and transferred
electrophoretically to pure nitrocellulose membranes (Biorad, Hercules,
CA). The membranes were washed two times with water and blocked with
constant agitation in freshly prepared Tris-buffered saline, pH 7.4, containing 0.05% Tween 20 and 3% nonfat dry milk (TBS-T-Milk) at
21°C for 30 min. The membranes were then agitated overnight in
4°C in TBS-T-Milk containing 0.75 µg/ml of anti-human Akt1/PKB
pleckstrin homology domain sheep IgG. After washing the membranes two
times with water, we agitated the membranes at 21°C for 90 min in
PBS pH 7.4, with 3% nonfat dry milk containing a rabbit anti-sheep
HRP-conjugated IgG at a dilution of 1:1,500. The nitrocellulose
membranes were subsequently washed in water two times, then in
PBS-0.05% Tween 20 for 3-5 min, and finally in 4-5 changes
of water. Blots were detected by enhanced chemoluminescence (Amersham,
Arlington Heights, IL). Bands corresponding to Akt1 kinase were
quantified by video densitometry (Bioimage 60S; Millipore, Bedford, MA).
Data evaluation. The results are expressed as means ± SE. Statistical significance was assessed using ANOVA followed by the Student-Newman-Keuls multiple comparison test.
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RESULTS AND DISCUSSION |
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Top
Abstract
Introduction
Methods
Results & Discussion
References
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Figure 1 depicts the time course of activity of Akt1 kinase in calf muscles of rats after intravenous injection of 0.1 U of insulin. Nonspecific background radioactivity was subtracted from measured radioactivities. Similar to observations by others (12, 31), the peak activity was achieved at 5 min after the injection. Therefore, in all subsequent studies with insulin, the skeletal muscles were always excised at this interval. Akt1 kinase activity in muscles of control rats injected with diluent is not shown, because the radioactivity of these muscles was not statistically different from nonspecific background radioactivity.
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To investigate how closely the insulin-stimulated activity of Akt1
kinase parallels the insulin-stimulated glucose uptake by muscles in
vivo, we performed studies on both plantaris and soleus muscles, two
hindlimb muscles with different fiber populations. The plantaris muscle
is composed of 53% fast-twitch oxidative-glycolytic fibers, 41%
fast-twitch glycolytic fibers, and 6% slow-twitch oxidative fibers
(3). In contrast, the rat soleus muscle consists predominantly (
80%)
of slow-twitch oxidative fibers (3).
Figure 2A depicts basal and insulin-stimulated uptakes of 2-deoxyglucose by plantaris and soleus muscles in vivo. There was no statistical difference in basal uptake between plantaris and soleus muscles. However, the soleus muscle exhibited an 83% (P < 0.01) higher insulin-stimulated 2-deoxyglucose uptake compared with the corresponding value in the plantaris muscle. As shown in Fig. 2, B and C, soleus muscle also showed a 101% (P < 0.001) higher insulin-stimulated activity of Akt1 kinase and a 105% (P < 0.001) greater abundance of Akt1 kinase than plantaris muscle. These observations indicate that there is a close direct correlation between the level of insulin-stimulated 2-deoxyglucose uptake and the abundance and magnitude of the insulin-stimulated activity of Akt1 kinase in slow-twitch and fast-twitch muscles. This correlation provides indirect support for the role of Akt1 kinase in insulin-stimulated glucose uptake by skeletal muscles in vivo.
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To assess the expression of isoforms of Akt kinase in skeletal muscles and to compare the effect of insulin and exercise on their activities, a parallel study was performed in which some rats were injected with 0.1 U of insulin intravenously, whereas other rats were subjected to electrical stimulation of calf muscles to induce muscle contractions. Calf muscles were excised from each rat either at 5 min after insulin injection or from the exercised hindlimb at 5, 15, and 25 min of exercise and were then analyzed for activities of Akt1, Akt2, and Akt3 kinases. Muscles of resting animals that did not receive insulin served as controls. The effect of 0.1 U of insulin and exercise on 2-deoxyglucose uptake by calf muscles was also determined. As shown in Fig. 3, the administration of insulin increased the activities of all three isoforms of Akt kinase compared with control muscles. The activities of both Akt1 and Akt2 kinases were increased 24-fold by insulin (P < 0.001). The multiple increase in activity of Akt3 kinase (P < 0.03) could not be calculated, because Akt3 kinase radioactivity in control muscles was not different from nonspecific background radioactivity (background radioactivity was subtracted from measured radioactivities). Under the same experimental conditions, administration of insulin resulted in a sevenfold increase in 2-deoxyglucose uptake by calf muscles (P < 0.001). In contrast, exercise did not have a stimulatory effect on all three isoforms of Akt kinase. As shown in Fig. 3, the exercised calf muscles exhibited a threefold increase of Akt1 kinase activity at 5, 15, and 25 min of exercise (all P < 0.003) but no change in activities of Akt2 and Akt3 isoforms even though 2-deoxyglucose uptake by muscles exercised for 25 min was 11-fold higher than in muscles of resting rats (P < 0.001).
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These results represent the first study on the effects of exercise on all three isoforms of Akt kinase and the first study using exercise in vivo. The absence of an effect of exercise on Akt2 kinase in the present study agrees with the recent report that electrically induced contractions of excised soleus and epitrochlearis muscles in vitro do not activate Akt2 kinase (5). Other isoforms of Akt kinase have not been measured in the in vitro study. The exercise-induced activation of Akt1 kinase observed in the present study was unexpected because it has been reported that inhibition of PI 3-kinase with wortmannin inhibits the insulin-stimulated glucose uptake but not the contraction- or hypoxia-stimulated glucose uptake by isolated rat muscles in vitro (15, 30). However, it is possible that Akt1 kinase is stimulated also by another pathway besides that including PI 3-kinase. This is supported by recent findings that Akt kinase can be stimulated by both PI 3-kinase-dependent and independent pathways in the same cell type (21, 22, 24).
It remains to be determined why exercise in vivo, unlike insulin, activates Akt1, but not Akt2 and Akt3 kinases, in skeletal muscle. This may be related to different functional roles of individual Akt kinase isoforms. An alternative explanation could be that Akt1 kinase is the dominant isoform of Akt kinase activated in skeletal muscle. Walker et al. (31) recently studied activations of individual isoforms of Akt kinase by insulin in adipocytes, hepatocytes, skeletal muscle, and L6 muscle cells and found them to be tissue- or cell type-dependent. In skeletal muscle, insulin exhibited a pronounced stimulatory effect on the activity of Akt1, whereas its effect on Akt2 and Akt3 isoforms was small despite the same abundance of Akt1 and Akt2 protein in muscle (31). Our studies with insulin were designed to compare the effect of insulin with that of exercise rather than to compare the effects of insulin on each of the isoforms of Akt kinase. Nevertheless, the absolute levels of insulin stimulated activities of Akt1, Akt2, and Akt3 kinases in Fig. 3 are consistent with the findings of Walker et al. (31).
Figure 3 shows that the peak activity of Akt1 kinase after the intravenous injection of a pharmacological dose of insulin was markedly higher than the sustained level of Akt1 activation induced by exercise. To date, there are no data on the degree of activation of Akt1 kinase (or any Akt kinase isoform) by physiological hyperinsulinemia; however, the degree of activation is likely to be much smaller than that shown in Fig. 3. Furthermore, the specificity of antibodies used for measuring the activities of individual isoforms of Akt kinase needs to be considered. Antibodies used for immunoprecipitation of Akt2 and Akt3 kinases in the present study are specific. In contrast, the antibody used for immunoprecipitation of Akt1 kinase recognizes the pleckstrin homology domain of Akt1 that is also present in molecules of Akt2 and Akt3 kinases. Consequently, the Akt1 immunoprecipitate is likely to be contaminated to some degree by the other two isoforms of Akt kinase. This could artificially augment the measured activity of Akt1 kinase under conditions in which Akt2 and Akt3 isoforms are also activated, such as after insulin administration (Fig. 3). However, such a contamination would not play a role in the measured activity of Akt1 kinase during exercise, because exercise does not activate Akt2 and Akt3 kinases.
In conclusion, the present study demonstrates that there is a close direct correlation between the magnitude of insulin-stimulated activity of Akt1 kinase and the level of glucose uptake in muscles with different fiber populations. The present study, together with recent observations of others (31), also indicates that insulin activates three isoforms of Akt kinase in skeletal muscle. Finally, the data show that exercise in vivo is associated with activation of Akt1 but not Akt2 and Akt3 kinases in contracting muscles. The degree of exercise-induced activation of Akt1 kinase appears to be disproportionally low in relation to the pronounced increase in 2-deoxyglucose uptake by exercising muscles, suggesting that Akt1 kinase plays a supporting, rather than controlling, role in the determination of glucose uptake by the contracting muscles in vivo.
Perspectives
Available evidence indicates that Akt kinase plays an important role in the translocation of GLUT-4 to the plasma membrane and the resulting stimulation of glucose uptake. The mechanism whereby activated Akt kinase causes the translocation of GLUT-4 to the plasma membrane and the number of steps between the activation of Akt kinase and GLUT-4 translocation is unknown. To date, three substrates of Akt kinase have been identified. Akt kinase phosphorylates serine residues in 6-phosphofructo-2-kinase (PFK2), which activates PFK2, leading ultimately to the stimulation of glycolysis (10). Akt kinase also phosphorylates serine residues in glycogen synthase kinase 3 (GSK3), which results in inhibition of GSK3 and stimulation of glycogen and protein synthesis (10). The third known substrate of Akt kinase is a protein called BAD (13). BAD is a member of the BCL-2 family of proteins. Phosphorylation of BAD at serine residue 136 by Akt kinase promotes cell survival (13). The substrate(s) involved in Akt kinase-mediated translocation of GLUT-4 to the plasma membrane is unknown (GLUT-4 itself is not thought to be a physiological substrate for Akt kinase). Identification of such substrate(s) is an important goal of future work.| |
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: J. Turinsky, Dept. of Physiology and Cell Biology, Albany Medical College (Mail Code 134), 47 New Scotland Ave., Albany, NY 12208.
Received 3 August 1998; accepted in final form 6 October 1998.
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Top
Abstract
Introduction
Methods
Results & Discussion
References
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