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and ß in skeletal muscle
,1
* Department of Anatomy and Physiology, Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy, Québec, G1V 4G2, Canada; and
Programme in Cell Biology, Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
2Correspondence: Department of Physiology and Lipid Research Unit, Laval University Hospital Research Center, 2705, Laurier Bld, Ste-Foy, (Québec), Canada, G1V 4G2. E-mail: andre.marette{at}crchul.ulaval.ca
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and ß (1.6- to 2.8-fold) in EDL muscles with a time course identical to that of stimulation of AMPK and glucose transport. The p38 MAPK inhibitor SB203580 abrogated the stimulatory effect of AICAR on glucose uptake. These results suggest that AICAR increases muscle glucose uptake by two mechanisms: 1) inducing selective recruitment of GLUT4 to the plasma membrane, and 2) activating p38 MAPK and ß, which may be involved in the activation of GLUT4—Lemieux, K., Konrad, D., Klip, A., Marette, A. The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases and ß in skeletal muscle.—Lemieux, K., Konrad, D., Klip, A., Marette, A. The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake via p38 mitogen-activated protein kinases and ß in skeletal muscle.
Key Words: glucose transport • exercise • contraction • insulin • plasma membrane
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2)
. Recent studies have suggested a role for AMP-activated protein kinase (AMPK) in the stimulatory effects of contraction on glucose uptake. Thus, exercise (3
, 4)
or electrically stimulated contraction (5
6
7)
increase the activity of AMPK, a heterotrimeric protein consisting of one catalytic subunit () and two noncatalytic subunits (ß, 
) (8
, 9)
. Moreover, several studies have shown that the cell-permeable AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) stimulates glucose uptake in fast-twitch muscles and that its effect is not additive to that of contraction (5
, 10
11
12)
. Further evidence for a role of AMPK in contraction-induced glucose uptake came from the work of Mu et al. (13)
, who showed that expression of a dominant inhibitory mutant of AMPK in transgenic mouse muscle reduced contraction-induced glucose uptake by 30–40%. AICAR has been reported to increase GLUT4 translocation to the plasma membrane in hindlimb muscles (14)
. However, it is still unknown whether AICAR also triggers the recruitment of GLUT4 to the T-tubules, which represent 60 to 80% of the total cell surface area in skeletal muscle fibers (15
, 16)
.
Exercise and contraction also activate p38 MAPK in rat skeletal muscle (17
18
19
20)
. We recently showed that incubation of isolated EDL muscles with the p38 MAPK inhibitor SB203580 reduced contraction-induced glucose uptake by 
50% (20)
. SB203580 inhibits insulin-induced glucose transport in both L6 muscle cells and 3T3-L1 adipocytes without affecting GLUT4 exposure at the cell surface (21)
. It was thus proposed that activation of p38 MAPK by contraction may be involved in the activation of GLUT4 in rat skeletal muscle. It was recently reported that AICAR increases the activity of GLUT1 transporters in clone 9 cells (22)
and that this effect is mediated by activation of p38 MAPK (23)
.
The goal of the present study was to test whether the AMPK activator AICAR increases muscle glucose uptake by inducing GLUT4 translocation to the plasma membrane and the T-tubule surface domains and/or by activating the p38 MAPK pathway. The results show that AICAR induces GLUT4 translocation but that the transporter is recruited only to the plasma membrane and not to the T-tubules. On the other hand, AICAR activates both p38 MAPK and p38 MAPKß, and SB203580 fully inhibits the ability of AICAR to stimulate glucose uptake in isolated muscle.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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with modifications based on Bergeron et al. (10)
. Measurement of steady-state AICAR-stimulated glucose uptake in muscle tissues was performed by measuring the incorporation of radiolabeled 2-deoxy-D-glucose [2-[1,2 3H(N)]-deoxyglucose (DG)] as previously described (24)
. Immediately after the clamp, rats were killed by decapitation and hindlimb muscles (EDL, tibialis, gastrocnemius, and quadriceps) were rapidly excised, cleaned of extraneous tissues, and frozen in liquid nitrogen. The muscles were kept at -80°C until use for 2-[3H]-DG incorporation or subcellular fractionation. For enzyme activity determinations after in vivo AICAR treatment, male Sprague-Dawley rats (200–250 g) were injected with AICAR (0.7 g/kg i.p.) for 30 min and EDL muscles were rapidly removed, clamp frozen, and stored at -80°C until processed as described below.
Subcellular membrane fractionation and Western blot
Plasma membranes, T-tubules, and intracellular membranes were isolated from 7–8 g of muscles (tibialis, gastrocnemius, and quadriceps) using a procedure developed in our laboratory (25)
. This subcellular fractionation protocol has been extensively characterized with immunologic and enzymatic markers (1
, 2
, 25)
. Membrane fractions (10 µg) were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot was performed as previously described (25)
. Immunoreactive bands were detected by the enhanced chemiluminescence method (Renaissance ECL kit, NEN Life Science, Boston, MA, USA).
Incubation protocols of isolated rat skeletal muscles and 2-deoxyglucose uptake
Isolation of extensor digitorum longus (EDL) muscles and determination of glucose uptake rates were performed as recently described (20)
. Muscles were incubated with AICAR (2 mM) and 2-deoxyglucose uptake was determined. In some experiments, muscles were preincubated with 10 µM SB203580 (or DMSO) for 20 min, then incubated for 30 min with AICAR in the absence or continued presence of SB203580. AICAR and SB203580 treatments were continued during the glucose uptake experiments if they were present during the previous incubations. For in vitro stimulation of AMPK and p38 MAPK activity by AICAR or insulin, EDL muscles were incubated with or without AICAR (2 mM) or insulin (0.2 mU/mL) for the times indicated in the figures, immediately blotted at 4°C, clamp frozen, and stored at -80°C until processed as described below.
AMPK activity and phosphorylation
AMPK activity was measured as described earlier (7)
. AMPK was immunopurified from muscles lysates with protein A-G Sepharose beads coupled to antibody directed against the -2 subunit of AMPK heterotrimer (kind gift of Dr. N. B. Ruderman). The immunocomplexes were collected and washed extensively. The AMPK was assayed against the SAMS peptide with the sequence HMRSAMSGLHLVKRR (26)
. Phosphorylation of AMPK was assessed by immunoblot using an anti-phospho-AMPK (Thr172) (1:1000 dilution; Cell Signaling, Beverly, MA, USA), as previously described (27)
.
p38 MAPK phosphorylation and kinase assay
p38 MAPK phosphorylation and activity were measured as described (20
, 28)
with the following modifications: p38 MAPK was immunoprecipitated from 300 µg of total proteins for 2–3 h with polyclonal anti-p38 MAPK or anti-p38 MAPKß antibodies (Santa Cruz, Santa Cruz, CA, USA) or with p38 MAPK antibody (kind gift from K. Seedorf, Novo Nordisk, Denmark) preadsorbed to protein G-Sepharose beads. Immunocomplexes were isolated and washed four times as previously described (20)
, and then used for Western blot with anti-phospho p38 (T180, Tyr182) MAPK antibody (Cell Signaling). In some experiments, muscle lysates (150 µg proteins) were directly subjected to SDS-PAGE and analyzed by Western blot with anti-phospho p38 MAPK antibody. When used for kinase assays, washed immunocomplexes were incubated for 30 min at 30°C with 50 µL reaction mixture (kinase buffer containing 200 µM ATP, 2 µg ATF-2 fusion protein per condition) in the absence or presence of 10 µM SB203580 on a platform shaker. The reaction was stopped by adding 25 µL 2x Laemmli sample buffer. Samples were heated for 30 min at 65°C, then vortexed and centrifuged for 5 min (1000 rpm). Fifty microliters of the supernatant were resolved by 10% SDS-PAGE, and immunoblotted for phospho-ATF-2 (1:500 dilution, cell signaling). Immunoblots were scanned within the linear range and quantitated using the computer software NIH image version 1.61 (NIH, Bethesda, MD, USA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). This was associated with a 4.25-fold stimulation of 2-deoxyglucose uptake in hindlimb muscles of AICAR-treated rats relative to control animals.
|
The effect of in vivo AICAR treatment on GLUT4 translocation is shown in Fig. 1
. GLUT4-enriched intracellular membrane (IM), plasma membrane (PM), and T-tubule (TT) fractions were isolated by subcellular fractionation of saline (vehicle control) and AICAR-stimulated muscles. Protein recoveries of PM, TT, and IM fractions were similar between control and AICAR-stimulated muscles (see legend to Fig. 1
). Figure 1A
shows immunoblots of one representative experiment whereas the mean effects of three or four independent membrane preparations are represented in Fig. 1B
. In accordance with previous studies (1
, 2
, 25)
, the plasma membrane marker 1-Na/K-ATPase was mainly enriched in the PM fraction whereas the 1-subunit of the dihydropyridine receptor (DHPr), a T-tubule-specific marker, was recovered mostly in the TT fraction. AICAR treatment induced GLUT4 recruitment from the IM fraction to the plasma membrane cell surface domain. Surprisingly, however, AICAR failed to increase GLUT4 translocation to the T-tubules.
|
Electrically induced contraction also induces the translocation of the transferrin receptor (TfR) from the intracellular membrane fraction to the plasma membrane (29)
. We therefore tested whether AICAR stimulated the translocation of TfR to the plasma membrane. As shown in Fig. 1A, B
, AICAR induced recruitment of the TfR from the GLUT4-enriched intracellular fraction to the plasma membrane but not to the T-tubule domain of the sarcolemma. To further confirm the effect of AICAR on TfR translocation to the plasma membrane, EDL muscles were isolated from normal rats, incubated with [125I]-transferrin (0.02 µCi/mL), and AICAR or saline were added for 30 min. AICAR doubled (2.0±0.4-fold, P<0.05) the uptake of [125I]-transferrin, confirming that it increases TfR recycling in muscle.
Role of p38 MAPK in AICAR-induced glucose uptake in muscle
In the next experiments, we tested the hypothesis that AICAR may also increase glucose transport in muscle by activation of the p38 MAPK pathway. We first tested the effects of in vivo AICAR treatment on p38 MAPK phosphorylation and activation in the EDL muscle. As shown in Fig. 2
A, B, AICAR treatment increased the phosphorylation of AMPK on Thr172, a site known to activate the enzyme (30)
and a good correlate of its activation (27)
. In vivo AICAR stimulation also enhanced phosphorylation of p38 MAPK in the EDL muscle (Fig. 2B
). Immunoprecipitation of individual isoforms further indicated that AICAR increased the phosphorylation of p38 MAPK and p38 MAPKß (Fig. 2A
). Phosphorylation of p38 MAPK was slightly but not significantly increased by AICAR (Fig. 2A
). Kinase activity measurements confirmed activation of both p38 MAPK and ß isoforms (Fig. 2C
). However, only p38 MAPK ß activation by AICAR reached the level of statistical significance in these in vivo studies.
|
It has been suggested that systemic factors may contribute to activation of p38 MAPK by exercise (19)
. To avoid the possible contribution of systemic or humoral factors in the AICAR effect on p38 MAPK, we conducted ex vivo studies in isolated EDL muscles. As depicted in Fig. 3
, AICAR induced a time-dependent increase in AMPK activity in EDL muscle, reaching an twofold stimulation after 30 min (Fig. 3A
) and an threefold increase in AMPK phosphorylation (Fig. 3B
). Figure 3C
further shows that AICAR increased p38 MAPK activity with a similar time course. AICAR enhanced the kinase activity of p38 MAPK and p38 MAPKß isoforms by 1.6 ± 0.1 and 1.8 ± 0.2-fold after 30 min, respectively. The stimulatory effect of AICAR on p38 MAPK was similar to that observed for insulin in the same conditions (Fig. 3C
). p38 MAPK activity was also inhibited when the p38 MAPK inhibitor SB203580 (10 µM) was added directly to the immunoprecipitates during the kinase assay, confirming the specificity of the immunoprecipitation (data not shown).
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Finally, we investigated whether AICAR-induced p38 MAPK activity is implicated in the stimulation of muscle glucose uptake. Addition of 2 mM AICAR to isolated EDL muscles induced a maximal twofold increase in glucose uptake after 40–45 min but a significant effect was already observed after 30 min of treatment (Fig. 4
A). Longer exposure to AICAR did not further increase glucose uptake (data not shown). Addition of SB203580 (10 µM) abrogated the effect of AICAR on muscle glucose uptake but failed to affect basal glucose uptake (Fig. 4B
). The p38 MAPK inhibitor did not affect AMPK activation by AICAR as assessed by its phosphorylation on Thr172 (Fig. 4C
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2
, 29)
and others (31)
have shown that contraction increases the amount of cell surface GLUT4 transporter proteins by inducing the translocation of the transporter to the plasma membrane and the T-tubules, the two subdomains of the muscle cell surface. AICAR infusion caused GLUT4 translocation to the plasma membrane in skeletal muscle (14)
; however, translocation to the T-tubules, the principal component of the surface area in muscle cells (15
, 16)
, was not assessed. The present work provides evidence that AMPK activation selectively increases GLUT4 translocation to the plasma membrane but not to the T-tubules. AICAR is the first stimulus known to increase muscle glucose uptake without detectable GLUT4 recruitment to the T-tubules. These results suggest that contraction stimulates GLUT4 translocation to the T-tubules through an AMPK-independent mechanism, which is consistent with the finding that contraction-induced glucose uptake is only partially inhibited in skeletal muscle expressing a dominant-negative AMPK (13)
.
The biochemical nature of the AICAR-sensitive intracellular GLUT4 compartment remains to be defined. Recent studies (29
, 31)
suggest that GLUT4 traffic into the recycling endosomes is implicated in contraction-stimulated GLUT4 recruitment in muscle. Indeed, contraction triggers GLUT4 translocation from a TfR-enriched vesicular compartment in skeletal muscle. Furthermore, translocation of GLUT4 from the TfR-enriched compartment was selective to the plasma membrane domain of the sarcolemma whereas GLUT4 from a TfR-depleted pool was also recruited to the T-tubules after contraction stimulation (29)
. The fact that AICAR induced GLUT4 translocation only to the plasma membrane suggests that the transporters were mobilized from the TfR-enriched compartment. Two additional observations are in accordance with a selective GLUT4 recruitment from the TfR-enriched intracellular compartment. First, AICAR induced TfR protein translocation to the plasma membrane but not to the T-tubules. Second, the AMPK activator increased recycling of the TfR, as revealed by measurement of [125I]-transferrin uptake in isolated muscles. Whether this AICAR-responsive TfR-enriched GLUT4 pool represents recycling endosomes, as previously suggested (29
, 31)
, remains to be firmly established by immunocytochemical studies complemented by detailed kinetics of [125I]-transferrin internalization in isolated muscles.
Given that the plasma membrane represents only 20–40% of the sarcolemmal surface area of muscle cells (15
, 16)
, it is unlikely that the stimulatory effect of AICAR on glucose uptake could be solely explained by its ability to induce GLUT4 translocation. Another potential mechanism by which AICAR may increase glucose uptake into skeletal muscle is through activation of cell surface GLUT4 transporters. It has been shown that p38 MAPK functions in a signaling pathway which modulates the activity of GLUT4 transporters in muscle and fat cells (21)
. In skeletal muscle, p38 MAPK is activated by insulin (20
, 32
, 33)
and by contraction (17
, 19
, 20)
and the p38 MAPK inhibitor SB203580 reduces insulin- and contraction-stimulated glucose uptake in isolated EDL muscles in vitro (20)
. AICAR increases the activity of GLUT1 transporters in clone 9 cells (22)
, and this effect is mediated by activation of p38 MAPK (23)
. It was therefore of interest to test whether AMPK signals through p38 MAPK for increasing glucose transport in skeletal muscle. Our data show that AICAR rapidly increases the phosphorylation and kinase activity of both p38 MAPK and p38 MAPKß in the EDL muscle. The finding that AICAR also induced p38 MAPK activation in vitro in isolated EDL muscles indicates that the in vivo effect cannot be solely attributed to humoral/systemic factors. Although p38 MAPK is also expressed in skeletal muscle and previously reported to be activated by long-term exercise (34)
, it was not found to be responsive to acute AICAR treatment. Thus AICAR, unlike contraction, may not activate p38 MAPK. However, it should be noted that p38 MAPK activity was found to be increased after prolonged (180–210 min marathon running) exercise, which is certainly not comparable with the acute (30 min) AICAR treatment used in our study. Furthermore, the responsiveness of p38 MAPK to exercise and AICAR may differ between rats and humans.
The activation of p38 MAPK and ß isoforms was temporally related to the stimulation of AMPK and muscle glucose uptake by AICAR. The effect of AICAR on glucose uptake was abrogated by 10 µM SB203580, suggesting that p38 MAPK and ß act downstream of AMPK to stimulate glucose uptake. The same concentration of SB203580 reduced the effect of contraction on glucose uptake by only 40% (20)
, possibly because contraction also activates p38 MAPK, which is not inhibited by SB203580 (35)
. This raises the interesting hypothesis that p38 MAPK activation by contraction may be part of a signaling cascade that stimulates GLUT4 translocation to the T-tubules, which, as suggested in the present study, is independent of AMPK activation.
Even with the most specific protein kinase inhibitors, caution must be expressed when used in cell-based assays (35)
. Although SB203580 is widely used as a potent and selective inhibitor of p38 MAPK and ß, it was recently shown to inhibit nucleoside transport in K562 cells and AMPK activation by AICAR in H-2K cells (36
, 37)
. However, we found that SB203580 does not affect AMPK activation by AICAR in EDL muscle, in line with previous studies in clone 9 cells (23)
. Thus, SB203580 abolishes AICAR-induced glucose transport most likely by inhibiting p38 MAPK and not by inhibiting transport of AICAR and activation of AMPK in muscle.
It is difficult to directly assess whether activation of p38 MAPK by AICAR increases GLUT4 activity. Current methods to assess GLUT4 translocation cannot distinguish between transporters that are fully inserted into the plasma membrane and T-tubules and those that are docked but not fused. The exofacial label ATB-[3H]BMPA cannot be used because it reacts with the active site of glucose transporters and, hence, does not distinguish between changes in number vs. activity of cell surface GLUT4 transporters. Determination of cell surface GLUT4 appearance using a different exofacial marker will be needed to resolve this important question.
In summary, the present results show that AICAR increases glucose uptake in skeletal muscle by two distinct mechanisms: 1) inducing selective recruitment of GLUT4 to the plasma membrane, and 2) activating both p38 MAPK and ß, which may be involved in the activation of GLUT4 at the cell surface.
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ACKNOWLEDGMENTS |
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antibody. This work was supported by grants from the Canadian Diabetes Association (A.M. and A. K.), in honor of the late Vernon J. Devine, of Jenny Tinkler and of Lillian G. Davis. A.M. was supported by an Investigator Award from the Canadian Institutes for Health Research. K. L. was supported by a studentship from the Canadian Institutes for Health Research. D.K. was supported by fellowships from the Swiss National Science Foundation (grant # 81ZH-57433), the Research Institute of The Hospital for Sick Children (Clinician Scientist Award), and the Zürcher Diabetes-Gesellschaft. |
FOOTNOTES |
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Received for publication December 13, 2002. Accepted for publication May 8, 2003.
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