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2 Copenhagen Muscle Research Centre, August Krogh Institute, and 1 Institute of Exercise and Sports Sciences, Copenhagen, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study investigated the localization of ATP-sensitive K+ (KATP) channels in human skeletal muscle and the functional importance of these channels for human muscle K+ distribution at rest and during muscle activity. Membrane fractionation based on the giant vesicle technique or the sucrose-gradient technique in combination with Western blotting demonstrated that the KATP channels are mainly located in the sarcolemma. This localization was confirmed by immunohistochemical measurements. With the microdialysis technique, it was demonstrated that local application of the KATP channel inhibitor glibenclamide reduced (P < 0.05) interstitial K+ at rest from ~4.5 to 4.0 mM, whereas the concentration in the control leg remained constant. Glibenclamide had no effect on the interstitial K+ accumulation during knee-extensor exercise at a power output of 60 W. In contrast to in vitro conditions, the present study demonstrated that under in vivo conditions the KATP channels are active at rest and contribute to the accumulation of interstitial K+.
microdialysis; interstitial potassium; glibenclamide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THERE IS A SIGNIFICANT K+ release from active skeletal muscle. Thus, in a recent study using microdialysis, the interstitial K+ concentration increased progressively with increasing work intensity, reaching >10 mM (13). The extracellular K+ accumulation may impair muscle function by reducing membrane excitability (8). Part of the K+ release during contractions is due to the activity of the voltage-dependent K+ channels activated during the action potentials, but the large K+ release leads to the hypothesis that other channels may also be involved. Such channels could be the ATP-sensitive K+ (KATP) channels or the Ca2+-sensitive K+ channels. For heart muscle, it has been proposed that the KATP channels are cardioprotective by virtue of their contribution to the action potential K+ current in metabolically stressed cells and their facilitation of recovery after such stress (2, 18).
The role of the KATP channels in skeletal muscle is less clear. KATP channels have been identified in skeletal muscle by electrophysiological methods (6, 21). It was demonstrated that ATP inhibits the KATP channels and that the inhibitory effect of ATP is reduced by lowering of pH (6). It was originally suggested that the channels are activated only in metabolically exhausted muscle fibers (4) and that the activity of the channels contributes to the decrease in force during fatigue in frog muscle (15). However, this hypothesis is not supported by later studies also using frog muscle (20). On the basis of recent studies in mice, it has been suggested that the channels can give some protection against ATP depletion and that the channels can influence force recovery after exercise (17). In addition, studies in KATP channel-deficient mice have led to the conclusion that the channels reduce the increase in resting (baseline) tension during fatigue and have no influence on the reduction in force, as originally suggested (9). The question is whether KATP channels are active at rest and influence the resting membrane potential. On the basis of Rb+ flux measurements in isolated mouse muscle, it has been concluded that KATP channels are inactive in unfatigued muscle (1, 17). However, flux measurements demonstrated a selective inhibition by the KATP channel inhibitor glibenclamide of the K+ efflux in resting rat hindlimbs perfused in situ (16). Another group of K+ channels, the large Ca2+-activated (BKCa2+) channels, are reported to be present in rat skeletal muscle T tubules (14). The function of these channels in muscle is unknown.
The aims of the present study were 1) to localize the KATP and BKCa2+ channels in human skeletal muscle and 2) to determine the functional importance of KATP channels in vivo for human muscle K+ distribution at rest and during muscle activity. To localize the channels in human skeletal muscle, membrane fractionation in combination with Western blotting, as well as immunohistochemistry, was used to localize the KATP and BKCa2+ channels at the subcellular level. Because some of the fractionation techniques used for subcellular localization require a large muscle mass, the studies on human needle biopsy material were supplemented with studies on rat muscle. To determine the functional importance of KATP channels in vivo, the KATP channel inhibitor glibenclamide was used with the microdialysis technique for determination of the interstitial K+ concentration at rest and during knee-extensor exercise.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Microdialysis Experiments
Subjects. The subjects were six healthy men with age, weight, and height as follows: 25 ± 1 yr, 77.6 ± 6.7 kg, and 182.9 ± 0.9 cm. The subjects were informed of any risk associated with the experiments before giving their consent to participate. The work fully conforms to American Physiological Society guidelines for research involving animals and humans, and the study was approved by the local ethics committee of Frederiksberg and Copenhagen communities.
Microdialysis. Two types of microdialysis probes were used: CMA60 (30 mm long, 0.5 mm diameter, 20 kDa cutoff; CMA Microdialysis) and homemade (40 mm long, 0.2 mm ID, 6 kDa cutoff). Two CMA60 and two homemade probes were inserted into the vastus lateralis muscle of each leg using local anesthesia (lidocaine, 20 mg/ml) of the skin and subcutaneous tissue. The intention was to insert the probes parallel to the muscle fibers. The four probes in one leg (intervention leg) were used for drug infusion and K+ measurements, and the four probes in the other leg (control leg) were used only for K+ measurements.
The perfusate was Ringer acetate containing (in mM) 130 Na+, 2 Ca2+, 4 K+, 1 Mg2+, 30 acetate, 3 glucose, and 1 lactate. 201Tl (thallous chloride injection liquid, Amersham Life Science; 4.6 MBq/l) was added to the syringes used for dialysate infusion to determine fractional release. Glibenclamide (glyburide, Calbiochem) was dissolved in Ringer acetate with Na2CO3 and added to the perfusate to a final concentration of 500 µM (pH ~10). To test whether pH alone had any effect on K+ balance, bicarbonate (pH 10) was applied in a control period. On the basis of the molecular weight of 494 and compared with other substances measured with microdialysis (13), the fractional release of glibenclamide from the probe is expected to be low (<20%); therefore, only a minor fraction of the drug added to the perfusate diffused into the muscles. The release of glibenclamide from the probe is therefore <5 × 10
10 mol/min (500 µM glibenclamide in the probe,
fractional release 0.2, pump rate 5 µl/min). It is impossible to
calculate the concentration in the tissue close to the probe, because
the dilution space and the amount carried away by the blood are
unknown. If it is assumed that the released glibenclamide is diluted in
1 cm3 of tissue, then the concentration after 1 min is
5 × 107 M, which is within the range reported in
the literature (3, 17, 24) to be relevant for inhibition
of KATP channels.
Experimental Procedure
The probes were flushed after insertion, connected to the pump (model 102, CMA Microdialysis), and perfused at 5 µl/min for 90 min (restitution period). Samples were then collected for three 10-min periods. In the period after drug infusion, samples were collected from control and intervention legs at 10, 20, and 30 min.The subjects then performed one-legged knee-extensor exercise (kicking
frequency 60 s1) on a Krogh ergometer that was modified
to permit the exercise to be confined to the quadriceps muscles. The
infusion pump rate in all exercise periods was 5 µl/min. The subjects
performed a warm-up trial at a power output of 40 W; the warm-up period
was followed by two 60-W exercise periods. Dialysate samples were collected for 2 min from the eight probes. Sampling was finished 2.25, 5.25, 10.25, and 15.25 min after the onset of each exercise period. The
collection of samples was displaced; the delay (40 s for CMA probes,
20 s for homemade probes) due to the volume of the outlet tubes
was taken into account. The weight of the sample tubes was determined
before and after sampling to validate the perfusion rate. Collection
from probes having >10% deviation between expected and collected
samples and probes having any sign of hemoglobin content in the
dialysate was immediately stopped, and the samples were not analyzed.
The K+ concentrations of the collected samples were
measured with a flame photometer (model FLM3, Radiometer) using lithium
as an internal standard. Five microliters of each dialysate sample were counted in a Packard auto-gamma counter to determine thallium loss.
Calculations
The relative loss (RL) of 201Tl was calculated as follows
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Channel Localization
Membrane separation.
Giant sarcolemmal vesicles, used in a membrane separation procedure,
were produced from rat and human muscle samples, as previously described (11). Marker enzyme analyses have shown that the
vesicular membrane is mainly of sarcolemmal origin (12).
Another membrane separation method based on ultracentrifugation and
discontinuous sucrose gradients was used to isolate the T tubule
fraction and the sarcolemmal (plasma membrane) fraction
(7). The Na+-K+ pump
2-subunit and the dihydropyridine (DHP) receptor
-subunit were used as marker enzymes for sarcolemma and T tubules,
respectively, to characterize the membrane fractions.
Western blot.
Rat and human muscle samples were homogenized in a sucrose buffer (in
mM: 250 sucrose, 30 HEPES, 2 EGTA, 40 NaCl, 2 phenylmethylsulfonyl fluoride, pH 7.4) with a Polytron 2100 and centrifuged at 1,000 g for 5 min. The supernatant was spun at 190,000 g for 90 min at 4°C. The pellet was resuspended in
Tris-SDS (10 mM Tris, 4% SDS, 1 mM EDTA, 2 mM phenylmethylsulfonyl
fluoride, pH 7.4), and protein content was determined with a BSA
standard (DC protein assay, Bio-Rad). Samples were subjected to
SDS-PAGE (Excell 8-18% gradient gel) and electroblotted to a
Millipore Immobilon-P polyvinylidene difluoride membrane. The membrane
was blocked by BSA, 0.1% Tween 20, and low-fat milk and incubated with
the primary antibody diluted in a BSA-containing buffer. After
treatment with the horseradish peroxidase-coupled secondary antibody
and repeated washing, the membrane was incubated with enhanced
chemiluminescence reagent (Amersham) and visualized on film. The
quantification of protein was performed by scanning the
film and analyzing band intensities with SigmaGel software. Samples
to be compared were always run on the same gel and with identical
amounts of protein per lane. The anti-DHP receptor
1-subunit antibodies (catalog no. 3-920) were obtained
from Affinity Bioreagents, anti-Na+-K+ pump
2-subunit antibodies (catalog no. 06-168) from Upstate Biotechnology, anti-Kir 6.2 (G-16, catalog no. 11228) from Santa Cruz
Biotechnology, and anti--BKCa2+ (catalog no. APC-021)
from Alomone Labs.
Immunofluorescence microscopy.
Immunofluorescence microscopy was used to localize the channels at the
subcellular level. Human muscle biopsies were embedded in Tissue-Tek
and frozen in liquid nitrogen. Samples were cut into 8-µm cross
sections in a cryostat and put on a glass slide. The sections were
fixed in 
20°C acetone for 5 min and thereafter in 4% formaldehyde
for 2 min. The following protocol was carried out in PBS at pH 7.2. Between each 1-h incubation, the fixed sections were washed in 3 ml of
PBS with 0.5% BSA. Nonspecific binding was reduced by blocking with
0.5% BSA for 1 h. Primary, secondary, and tertiary antibodies
were diluted in 0.5% BSA. Samples were incubated in primary antibodies
(1:1,000), secondary antibodies (biotinylated rabbit anti-goat IgG,
1:600), and, finally, tertiary antibodies (streptavidin, 1:100) to
amplify the signal. The last procedure was carried out without BSA. The
sections were mounted with Vectorshield and examined in a fluorescence
microscope. The samples were stored at 20°C until photographed.
Statistics
Values are means ± SE. For each subject, an average value for the microdialysis probes was determined for each leg. An overall average was then calculated from the individual means. Differences between the intervention and control leg were tested using two-way ANOVA for repeated measures. Differences within the intervention leg were tested using one-way ANOVA for repeated measures. When differences were found, a t-test was used to identify the points of difference. P < 0.05 was considered significant (SigmaStat software).| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Interstitial K+ at Rest
At the end of the 90-min restitution period after probe insertion, the interstitial K+ concentration was 4.5 ± 0.2 mM in the control leg and 4.5 ± 0.3 mM in the intervention leg. A perfusate pH of 10 did not induce any difference in interstitial K+ between the control and the intervention leg. Glibenclamide infusion for 30 min reduced (P < 0.05) interstitial K+ in the intervention leg to 4.0 ± 0.1 mM (Fig. 1). After glibenclamide was washed out for 20 min, K+ in the intervention leg was 4.2 ± 0.3 mM, which was not different from the concentration in the control leg (4.4 ± 0.1 mM).
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Interstitial K+ During Exercise
Interstitial K+ in the control and intervention leg was identical after the 40-W warm-up period. The first 60-W exercise period (without drugs) increased interstitial K+ in both legs to 10-11 mM. Glibenclamide was then added to the perfusate in the intervention leg 15 min before the second 60-W bout. The peak interstitial K+ during the second exercise bout (~9 mM) was lower (P < 0.05) than that during the first bout, but there was no difference between the control and the intervention leg (Fig. 2).
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Localization of K+ Channels in Rat Skeletal Muscle
Antibodies to the DHP receptor and the Na+-K+ pump2-subunit were used
to characterize the membrane fractions obtained from rat muscle. The T
tubule marker DHP was absent in the sarcolemmal giant vesicles but
could be detected in the sarcolemmal fraction obtained by
sucrose-gradient ultracentrifugation. The highest density of the DHP
receptor was found in the T tubule fraction. The
Na+-K+ pump 2-subunit was mainly
found in vesicles and the sarcolemmal fraction, which were labeled
11-12 times more intensely than the muscle homogenate. This
purification index is in agreement with a mainly sarcolemmal
localization of the pump. The distribution of the KATP
channels demonstrated a great similarity to the distribution of the
pump, suggesting that the KATP channels are mainly located in the sarcolemma. In contrast, the BKCa2+ channels were
more abundant in the T tubule fraction, suggesting a higher density
than in the sarcolemma (Fig. 3).
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Distribution of KATP and BKCa2+ Channels in Human Skeletal Muscle on the Basis of Western Blot Analysis
Because of the limited amount of tissue available, only the giant vesicle method was used to purify sarcolemmal membranes from human muscle. The Kir 6.2 subunit of the KATP channel was present in a higher density (P < 0.05) in vesicles than in homogenates (n = 4). In contrast, the BKCa2+ protein content was clearly lower in vesicles than in homogenates (Fig. 4).
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Immunohistochemistry of Human Skeletal Muscle
The immunnohistochemical pictures demonstrated that the Kir 6.2 protein is present in the surface membrane of human skeletal muscle fibers. The staining was seen in all fibers, suggesting the presence of KATP channels in all fiber types (Fig. 5A). The labeling of the surface membranes was not seen in negative control images (Fig. 5B), which were obtained with an identical procedure, but without primary antibodies. Fluorescence was also seen in some distinct areas near the surface. These spots might be in the area of the capillaries; this possibility is supported by the limited number at the surface of each fiber. Similar spots were also seen in the negative control situation (without primary and secondary antibodies) and are therefore considered to be autofluorescence from compounds near the capillaries.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major findings in the present study are as follows.
1) KATP channels are mainly located in the
plasma membrane. 2) KATP channels appear to be
present in all fiber types. 3) KATP channels are
active in resting human muscle. In the present study, we used local
drug application in combination with the microdialysis technique, instead of systemic ingestion. The advantage is that systemic effects,
such as effects on pancreatic 
-cells and increased insulin level
(2), are avoided. Therefore, insulin-induced effects on
K+ balance mediated by activation of the
Na+-K+ pump (5) can be excluded.
Importance of KATP Channels
The interstitial K+ concentration can be described as a balance between K+ release mediated by various channels and reuptake mediated by the Na+-K+ pump. The pronounced effect of the KATP channel inhibitor glibenclamide on interstitial K+ at rest suggests that KATP channels contribute significantly to the membrane permeability in resting human muscle.The finding that KATP channels in human skeletal muscle are active at rest is surprising in light of the first hypothesis for the function of these channels, which were considered to be active only in exhausted cells (1, 4, 22). Voltage-clamp studies of frog muscle membranes have demonstrated that the channels are closed in patches from resting muscle (21), and studies in isolated mouse muscle have shown that KATP channel inhibition had no effect on membrane K+ permeability and the resting membrane potential in unstimulated isolated muscle (1, 17). In contrast, glibenclamide is reported to reduce K+ efflux in rat muscle perfused in situ (16). One explanation for these discrepancies could be species differences. Another explanation could be that the KATP channels are inactive under in vitro conditions but active under in vivo conditions: some factors that are responsible for the opening of KATP channels in resting muscle are lost during preparation of isolated frog and mouse muscle, and these factors are not present in the media used in patch-clamp studies. It has been reported that the KATP channels can be activated by lactate and pyruvate (10), protons (6, 22), adenosine and GTP (3), and nitric oxide (19, 23). The opening of KATP channels in resting human muscle could theoretically be due to a combined effect of several of these factors. However, inasmuch as the concentrations of these factors are low at rest, it is unlikely that they contribute to the opening of the KATP channels. Insulin, on the other hand, is likely to be involved in the opening of KATP channels at rest, inasmuch as insulin has been demonstrated to increase the KATP current in patch-clamped rat muscle fibers (24, 25).
During muscle activity, some K+ is released because of the activity of the voltage-dependent K+ channels associated with the action potentials. The present data suggest that glibenclamide has no effect on the interstitial K+ increase during exercise, which seems to indicate that KATP channels do not contribute to the increased K+ release. However, some reservations can be discussed. First, it could be argued that the increased blood flow during exercise removes glibenclamide, resulting in an insufficient inhibition. On the other hand, muscle movements have been found to nearly double the fractional release of compounds from the microdialysis probe. It is therefore likely that the release of glibenclamide from the probe is substantially increased during muscle exercise, which could compensate for an increased washout due to the increased blood flow. Second, it is not known whether glibenclamide inhibition results in a membrane depolarization in human muscle, but the apparent lack of effect of glibenclamide could be related to such changes in membrane potential, resulting in an increased driving force for K+, a mechanism that could blur the contribution of KATP channels during muscle activity. On the other hand, the lower interstitial K+ concentration in the glibenclamide experiments tends to hyperpolarize the fibers, which acts in the opposite direction. Although interference from the above-mentioned mechanisms cannot be completely ruled out, it is concluded that KATP channels are not major contributors to the increased K+ release during muscle exercise.
Subcellular Localization of K+ Channels
Membrane fractionation techniques and immunohistochemistry were used to localize the K+ channels in muscle. Although the Western blotting technique does not allow measurements of absolute channel densities, some conclusions can be drawn from the relative densities. If the relative densities of the KATP and BKCa2+ channels in the different muscle fractions are compared with the density of the marker enzymes (Na+-K+ pump and DHP receptor), it can be concluded that the KATP channels have a higher density in the sarcolemma, whereas the BKCa2+ channels have a higher density in the T tubule membranes. The sarcolemmal localization of the KATP channels and the effect of the specific inhibitor glibenclamide reported here are in agreement with a role for these channels in membrane permeability and regulation of the interstitial K+ concentration at rest.Summary
KATP channels located in the sarcolemma contribute to the permeability of resting human skeletal muscle and are therefore important for the interstitial K+ balance. The finding that the inhibitor glibenclamide had no effect during exercise suggests that the KATP channels are not important for the K+ release during contractions in human muscle.| |
ACKNOWLEDGEMENTS |
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This study was supported by Danish National Research Foundation Grant 504-14 and the NOVO Nordisk Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. Juel, Copenhagen Muscle Research Centre, August Krogh Institute, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen, Denmark (E-mail: cjuel{at}aki.ku.dk).
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.
First published September 27, 2002;10.1152/ajpregu.00303.2002
Received 28 May 2002; accepted in final form 23 September 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A. K. Hansen, T. Clausen, and O. B. Nielsen Effects of lactic acid and catecholamines on contractility in fast-twitch muscles exposed to hyperkalemia Am J Physiol Cell Physiol, July 1, 2005; 289(1): C104 - C112. [Abstract] [Full Text] [PDF]
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A. R. Gosmanov, Z. Fan, X. Mi, E. G. Schneider, and D. B. Thomason ATP-sensitive potassium channels mediate hyperosmotic stimulation of NKCC in slow-twitch muscle Am J Physiol Cell Physiol, March 1, 2004; 286(3): C586 - C595. [Abstract] [Full Text]
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J. J. Nielsen, M. Mohr, C. Klarskov, M. Kristensen, P. Krustrup, C. Juel, and J. Bangsbo Effects of high-intensity intermittent training on potassium kinetics and performance in human skeletal muscle J. Physiol., February 1, 2004; 554(3): 857 - 870. [Abstract] [Full Text] [PDF]
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) and the intervention (
) leg
during a 16-min 60-W exercise bout; then glibenclamide was added to the
perfusate of the intervention leg, and the exercise period was
repeated. Values (means ± SE) are not significantly different by
ANOVA.
