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Copenhagen Muscle Research Centre, Institute of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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It has been proposed that the activation state of pyruvate dehydrogenase (PDH) may influence the rate of skeletal muscle O2 uptake during the initial phase of exercise; however, this has not been directly tested in humans. To remedy this, we used dichloroacetate (DCA) infusion to increase the active form of PDH (PDHa) and, subsequently, measured leg O2 uptake and markers of anaerobic ATP provision during conditions of intense dynamic exercise, when the rate of muscle O2 uptake would be very high. Six subjects performed brief bouts of one-legged knee-extensor exercise at ~110% of thigh peak O2 uptake (65.3 ± 3.7 W) on several occasions: under noninfused control (Con) and DCA-supplemented conditions. Needle biopsy samples from the vastus lateralis muscle were obtained at rest and after 5 s, 15 s, and 3 min of exercise during both experimental conditions. In addition, thigh blood flow and femoral arteriovenous differences for O2 and lactate were measured repeatedly during the 3-min work bouts (Con and DCA) to calculate thigh O2 uptake and lactate release. After DCA administration, PDHa was four- to eightfold higher (P < 0.05) than Con at rest, and PDHa remained ~130% and 100% higher (P < 0.05) after 5 and 15 s of exercise, respectively. There was no difference between trials after 3 min. Despite the marked difference in PDHa between trials at rest and during the initial phase of exercise, thigh O2 uptake was the same. In addition, muscle phosphocreatine utilization and lactate production were similar after 5 s, 15 s, and 3 min of exercise in DCA and Con. The present findings demonstrate that increasing PDHa does not alter muscle O2 uptake and anaerobic ATP provision during the initial phase of intense dynamic knee-extensor exercise in humans.
blood flow; lactate; creatine phosphate; dichloroacetate
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ALTHOUGH THE MECHANISMS
RESPONSIBLE for the delay in muscle O2 uptake at the
onset of exercise remain controversial (for review see Ref.
25), recent studies have suggested that this phenomenon is
not due to limited O2 availability but, rather, the ability of the muscle cells to utilize O2 (3,
9-11). One mechanism potentially involved in a local
limitation to O2 uptake is "delayed" activation of the
enzyme pyruvate dehydrogenase (PDH). PDH is considered rate limiting
for pyruvate oxidation in skeletal muscle, and its activity is subject
to strict regulatory control. The active form of PDH (PDHa)
and PDH flux must be kept low in resting muscle to prevent unnecessary
carbohydrate utilization and flux through the enzyme must be rapidly
accelerated during strenuous exercise to meet the increased demand for
carbohydrate-derived acetyl-CoA (14). A possible role for
PDH in regulating muscle O2 uptake has been suggested by
several recent studies that employed the pharmacological agent
dichloroacetate (DCA). DCA administration was shown to markedly
increase PDHa in skeletal muscle and attenuate markers of
anaerobic ATP provision during electrically evoked contractions in
animals and during submaximal exercise in humans (12,
22-24). For example, Timmons et al. (22)
reported that pretreatment with DCA resulted in a ~50% reduction in
muscle phosphocreatine utilization during 8 min of knee-extensor
exercise at an intensity of ~45% of leg peak O2 uptake
(
O2 peak). This observation was
confirmed by Howlett and colleagues (12), who showed that DCA infusion attenuated muscle degradation after 30 s of exercise and lactate accumulation after 2 min of submaximal cycle exercise at
~65% of maximal O2 uptake
(O2 max). It was hypothesized that the
availability of acetyl groups to the tricarboxylic acid (TCA) cycle,
which is increased after PDH activation by DCA, is a key determinant of
muscle O2 uptake at the start of exercise (22,
23). To our knowledge, however, there have been no direct measurements of muscle O2 uptake during exercise after DCA
administration in humans.
Thus the aim of the present study was to determine whether manipulation of PDHa would alter muscle O2 uptake or markers of anaerobic ATP provision during the initial phase of intense exercise in humans (i.e., when the rate of muscle O2 uptake would be high and pyruvate is the primary source for the citric acid cycle). To examine this issue, subjects performed intense dynamic knee-extensor exercise on several occasions: under noninfused control (Con) and DCA-supplemented conditions.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Six healthy men, ranging in age from 21 to 24 yr, with an average height of 178 (range 172-183) cm and a mean body mass of 72.5 (range 67.9-78.3) kg, participated in the experiment. The subjects were fully informed in advance of the risks and discomfort associated with the experimental procedures, and all provided written consent. The study was approved by the Ethics Committee of Frederiksberg and Copenhagen.
Experimental protocol. Subjects were instructed to consume a light breakfast ~3 h before an experimental trial. After the subjects reported to the laboratory and rested in the supine position for ~30 min, a catheter was inserted into a femoral artery under local anesthesia. The tip was positioned 1-2 cm proximal to the inguinal ligament. A catheter was also inserted into the femoral vein of the leg to be exercised, ~1-2 cm distal to the inguinal ligament. A thermistor for measurement of venous blood temperature was inserted through the catheter and advanced 8-10 cm proximal to the tip.
At ~1 h after insertion of the catheters, subjects performed a 3-min bout of dynamic knee-extensor exercise in the supine position on an ergometer that permitted the exercise to be confined to the quadriceps muscle (1). The external power output was 65.3 ± 3.7 W, corresponding to ~110% of thighO2 peak, and the kicking frequency was
60 rpm. At this work intensity, subjects would typically have been
exhausted after ~4 min. Just before exercise, the leg was passively
moved for 5 s to accelerate the flywheel. Blood was drawn from the
femoral artery and vein ~10 and 5 s before the exercise and
~2, 6, 10, 14, 29, 45, 60, 90, 120, 145, and 165 s during
exercise. In addition, femoral venous blood flow was measured by the
thermodilution technique (2) approximately every 30 s
after ~1 min of the first exercise bout as well as ~3 s before and
after 5, 35, 60, 90 and 160 s of exercise when the exercise bout
was repeated after 1 h of rest. Values of blood flow obtained at
the same time during the first exercise bouts agreed with the values
after 60 min of rest for Con (4.36 ± 0.30 vs. 4.45 ± 0.23 l/min after 67 s, 4.83 ± 0.46 vs. 5.13 ± 0.44 l/min
after 99 s, and 5.63 ± 0.70 vs. 5.39 ± 0.58 l/min
after 152 s) and DCA (4.32 ± 0.48 vs. 4.58 ± 0.23 l/min after 67 s and 5.77 ± 0.50 vs. 5.48 ± 0.54 l/min
after 166 s) with a coefficient of variation (CV) of 5.4%. Thus,
in Con and DCA, the blood flow values after the rest period were used
in the calculations. An occlusion cuff placed just below the knee was
inflated (220 mmHg) during the exercise to avoid blood contribution from the lower leg. A needle biopsy sample was obtained from the vastus
lateralis muscle under local anesthesia before and after each of the
exercise bouts.
The exercise protocol was performed on two occasions separated by ~14
days. On one occasion, DCA (sodium salt, pH 7.0, 50 mg/kg body mass)
was infused (50 mg/ml) into the femoral vein over a 30-min period,
ending 10 min before the start of exercise (DCA). On the other
occasion, no infusion was performed (Con). The same leg was exercising
in the Con and DCA experiments, which were performed in a
counterbalanced order.
In addition, on two separate occasions within 3 wk of the main
experiments, subjects performed knee-extensor exercise at the same work
intensity for 5 and 15 s, separated by a 45-min rest period, under
Con and DCA-supplemented conditions. A muscle biopsy from the vastus
lateralis muscle was obtained before and after the 5-s exercise bout
and after the 15-s work bout. For the DCA-supplemented trial, subjects
received an extra dose of 25 mg/kg body mass between bouts, 15 min
before the start of the 15-s exercise bout. Thus, in total, two needle
biopsy samples were obtained at rest, and single samples were obtained
after 5 s, 15 s, and 3 min of exercise for the DCA and Con
conditions. There were no differences between the two rest biopsies
within a given condition with regard to metabolite concentrations or
enzyme activity, and data for all biopsy samples are presented.
Blood analyses.
O2 saturation of blood and hemoglobin concentration were
determined spectrophotometrically (Radiometer OSM-3 hemoximeter). The
hemoximeter was calibrated using the cyanmethemoglobin method (6). Hematocrit was determined in triplicate using
microcentrifugation. A 100-µl aliquot of each blood sample was
hemolyzed within 10 s of sampling using a 1:1 dilution with a
buffer solution (Yellow Spring Instruments, Yellow Springs, OH), to
which Triton X-100 (20 g/l) was added to determine lactate (YSI 23 lactate analyzer, Yellow Spring Instruments) (7). The
remainder of the blood sample was placed in ice-cold water and
centrifuged rapidly for 30 s. From this sample, plasma was
collected and stored at 
80°C until subsequent analysis for pyruvate
using a fluorometric assay (15).
Muscle analyses.
Needle biopsy samples were immediately frozen in liquid nitrogen and
stored at 80°C. A 20- to 30-mg piece was removed from each biopsy
and used to determine PDHa using the method of
Constantin-Teodosiu et al. (5) as modified and described
by Putman et al. (20). The remainder of the frozen muscle
sample was weighed before and after it was freeze-dried to determine
water content. After the sample was freeze-dried, it was dissected free
of blood and connective tissue, and the muscle tissue was extracted in
a solution of 0.6 M perchloric acid and 1 mM EDTA, neutralized to pH
7.0 with 2.2 M KHCO3, and stored at 80°C. Muscle
extracts were subsequently analyzed for creatine phosphate and lactate
using fluorometry (15).
Muscle mass. The mass of the quadriceps femoris muscle group was estimated using magnetic resonance imaging. Briefly, for each subject, 30-33 parallel axial T1-weighted images (sections) of the right thigh were obtained with a multislice spin-echo FLASH sequence (TR = 500 ms, TE = 15 ms) using a body coil. Slice thickness was 3 mm, with a gap of 12 mm between each slice. Pixel size was 1.2 mm2. This setting was selected to optimize image quality and clearly separate muscle, bone, fat, and connective tissue. Image analyses were performed using NIH Image software. The mean knee-extensor mass of the experimental leg was 2.35 kg (range 1.94-2.79 kg).
Calculations. The uptake/release of O2 and lactate across the thigh was calculated by multiplying the blood flow by the femoral arteriovenous difference in O2 content and lactate concentration, respectively. Pyruvate exchange was calculated in a similar manner, except leg plasma flow was used. A continuous blood flow curve was constructed for each subject using a linear connection of consecutive data points to obtain time-matched values for blood flow and blood measurements. Lactate production during exercise was calculated as the sum of muscle lactate accumulation and total lactate release, determined as the area under the lactate release curve, expressed per unit active muscle.
To determine the mean transit time (MTT) of the blood from the femoral artery to the collecting site in the femoral vein, four of the subjects performed the main experimental protocol a third time on a separate occasion (without DCA infusion), as described previously (3). Briefly, the experimental conditions and position of the catheters were the same as in the main experiments. Before and frequently during the exercise, indocyanine green dye (Cardiogreen, Becton Dickinson) was injected rapidly into the femoral artery, and immediately thereafter the artery was flushed with isotonic saline. Blood was withdrawn from the femoral vein for measurements of dye concentration using a linear densitometer, and MTT was detected as the time from injection to the time when the curve peaked, corrected by transit time of catheter. The MTT values for Con were used to make calculations during the DCA experiment. This assumption appears valid, since no differences in thigh blood flow during exercise were observed between Con and DCA (see above). On the basis of MTT, the average time to which the collected artery and venous blood represented capillary blood was estimated as described previously (3). All blood variables are presented in relation to mean time at the capillary. For the two subjects where no MTT values were obtained, average values were used.Statistics. Data were analyzed using two-way analysis of variance with repeated measures. A significance level of 0.05 was chosen. If a significant interaction was detected, data were subsequently analyzed using a Newman-Keuls post hoc test. Unless otherwise noted, values are means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Muscle PDH.
In Con muscle, PDHa at rest was ~10% of PDHa
at the end of the 3-min exercise bout, and it increased to 28 and 38%
after 5 and 15 s, respectively (Table
1). Compared with Con, DCA infusion elevated (P < 0.05) PDHa by four- to
eightfold at rest (Table 1), by 130 and 100% after 5 and 15 s of
exercise, respectively, but no difference was observed at the end of
exercise (Fig. 1).
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Thigh O2 uptake.
In Con and DCA, thigh blood flow increased from ~1.7 l/min just
before exercise to 5.4 l/min at the end of exercise (Fig. 2).
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Muscle creatine phosphate.
Muscle creatine phosphate decreased by ~15 and 25% during the first
5 and 15 s of exercise, respectively, reaching a level corresponding to 30% of rest (24 mmol/kg dry wt) at the end of exercise in Con and DCA (Table 1). Consequently, the average rates of
creatine phosphate degradation were the same in Con and DCA (Fig.
4).
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Thigh pyruvate exchange.
In DCA, arterial and venous pyruvate were lower (P < 0.05) than in Con before and throughout exercise (Fig.
5A). After 90 s of
exercise, pyruvate release was higher (P < 0.05) in
DCA than in Con (Fig. 5B).
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Lactate production.
No differences between Con and DCA were observed in the increase of
muscle lactate in the first 5 and 15 s of exercise or in the last
phase of exercise, with the total increase during exercise being ~80
mmol/kg dry wt in Con and DCA (Table 1). Arterial lactate was lower
(P < 0.05) in DCA than in Con before and throughout exercise, and femoral venous lactate was lower (P < 0.05) before and during the first 14 s of exercise (Fig.
6A). In DCA, net lactate release was higher (P < 0.05) after 30 s of
exercise and toward the end of exercise than in Con (Fig.
6B). The average rates of lactate production were the same
in Con and DCA (Fig. 7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major findings from the present study were that although DCA
infusion increased PDHa at rest and during the first
15 s of intense exercise compared with the control condition,
muscle O2 uptake, creatine phosphate degradation, and
lactate production were not affected. These observations suggest that
the delayed muscle respiratory response during the initial phase of
intense dynamic exercise in humans (~110% of thigh
O2 peak) is not due to a lag in PDH activation.
Under control conditions, PDHa after 15 s of exercise
was only about one-third of that at the end of 3 min of work, at which time the enzyme was likely fully converted to the active form (19). Few data are available regarding the time course for
PDH activation during the initial seconds of exercise. However, Parolin et al. (16) reported that PDH increased from 14% active
at rest to 48% after 6 s of maximal isokinetic cycling and was
almost totally activated by 15 s. In addition, Howlett et al.
(13) recently reported a 65% transformation of PDH to the
active form after 10 s of maximal sprint cycling. The slower
activation in the present study than in these previous two studies may
be related to exercise intensity, e.g., maximal cycling (>300% of the
intensity eliciting O2 max) vs. the
power output (~110% of thigh O2 peak) in the present study, which
was sustained for 3 min. Although a number of mechanisms could be
involved, one potential factor is difference in mitochondrial
Ca2+ released from the sarcoplasmic reticulum, which is
believed to be important for the initial activation of PDH during
contraction (26).
The observations that PDH was only partly activated and that there was
a significant accumulation of muscle lactate after 5 and 15 s of
exercise indicate that the rate of pyruvate production from glycolysis
was in excess of mitochondrial pyruvate oxidation and could be
interpreted to suggest that flux through PDH was limiting for
O2 uptake at the start of exercise. However, we did not
observe any elevation in the rate of muscle O2 uptake after DCA administration, despite the fact that this manipulation markedly increased PDHa at rest as well as after 5 and 15 s of
exercise compared with the control trial. It should be considered
whether the measurements of leg O2 uptake are sensitive
enough to detect a possible difference in O2 uptake. The
average thigh blood flow in the initial phase of exercise was the same
in Con and DCA, but the individual differences between Con and DCA were
greater in the 1st min (CV = 12%) than in the last 2 min (CV = 6%). However, because thigh blood flow also was the same in Con and
DCA just before and during the remaining part of exercise, it seems
unlikely that blood flow in Con and DCA was different in the early
phase of exercise. Some variation in arteriovenous O2
difference was also observed in the 1st min of exercise (CV = 14%) and less during the last 2 min (CV = 3%). However, there
was not even a tendency for the O2 extraction to be higher
in DCA, since half of the subjects had higher arteriovenous
O2 difference values in the first phase of exercise in Con
than in DCA. In another knee-extensor study, a measurably higher
O2 extraction (<20 ml/l) was observed after a few seconds
of repeated exercise (4). Thus the lack of difference in
arteriovenous O2 difference and thigh O2 uptake
between Con and DCA appears not to be caused by the measurement of
O2 extraction and blood flow not being sensitive enough.
Moreover, the DCA treatment did not change the rate of creatine
phosphate degradation or lactate production in the exercising muscles,
indicating that the anaerobic ATP provision was not changed with DCA
infusion. Thus these data suggest that the activation state of PDH does
not limit mitochondrial respiration during the initial phase of intense
(~110% O2 peak) dynamic
knee-extensor exercise in humans.
Although the effect of DCA infusion on muscle O2 uptake has not been studied previously, a number of recent investigations have examined the effect of DCA administration on skeletal muscle anaerobic metabolism in animals and humans. When PDH in resting canine gracilis muscle was activated by pretreatment with DCA, the estimated anaerobic energy contribution during electrically induced contraction was reduced, suggesting an increased aerobic contribution (24). In a human study conducted by the same group of investigators (22), a threefold increase in resting muscle PDH activity and a fivefold increase in muscle acetylcarnitine were observed after DCA infusion. During a subsequent bout of one-legged knee-extensor exercise, muscle creatine phosphate was significantly higher (30%) after 8 min of contraction than in a control situation; however, there were no differences between conditions in muscle lactate. In another human study using partial ischemia, Timmons et al. (23) observed that DCA infusion reduced creatine phosphate degradation and muscle lactate accumulation by ~50% after 3 min of submaximal, single-leg knee-extension exercise, but there were no differences after 8 min of exercise. In agreement with these findings, Howlett et al. (12) reported that muscle creatine phosphate utilization and lactate accumulation after 2 min of submaximal exercise were reduced after pretreatment with DCA. On the other hand, Parolin et al. (17) reported that, under hypoxic conditions, DCA infusion did not affect muscle creatine phosphate utilization during the 1st min of exercise, whereas muscle creatine phosphate was higher and muscle lactate was lower after 15 min of exercise than in a control situation. The precise explanation for these observations is not clear, since DCA exerts a complex myriad of effects in numerous tissues (for review see Ref. 21). It has been hypothesized that, by activating PDH and elevating the level of muscle acetyl-CoA and acetylcarnitine, DCA increases the availability of substrate for the TCA cycle and, thereby, increases the rate of mitochondrial respiration after onset of exercise (23). It has also been suggested that DCA might function to expand the pool of TCA cycle intermediates (TCAI) in resting skeletal muscle and, therefore, augment TCA cycle flux on contraction. However, it was recently shown that DCA actually lowers the total concentration of muscle TCAI at rest and does not alter the steady-state concentration of TCAI during exercise (8).
In contrast to some of the studies cited above, we did not observe any
differences between trials in creatine phosphate degradation or lactate
accumulation during exercise. At first glance, the mean values for
muscle creatine phosphate and lactate (Table 1) might indicate that the
anaerobic energy production was (nonsignificantly) lower during the
first 15 s in the DCA than in the Con trial, but this difference
was largely due to one subject who had a markedly higher anaerobic
energy production in Con (Fig. 8). The
difference in anaerobic energy production calculated from average
values would have corresponded to a difference in O2 uptake
and O2 extraction of ~125 ml/min and 50 ml/l,
respectively, between Con and DCA. These differences are far above the
detection limit of the method, since a significant difference in
O2 extraction of 20 ml/l has been observed when intense
exercise was repeated (4).
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The extent of PDH activation after DCA administration in the present study was greater than that reported by Timmons and co-workers (22, 23) and smaller than that found by Howlett et al. (12), so this appears not to be the reason for the different findings. A more likely explanation is the difference in the intensity of the muscle contractions between the present study and several other studies in which submaximal workloads were employed (12, 22). In support of this suggestion, Howlett et al. (13) did not observe any effect of DCA infusion on muscle phosphocreatine degradation and lactate accumulation during 10 s of maximal cycling. It should also be considered that the lower muscle lactate concentration observed in mixed muscle biopsies during submaximal exercise after DCA infusion (12, 22, 23) may not be solely due to an enhanced rate of pyruvate oxidation. Lactate release was not measured in these previous studies; however, in the present study, we observed a higher rate of lactate release after 30 s of exercise after DCA administration. Moreover, during submaximal exercise, not all the muscle fibers may be activated, and the elevated activity of PDH in the inactive and partly active muscle fibers in the contracting muscles may have led to a greater conversion of lactate to pyruvate subsequent to an elevated rate of pyruvate oxidation. This hypothesis is supported by the observation that muscle lactate was not lowered after 30 s, but after 2 min of exercise in the study by Howlett et al. (12), indicating that removal of lactate, rather than production of lactate, was influenced. Although the present findings do not rule out the importance of PDH activation and/or acetyl group availability in determining muscle O2 utilization at the start of submaximal exercise, these factors do not appear to be important in regulating muscle respiration and anaerobic metabolism during the initial phase of intense contraction. As recognized by Howlett and colleagues (13), there could be a limit to oxidative metabolism within the muscle at sites other than PDH, such as the TCA cycle or the electron transport chain.
In summary, the present findings demonstrate that DCA infusion
increased PDHa at rest and during the initial phase of
intense exercise but did not alter muscle O2 uptake,
creatine phosphate utilization, or muscle lactate production. These
data suggest that the activation state of PDH is not limiting for
muscle O2 utilization during the first phase of intense
dynamic exercise (~110% of O2 peak)
in humans.
Perspectives
The workload for this study was selected to ensure that muscle activation was complete, that muscle O2 demand was high, and also that pyruvate-derived acetyl-CoA was the primary fuel source for mitochondrial respiration. Our findings indicate that the rate of PDH activation does not limit muscle O2 uptake during the initial phase of intense dynamic exercise in humans. Evidence has also been presented to suggest that, under these conditions, muscle O2 uptake is not limited by O2 delivery. Thus, if it is assumed that the delay resides within the muscle, future studies should examine the citric acid cycle and electron transport chain for potential sites of limitation to muscle O2 uptake during the initial phase of contraction.| |
ACKNOWLEDGEMENTS |
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We thank Merete Vannby, Ingelise Kring, and Winnie Tagerup for excellent technical assistance.
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FOOTNOTES |
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The study was supported by Danish National Research Foundation Grant 504-14. In addition, support was obtained from Team Danmark and The Sports Research Council (Idrættens Forskningsråd). M. J. Gibala was supported by a Postdoctoral Fellowship Award from the Natural Sciences and Engineering Research Council of Canada.
Address for reprint requests and other correspondence: J. Bangsbo, The August Krogh Institute, LHF, Universitetsparken 13, DK-2100 Copenhagen Ø, Denmark (E-mail: jbangsbo{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.
Received 11 January 2001; accepted in final form 6 September 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1 · kg wet
wt
) and with
prior DCA infusion (
). Values are means ± SE.
* Significantly
different from 0-15 s.
