1 Department of Medicine, McMaster University Medical Centre, Hamilton, Ontario L8N 3Z5; 3 Department of Kinesiology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada; and 2 Department of Clinical Chemistry, Huddinge University Hospital, Karolinska Institute, S-141 86 Huddinge, Sweden
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ABSTRACT |
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Muscle metabolism,
including the role of pyruvate dehydrogenase (PDH) in muscle lactate
(Lac) production, was
examined during incremental exercise before and after 7 days of
submaximal training on a cycle ergometer [2 h daily at 60% peak
O2 uptake
(
O2 max)].
Subjects were studied at rest and during continuous steady-state
cycling at three stages (15 min each): 30, 65, and 75% of the
pretraining
O2 max.
Blood was sampled from brachial artery and femoral vein, and leg blood flow was measured by thermodilution. Biopsies of the vastus lateralis were obtained at rest and during steady-state exercise at the end of
each stage.
O2 max,
leg O2 uptake, and the maximum
activities of citrate synthase and PDH were not altered by training;
muscle glycogen concentration was higher. During rest and cycling at 30%
O2 max, muscle
Lac
concentration
([Lac
]) and leg
efflux were similar. At 65%
O2 max, muscle
[Lac
] was lower
(11.9 ± 3.2 vs. 20.0 ± 5.8 mmol/kg dry wt) and
Lac
efflux was less
[
0.22 ± 0.24 (one leg) vs. 1.42 ± 0.33 mmol/min] after training. Similarly, at 75%
O2 max, lower muscle
[Lac
] (17.2 ± 4.4 vs. 45.2 ± 6.6 mmol/kg dry wt) accompanied less release (0.41 ± 0.53 vs. 1.32 ± 0.65 mmol/min) after training. PDH in its active form
(PDHa) was not different between
conditions. Calculated pyruvate production at 75%
O2 max fell by 33%,
pyruvate reduction to lactate fell by 59%, and pyruvate oxidation fell by 24% compared with before training. Muscle contents of coenzyme A
and phosphocreatine were higher during exercise after training. Lower
muscle lactate production after training resulted from improved matching of glycolytic and PDHa
fluxes, independently of changes in muscle
O2 consumption, and was associated
with greater phosphorylation potential.
lactate; oxygen uptake; pyruvate dehydrogenase; glucose transporters; glycogen; leg blood flow; free fatty acids; phosphorylation potential
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INTRODUCTION |
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LONG-TERM ENDURANCE (submaximal) training carried out over periods of at least several weeks leads to a reduction in muscle glycogen utilization and lactate production, with greater use of fats as fuel during submaximal exercise (17). These changes have been ascribed to improvements in oxygen delivery through increases in muscle capillarization, greater metabolic oxidative capacity related to increases in mitochondrial content, and increased activity of enzymes taking part in the citric acid cycle and fat oxidation. Recently, short-term (6-10 days) endurance training has also been shown to shift metabolism from carbohydrates to fats, with less lactate production, before any increases in mitochondrial oxidative capacity have occurred (15, 16, 24), calling into question the importance of increasing oxygen delivery and oxidative capacity in explaining the effects of training on the choice of fuels for exercise. Muscle biopsy and whole body substrate turnover studies have shown that muscle glycogen and glucose utilization are decreased and less lactate is produced (8, 15, 16, 21, 23, 24). Intramuscular triglycerides are oxidized to a greater extent, without increases in the oxidation of plasma-derived free fatty acids (20, 21, 23, 24).
A reduction in blood lactate accumulation is uniformly found after endurance training (17), and because traditionally lactate formation has been considered to be secondary to exercise-induced tissue hypoxia, improvements in oxygen delivery and utilization have been considered to be the causal mechanisms. An alternative view of lactate formation (29) is that it results from an imbalance between the rates of pyruvate production by glycolysis and of pyruvate oxidation by the pyruvate dehydrogenase enzyme complex (PDHc) (26) and enzymes of oxidative phosphorylation (29). Because the equilibrium constant of the lactate dehydrogenase system markedly favors lactate over pyruvate, small changes in pyruvate concentration are associated with large increases in lactate formation.
Recently, it has been demonstrated (8) that the reduction in muscle
lactate production after short-term training is associated with a
reduction in glycogenolytic rate, related to posttransformational downregulation of glycogen phosphorylase activity, modulated by decreases in both PO24 and AMP. In
all these previous studies, reductions in lactate accumulation were
larger than the accompanying reductions in glycogenolysis. Recent
lactate tracer studies have shown that after short-term training (22), there is in addition to a lower muscle lactate production a greater rate of lactate clearance from the blood.
Because PDHc controls the rate of acetyl-CoA formation from pyruvate, the effects of training on lactate metabolism may be explained by an increase in the active form of PDHc (PDHa). Greater conversion of pyruvate into acetyl-CoA may allow greater oxidative phosphorylation and lower pyruvate concentration, accompanied by lower lactate formation. Because previous studies of short-term training have shown no increase in mitochondrial enzymes, any increases in lactate clearance and pyruvate oxidation are likely to result from altered PDHa regulation at submaximal workloads, rather than increases in the total PDHc activity (PDHt). However, the role of increased transformation of PDHc to PDHa in attenuating net muscle lactate production after short-term training has not been established. The purpose of the present study was to examine the regulation of PDHa during exercise before and after this type of training.
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METHODS |
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Subjects
Seven male subjects [age 23.4 ± 1.5 (SE) yr, height 181 ± 2 cm, weight 81.4 ± 4.1 kg] participated in this study. Approval was obtained from the ethics committees of McMaster University and the McMaster University Medical Centre. Written informed consent was obtained from all subjects after an explanation of the attendant risks associated with the study protocol.Training Protocol
Before training, subjects completed a progressive exercise test on a cycle ergometer to determine peak oxygen uptake (Experimental Protocol
On the morning of each experiment, subjects ate a standard light meal, consisting primarily of carbohydrate, and reported to the laboratory 1-2 h later. The femoral vein was catheterized percutaneously by means of the Seldinger technique, after administration of 3-4 ml of xylocaine, as described by Bernéus et al. (4). The brachial artery was catheterized percutaneously (4) with a radiopaque Teflon catheter after local anesthesia with 0.5 ml of xylocaine. Catheters were maintained patent with sterile nonheparinized saline solution. Leg blood flow was determined using the thermodilution method, as described by Andersen and Saltin (1): 10 ml of nonheparinized saline were injected, and leg blood flow was determined from the change in temperature as a function of time by use of a portable CO monitor (Spacelab, Redmond, WA). At least three measures were recorded at each time point and averaged.Before and after training, four biopsy sites were prepared superficial
to the vastus lateralis after local anesthesia. Subjects remained
sitting and inactive for 20 min (preexercise), followed by cycling for
15 min each at 30, 65, and 75% of their pretraining O2 max. Respiratory
measurements were made during the last 5 min of the preexercise period
and between 8 and 12 min of each exercise stage. Blood samples from the
femoral vein and the brachial artery were simultaneously drawn at rest
and at 9 and 13 min of each exercise stage. Leg blood flow was measured
immediately after blood sampling at both 9 and 13 min. Biopsies of the
vastus lateralis were obtained at rest just before the start of
exercise and at the end of each exercise stage, and these were
immediately frozen in liquid nitrogen and stored in liquid nitrogen
until analyzed.
Blood Sampling and Analysis
Arterial and venous blood samples were drawn in heparinized plastic syringes and placed on ice. One portion of each sample was deproteinized in 6% perchloric acid (PCA) and stored atMuscle Analysis
PDHa and PDHt were analyzed as previously described (10, 26). To compensate for contamination of muscle homogenates with blood or connective tissue, PDHa and PDHt measures were corrected to the highest total creatine in a series of biopsies obtained from each subject on a given day. Muscle glycogen was determined fluorometrically using the enzymatic end-point method described by Bergmeyer (3). Neutralized PCA extracts of freeze-dried, dissected, and powdered muscle samples were analyzed for acetyl-CoA, free CoASH, total CoA, acetylcarnitine, free carnitine, and total carnitine according to the method of Cederblad et al. (7). ATP, ADP, glucose, glucose 6-phosphate (G-6-P), fructose 6-phosphate (F-6-P), glycerol 3-phosphate (G-3-P), pyruvate, lactate, and phosphocreatine (PCr) were determined by the methods of Bergmeyer adapted for fluorometry. PCA extracts were corrected to the highest total creatine concentration within a series of biopsies obtained from each subject on a given day. Muscle wet-to-dry ratios were determined by weighing the frozen muscle samples before and again after freeze-drying. Maximal citrate synthase (CS) activity was determined according to Bergmeyer. Maximal CS activity was measured on each biopsy in duplicate on two different occasions for each subject. Because no differences were found between the two sets of independent measures, between conditions, or across time within a condition, the data were pooled and presented as pre- and posttraining. Muscle GLUT-1 and GLUT-4 transporter contents were determined by Western blot analysis (25).Leg Uptake and Release of Metabolites and O2
Uptake and release of metabolites (glucose, free fatty acids, glycerol, and lactate) and O2 were calculated from their whole blood contents in arterial and venous blood and leg blood flow. Because there were no differences in Hct over time within a condition or between matched arterial and venous samples, blood samples were not corrected for fluid shifts. Also, because subjects were in steady state, with no significant differences in blood flows or metabolite concentrations between 9 and 13 min of each exercise stage, the two values at these time points were averaged to obtain one value for each.Calculation of Pyruvate Production and Oxidation and Lactate Production
Pyruvate production was calculated from the sum of the rates of glycogen breakdown and glucose uptake minus the sum of the rates of accumulation of muscle glucose, G-6-P, and F-6-P by use of wet weight concentration differences and with the assumption that working muscle amounted to 4.3 kg/leg. Because net lactate release across the leg was measured during the steady state of each workload, with most lactate being produced earlier in exercise, net lactate release over the complete exercise period was instead calculated from changes in arterial blood lactate concentration by assuming a distribution volume of 0.6 × body weight. Pyruvate oxidation was calculated as pyruvate production minus lactate production.Statistical Analysis and Summary of Data
Data were analyzed using two-way ANOVA with repeated measures over time, except where otherwise stated. When a significant F ratio was found, the Newman-Keuls post hoc analysis was used to compare means over time and between conditions. The following data were analyzed using a 2-tailed paired dependent-samples Student's t-test: relative and absolute ![]() |
RESULTS |
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O2 max and
Respiratory Gas Exchange Responses to Training and Cycling Exercise
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Muscle Metabolism
ATP, ADP, and PCr.
Muscle ATP and ADP concentrations (Table 3)
were unaltered by exercise or as a result of training. Before training,
PCr concentration ([PCr]) decreased with each increase in exercise
intensity from 30 to 75%
O2 max. However, after
training, [PCr] did not decrease further from 65 to 75%
O2 max, being higher at
this level of exercise than before training (Table 3).
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Glycogen.
After training, intramuscular glycogen was greater at rest and
throughout each stage of the exercise protocol (Table 3). Glycogen
utilization during cycling at 30 and 65% of
O2 max was not
different between the pretraining and posttraining conditions. However,
at 75%
O2 max,
pretraining glycogen utilization (113.2 ± 14.6 mmol/kg dry wt) was
42.5 mmol/kg dry wt greater (P < 0.02) than in the posttraining condition (70.7 ± 13.9 mmol/kg dry
wt).
Glucose, G-6-P,
F-6-P, and
G-3-P.
Intramuscular accumulation of glucose was similar between conditions at
each stage, except at 75%
O2 max, where it was
lower posttraining (Table 3). Muscle
G-6-P and
G-3-P contents were also lower after
training (Table 3). F-6-P (Table 3)
was not different between the pre- and posttraining conditions.
Lactate and pyruvate.
Muscle lactate concentration ([lactate]) (Fig.
1) was significantly lower after training
(main effect P < 0.03). Before
training, muscle [lactate] increased progressively from 4.3 ± 0.5 mmol/kg dry wt at rest to 9.0 ± 3.8 at 30%, 20.0 ± 5.8 at
65%, and 45.2 ± 6.6 mmol/kg dry wt at 75%
O2 max. In the
posttraining condition, muscle [lactate] did not increase
above the initial preexercise value of 4.2 ± 0.4 at 30% (4.3 ± 0.3) but then increased to 11.9 ± 3.2 and 17.2 ± 4.4 mmol/kg dry wt
at 65 and 75% of
O2 max, respectively.
Muscle pyruvate concentration ([pyruvate]) progressively increased to the same extent, with increasing workload in both the pre-
and posttraining conditions up to 65%
O2 max (Fig. 1). At
75%
O2 max, however,
posttraining muscle [pyruvate] (0.57 ± 0.07 mmol/kg dry
wt) was 32% lower than the pretraining value (0.75 ± 0.06 mmol/kg dry wt) (Fig. 1).
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PDHa.
PDHt was similar before and after
training (Table 1). Before training, the preexercise
PDHa level (Fig.
2) was 0.87 ± 0.11 mmol · min1 · kg
wet wt
1 and increased to
1.81 ± 0.29, 3.58 ± 0.76, and 3.89 ± 0.87 mmol · min
1 · kg
wet wt
1 after cycling at
30, 65, and 75%
O2 max, respectively.
After training, PDHa was not
different from the pretraining condition at matched time points, being
0.84 ± 0.10 mmol · min
1 · kg
wet wt
1 before cycling
exercise and 1.65 ± 0.24, 2.60 ± 0.13, and 3.78 ± 0.36 mmol · min
1 · kg
wet wt
1 at 30, 65, and 75%
O2 max, respectively.
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CoA, carnitine, and acetylated forms.
Total muscle CoA content increased as a result of short-term training
(Table 4). When averaged across all four
biopsies within each condition, this amounted to a 25% increase
(P < 0.03) in the mean total CoA
content posttraining (pre- vs. posttraining: 75.4 ± 5.4 vs. 94.6 ± 11.2 mmol/kg dry wt). Acetyl-CoA increased to the same extent with
increasing exercise intensity in both conditions (Table 4). Free CoASH
behaved in a reciprocal fashion, decreasing as a function of increasing
exercise intensity (Table 4). Total muscle carnitine content was not
altered by cycling exercise or by training (Table 4), the averages of
four biopsies taken before and after training being 20.3 ± 1.6 and
20.3 ± 2.0 mmol/kg dry wt, respectively. Acetylcarnitine followed a
similar pattern as acetyl-CoA, increasing as a function of increasing exercise intensity, with the exception that acetylcarnitine
accumulation was attenuated at 65 and 75%
O2 max
posttraining (Table 4). Free carnitine decreased in a reciprocal manner
and did not differ between conditions, except at 65%
O2 max posttraining,
when it was greater.
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Metabolite Exchange Across the Leg
Leg blood flow and O2 uptake.
Leg blood flow progressively increased from preexercise (i.e., rest) to
65% O2 max
to the same extent in the pre- and posttraining conditions (Table
5). However, at 75%
O2 max, leg blood flow was 0.84 l/min greater after training.
O2 uptake across the leg was not
altered by training (Table 5).
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Blood lactate.
At rest and during cycling at 30%
O2 max,
arterial [lactate] (Table 5) did not differ within or
between conditions, but at 65 and 75%
O2 max, there was a
progressive increase in both conditions. However, after training,
arterial [lactate] values were lower at 65 and 75%
O2 max (Table 5).
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Blood glucose and muscle glucose transporters. Arterial glucose concentration ([glucose]) was similar at all power outputs in both pre- and posttraining conditions (Table 5). Leg glucose uptake (Fig. 3) did not differ between conditions. Training resulted in a 43% increase in GLUT-4 glucose transporter content but no change in GLUT-1 content (Table 1).
Blood free fatty acids and glycerol. Arterial free fatty acid (FFA) concentrations were not altered by training or as a result of the exercise protocol (Table 5). No changes were observed between conditions in the net uptake or release of FFA before and during cycling exercise (Fig. 4).
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Pyruvate production, oxidation, and conversion to lactate.
During cycling exercise at 75%
O2 max, pyruvate
production was reduced by 33% posttraining, whereas pyruvate oxidation
decreased by 24%; lactate production was reduced by 59% (Table
6).
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DISCUSSION |
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The present study examined the effects of short-term training on some
biochemical responses to 45 min of continuous exercise, consisting of
15 min each at 30, 65, and 75%
O2 max. Although there
were no significant differences in glycogen utilization and lactate
production at 30%
O2 max, lactate
accumulation in muscle and blood was lower at 65 and 75%
O2 max after training. The most marked changes associated with training were observed at the
highest load; there was a 33% decrease in pyruvate production, a 59%
decrease in pyruvate conversion to lactate, and a 24% decrease in
pyruvate oxidation (Table 6). The decrease in pyruvate production at
this load was explained by a 30% decrease in glycogen degradation and
a small, nonsignificant reduction in glucose utilization. Pulmonary and
leg O2 uptake and the activity of
mitochondrial CS were unchanged. The total activity of the
PDHc and the proportion in its
active form (PDHa) were
unchanged. An increase in the total muscle content of CoA was observed,
and [PCr] was also higher after training.
Previous studies of short- and long-term training have suggested that
the decrease in muscle and blood lactate concentrations is the result
of both a decrease in lactate production from glycolysis and an
increase in its metabolic clearance from the circulation. Isotope
tracer studies in rats (11, 12) and humans (19, 22) have demonstrated
that reductions in blood lactate with training are associated with
increases in clearance of lactate from the plasma pool rather than
reductions in its appearance into plasma from muscle. In the present
study, after training, lower blood and muscle [lactate]
values at 75% O2 max
during steady state were associated with a lower rate of glycolysis, and efflux of lactate from muscle (appearance) was associated with a
smaller increase in pyruvate oxidation (clearance). The lower activation of glycogenolysis and glycolysis posttraining may be
related to the higher [PCr], itself an indication of higher phosphorylation potential of the high-energy phosphate pool (ATP, ADP,
AMP, and PCr), concomitant with a lower
PO2
4 concentration (8, 15, 22,
24). PO2
4 is known to act as a
substrate for phosphorylase a, having
a relatively high Michaelis-Menten constant that is decreased by
increases in AMP concentration (27). The phosphorylation potential will thus have a direct effect on the rate of glycogen degradation, as well
as a direct influence on the activity of phosphofructokinase via the
ATP/ADP ratio.
An increase in phosphorylation potential has been observed, both after short-term training (8, 15, 22, 24) and when the availability of FFA for muscle metabolism is increased by infusion of fat emulsion (13) and caffeine ingestion (28). In all these situations, increased [PCr] and decreased calculated concentrations of free ADP and AMP have been accompanied by glycogen sparing during exercise. Similar findings were reported by From et al. (14) in studies of heart muscle. Thus, when FFA availability is increased, oxidative phosphorylation is enhanced, glycogen utilization and lactate formation decrease, and there is a lower PCr degradation.
A reduction in glycogenolytic rate during exercise after training was
associated with reductions in pyruvate oxidation. As this reduction was
unaccompanied by changes in PDHt
(Table 1) or PDHa (Fig 2), we
infer that it is due to a reduction in pyruvate availability secondary
to a lower rate of glycogenolysis. The decrease in pyruvate oxidation
may be compensated for by an increase in FFA oxidation. This argument
is supported by calculations of the amount of FFA (palmitate) that
would be needed to account for this difference in oxidative ATP
production, showing that only 4.5 mmol of palmitate would be
required for each leg during 15 min of exercise at 75%
O2 max posttraining.
Small increases in fat oxidation may not have a significant effect on
measured RER (seen at 30 and 65%
O2 max but
not at 75%
O2 max),
because this measurement is too insensitive to reveal such small
increases in fat oxidation. Increases in fat oxidation during exercise
posttraining have been observed in many studies (17, 20), including
those employing short periods of training (8, 9, 21, 23, 24). The 25%
increase in total CoA observed in the present study may have an impact
on fatty acid utilization, because both the acylation and the transport
of fatty acids are dependent on CoA availability.
The results of isotope studies carried out pre- and posttraining (19,
22) were interpreted to indicate an increase in pyruvate oxidation
posttraining. Because PDHa
catalyzes the flux-generating step of pyruvate oxidation by the TCA
cycle (2), and in view of the isotope studies, we hypothesized that
lower net lactate production after training resulted from an increase
in PDHa. Although we did not find
changes in PDHa to account for
reductions in lactate accumulation posttraining, our measurements were
made after 15 min of cycling at a given power; thus it is still
possible that PDHa or the
allosteric regulators of PDHc
transformation were altered during the transition to a steady state,
from rest to exercise or from one load to a higher one. Recently,
Timmons and co-workers (30, 31) employed the isolated dog gracilis
model to study the effects of increases in the rate of PDH activation by dichloroacetate at the onset of muscle contraction. They found that
PDH activation, with concomitant increases in acetylcarnitine concentration before muscle stimulation, resulted in less lactate production during ischemic contractions. However, in the present study
after training, acetylcarnitine accumulation was less just before the
onset of the highest exercise intensity (75%
O2 max), in which the
reduction in lactate production was greatest. Thus the association
between increases in fat utilization and reductions in lactate
production after short-term training observed in the present study may
be mediated through different mechanisms from those in the animal model
used by Timmons et al. (31).
Isotopic studies of the effects of training suggested that training was associated with an increase in lactate clearance from the plasma pool, with no change in the appearance rate of lactate into the pool. This finding is in contrast to the results of the present study, which utilized measurements of intramuscular concentration of metabolites with arteriovenous lactate concentrations and flow. These measurements suggested that there was both a reduction in muscle lactate production and a lower efflux of lactate from muscle. A narrowing of the concentration gradient for lactate between arterial blood and muscle is presumably accounted for by an increase in the content of the sarcolemmal monocarboxylate transporter (MCT1) found in the present subjects and reported elsewhere (5). This increase in MCT1 would increase bidirectional exchange of lactate between the plasma and intracellular compartments and also account for the increases in lactate clearance from the plasma pool that were observed in isotope studies.
In the present study, leg blood flow during exercise was increased by training (Table 5). This finding is consistent with increased capillary density associated with type IIa fibers recently reported (16), which provides a morphological basis for the physiological change observed in our subjects (Table 5). Thus it is possible that the uptake of exogenous blood-borne substrates and/or endogenous fat utilization may be enhanced during the non-steady-state period at the onset of cycling exercise after training.
Previous studies using short-term training to examine the early adaptations of muscle glucose metabolism during submaximal aerobic cycling have reported greater GLUT-4 content (25) and maximal hexokinase activity (9, 24). Although such changes should serve to increase plasma glucose uptake and utilization, tracer studies (9, 21, 23) have paradoxically reported a reduction in whole body plasma glucose turnover during cycling exercise after training. Lower rates of glucose appearance from hepatic gluconeogenesis and disappearance from the plasma pool were thought to result from lower hormonally induced hepatic glucose production and lower glucose utilization by trained muscle (9, 21, 23), respectively. However, the use of labeled glucose tracers to determine glucose turnover may underestimate glucose utilization, because labeled glucose can be converted to metabolites that are not oxidized (18). Furthermore, short-term training may increase this conversion, creating the impression of lower glucose utilization posttraining. In the present study, there were no differences in the preexercise rates of glucose uptake (Fig. 3), arterial glucose concentrations (Table 5), or muscle glucose content (Table 3), but muscle glycogen levels (Table 3) were considerably greater posttraining. Whereas there were no changes in the content of the GLUT-1 glucose transporter (Table 1), GLUT-4 content (Table 1) increased by 43% after training. Thus greater preexercise glycogen levels posttraining can be attributed to enhanced glycogen synthesis mediated by greater insulin-stimulated glucose uptake by GLUT-4 and greater maximal activities of hexokinase and glycogen synthase during the recovery periods between each training session. This suggestion is supported by a previous report demonstrating similar changes after 7 consecutive days of chronic low-frequency electrical stimulation (6).
Summary and Conclusions
This study examined mechanisms of altered muscle lactate production during cycling exercise in humans after 7-8 days of training on a cycle ergometer at 60% ![]() |
ACKNOWLEDGEMENTS |
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We thank T. Bragg, R. Davidson, C. French, Dr. M. Ganagaragah, and G. Obminski for excellent technical assistance with these experiments.
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FOOTNOTES |
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This study was supported by the Canadian Medical Research Council (MRC), the Heart and Stroke Foundation of Ontario, the Natural Sciences and Engineering Research Council of Canada, and the Canadian Diabetes Association. C. T. Putman and M. G. Hollidge-Horvat were supported by Studentships from the MRC. G. J. F. Heigenhauser is a Career Investigator of the Heart and Stroke Foundation of Ontario.
Present address of C. T. Putman: Faculty of Biology, University of Konstanz, Box M641, D-78457 Konstanz, Germany.
Address for reprint requests: G. J. F. Heigenhauser, Dept. of Medicine, McMaster Univ. Medical Centre, 1200 Main St. West, Hamilton, ON, Canada L8N 3Z5.
Received 15 April 1997; accepted in final form 8 April 1998.
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