1 Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1; and 2 Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom
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ABSTRACT |
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To
investigate the effects of a single session of prolonged cycle exercise
[60% peak O2 uptake
(O2 peak) for 5-6 h] on metabolic
adaptations in working vastus lateralis muscle, nine untrained males
(peak O2 uptake = 47.2 ± 1.1 ml · kg
1 · min
1, means ± SE) were examined before (Pre) and at 2 (Post-2), 4 (Post-4), and 6 (Post-6) days after the training session. On the basis of 15 min of
cycle exercise at 59%
O2 peak, it was
found that training reduced (P < 0.05) exercise muscle
lactate (mM) at Post-2 (6.65 ± 0.69), Post-4 (7.74 ± 0.63),
and Post-6 (7.78 ± 1.2) compared with Pre (10.9 ± 1.3). No
effect of training was observed on exercise ATP, phosphocreatine, and
glycogen levels. After the single session of training, plasma volumes
were elevated (P < 0.05) at Post-2 (6.7 ± 1.7%), Post-4 (5.86 ± 1.9), and Post-6 (5.13 ± 2.5). The
single exercise session also resulted in elevations (P < 0.05) in the monocarboxylate transporters MCT1 and MCT4 throughout the 6 days after exercise. Although epinephrine and norepinephrine both
increased with exercise, only norepinephrine was reduced (P < 0.05) with training and only at Post-4. These
results indicate that regulation of cellular lactate levels occurs
rapidly and independently of other metabolic adaptations. It is
proposed that increases in MCT and plasma volume are at least partly
involved in the lower muscle lactate content observed after the
training session by increasing lactate membrane transport and removal, respectively.
muscle metabolism; hypervolemia; lactate transporters
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INTRODUCTION |
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THERE APPEARS TO BE
little disagreement that extensive metabolic adaptations can be
observed in working skeletal muscle in humans soon after the onset of
prolonged submaximal cycle training (15, 24) and
that training increases oxidative potential, as evidenced by increases
in the maximal activities of a number of representative enzymes
(24). It is also known that training attenuates the
reductions in high-energy phosphate concentration during submaximal
exercise in the absence of changes in steady-state oxygen consumption
(O2) (16, 33).
Collectively, these adaptations result in an increase in respiratory
control sensitivity, allowing a given level of oxidative
phosphorylation to be achieved at lower levels of the putative
effectors such as free ADP (ADPf) and inorganic phosphate
(Pi) (24). The improved energy potential and
lower metabolic by-product accumulation (i.e., Pi,
ADPf, AMPf) also appear to be coupled to other
metabolic adaptations. Reductions in glycogenolysis and glycolysis are
postulated to occur in conjunction with allosteric-mediated depressions
in the activity of phosphorylase and phosphofructokinase (PFK), two key
enzymes that are regulated, at least in part, by the levels of the
adenine nucleotides and Pi (6, 24). Trained
muscles characteristically demonstrate a reduced rate of glycogen
depletion and a lower lactate accumulation with submaximal exercise
(15, 24).
A popular theory that has long dominated current thinking is that the increases in oxidative potential are mechanistically linked to the increase in respiratory control sensitivity (24). Our group (15) and more recently another group (36), using a variety of short-term training models, have reported that the metabolic changes that are observed during exercise can occur in the absence of increases in maximal activities of selected citric acid cycle enzymes. However, Spina et al. (42) and Chesley et al. (6), using a training model similar to one that we have previously employed, namely 2 h of cycling exercise per day for 7 consecutive days (18), reported that the metabolic adaptations do not occur in the absence of increases in oxidative potential. Not surprisingly, Spina et al. (42) have concluded that compositional changes within the muscle cell, namely at the level of the mitochondria, are fundamental for adaptations in exercise metabolism. However, it is becoming increasingly clear that a number of early adaptations, both within and outside the muscle cell, may impact on the metabolic events that occur. Collectively, these findings suggest that at least some of the alterations that occur in the metabolic behavior of the working muscle with training need not be coupled to changes in mitochondrial potential and improvement in energy status. One such example is the regulation of intracellular lactate turnover.
In humans, the intracellular lactate content is a product of both production, mediated by increases in glycolysis, and removal, mediated by transport, either out of the cell or into the mitrochondria. Although several studies have reported that increases in lactate clearance represent an important mechanism for management of lactate levels during exercise after training (8, 9) and that this adaptation may be realized soon after the onset of regular exercise (31), the findings are regarded as controversial, given the assumptions inherent in the procedure used to measure lactate turnover, namely stable isotopes (28). However, several early responses to training could conceivably alter lactate clearance.
One central property that could alter lactate removal kinetics and that is extremely sensitive to activity level is the plasma volume (PV). Exercise is a potent stimulus for eliciting increases in PV (7, 20). Increases in PV occur soon after the onset of training (20), with significant effects realized with just 1 day of exercise (10, 40). Increases in PV are known to have dramatic effects on cardiovascular function during exercise, modifying both cardiac performance (11, 13, 19, 22, 27, 46) and peripheral blood flow (5). Increases in PV also attenuate the time-dependent increases in catecholamines, both epinephrine (Epi) and norepinephrine (NE) during exercise (14). Conceivably, these adaptations occurring in response to elevations in PV could effect alterations in muscle metabolic behavior during exercise. To examine this possibility, we have artificially expanded PV with Macrodex, a high-molecular-weight compound dissolved in saline, and examined the effects of the hypervolemia on metabolism in the working muscle (17). Compared with the control condition, hypervolemia resulted in a lower muscle lactate content (17). In additional work, we have also been able to demonstrate that PV expansion increases blood flow to the working muscle (37).
Lactate removal may also be regulated by the cellular content of the monocarboxylate transporters (MCT) (26). A family of these transporters has been identified, two of which have been reported to exist significantly in skeletal muscle (26). In human muscle, increases in both transporters MCT1 and MCT4 have been reported to occur with training (34) and, in the case of MCT1, early in training (1). Given the significance of these transporters in the transmembrane exchange of lactate, it is conceivable that increased lactate clearance could be coupled to elevations in MCT1 and/or MCT4 in muscle.
In this study, we have used a single exercise session extending for 5-6 h in an attempt to elicit increases in PV and muscle and MCT expression and examined the exercise metabolic alterations during an extended period of recovery after the training session. We have hypothesized that reductions in muscle lactate concentration would occur in association with an expansion of PV and increases in MCT1 and MCT4 in exercised muscle. We have reasoned that a single extended training session would provide the stimulus at least for increases in PV (10, 40) without altering muscle oxidative potential and the energy metabolic status of the working muscle.
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METHODS |
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Subjects.
Nine healthy, untrained males were recruited to participate in the
study. Subject characteristics included a mean age of 21.4 ± 1.2 yr (mean ± SE), height of 175 ± 2.0 cm, and weight of
70.6 ± 1.6 kg. Maximal responses obtained during a progressive
cycle exercise to fatigue included a peak oxygen consumption
(O2 peak) of 3.33 ± 0.11 l/min,
heart rate peak of 193 ± 3.7 beats/min, and
EBTPS of 141 ± 9.0 l/min. Because
the objective of the study was to determine the response to a single
prolonged training session, particular care was taken to ensure that
the subjects did not engage in any vigorous large muscle group activity
on a regular basis and that they had been relatively inactive for
2
wk before entry into the study. The study was approved by the Office of Human Research and Animal Care, as is required, before obtaining written consent from the participants.
Experimental design.
To examine the adaptations to a single session of prolonged submaximal
exercise, subjects performed a standardized cycle test for 15 min at
59% O2 peak before the training
session (Pre) and at 2 (Post-2), 4 (Post-4), and 6 (Post-6) days after the training session. The single session of cycle training was performed for 5-6 h at ~60%
O2 peak in normal ambient conditions.
Due to fatigue, rest periods were provided after 60 min of exercise.
Rest periods were not included in the training time. Water was provided
ad libitum throughout the session. Individual
O2 peak values, used to establish power
outputs, were determined
1 wk before the submaximal test. The 15-min
protocol was selected because we have previously shown that most of the muscle metabolic adaptations (less-pronounced decreases in high-energy phosphates, lower lactate) occur within this period (16).
Measurements of respiratory gas exchange, cardiovascular function, and
blood and muscle metabolites were performed both before and during exercise.
Test protocols.
To measure O2 peak and related
parameters, a progressive-step protocol with an electronic cycle
(Quinton 870) was performed until fatigue. This test involved 4 min of
unloaded cycling, followed by 16-W increments in work loads every 2 min. Respiratory gas measurements were performed using an open-circuit system. Peak values were those obtained over a 30-s period. Both the
test protocol and the gas collection system have been previously described (16, 17). Arterialized blood samples
were obtained from a 20-gauge catheter inserted into a heated dorsal
hand vein.
Analytical procedures. Measurements of muscle high-energy phosphate compounds, glycogen, and metabolites were performed using fluorometric techniques on freeze-dried tissue according to the procedures of Harris et al. (21) and as previously published by our group (16, 32). To adjust for contamination by blood, fat, and connective tissue, all metabolites for each sample, including lactate, were corrected to the average total creatine (TCr) content for each individual. Neither exercise nor the single training session altered TCr (P > 0.05). During a given analytical session, all samples for a given metabolite and for a given individual were analyzed with each individual sample measured in duplicate.
To examine training effects on the potential of the energy metabolic pathways and segments, we measured the maximal activities of a number of enzymes, which are representative of different metabolic pathways and segments, in tissue obtained from the preexercise biopsy. Both citrate synthase (CS) and malate dehydrogenase (MDH) were selected to represent oxidative potential, 3-hydroxyacyl-CoA dehydrogenase (3-HAD) for fat oxidation, and hexokinase for glucose phosphorylation. These measurements were performed according to the procedures of Henriksson et al. (23) on samples hand homogenized in a phosphate buffer (pH 7.4) containing 0.02% BSA, 4 mM mercaptoethanol, and 0.5 mM EDTA. Homogenates were diluted in 20 mM imidazole buffer with 0.2% BSA. Enzymatic activities were measured on aliquots extracted from each homogenate that had been frozen and stored atStatistical procedures. Both one- and two-way analysis of variance procedures (ANOVA) for repeated measures were used to analyze the results. One-way ANOVA procedures were used when only a single measurement was obtained before the training session and during recovery, as in the case of the enzyme determinations. Where the time-dependent effects of exercise were included, as in the case of the metabolites, a two-way ANOVA was selected. Where significance for a particular variable was found, post hoc analysis was performed by the Newman-Keuls technique. Significance was set at the P < 0.05 level for all comparisons.
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RESULTS |
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Preexercise or resting PV was altered with the training session. An elevation in PV of 6.7 ± 1.7% was observed ~48 h after the prolonged exercise session. This effect persisted at both 4 (5.86 ± 1.9%) and 6 days (5.13 ± 2.5%) of recovery.
Ventilatory gas exchange measured during the submaximal exercise test
before the training session and during the recovery period is presented
in Table 1.
O2, CO2 production, and,
consequently, respiratory exchange ratio, were not found to be altered,
regardless of the days of recovery.
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The blood concentration of Epi was altered by exercise but not by the
single training session (Fig. 1).
However, both exercise and training altered NE levels. For both NE and
Epi, the 15 min of exercise resulted in increased concentrations. For
NE, the concentrations were lower at 15 min of exercise at Post-4
compared with pretraining and Post-2 and Post-6.
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With the exception of ATP, all of the muscle metabolites measured were
altered with exercise (Table 2; Fig.
2). As expected, phosphocreatine (PCr)
and glycogen were reduced with exercise, whereas Pi, Cr,
and lactate were increased. The single training session was found to
alter only the Pi and lactate response. For Pi,
a main effect was found such that the concentrations recorded at Post-4
and Post-6 of the recovery period were lower than what was observed
before and at Post-2 of the training. For lactates, the training effect
was specific to the exercise (Fig. 2). At Post-2, Post-4, and Post-6,
lactates were lower than what was observed before training.
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The training session was without effect on the maximal activities of
the citric acid cycle enzymes (CS, MDH), the glucose phosphorylation
enzyme (hexokinase), and the enzyme of -oxidation, (3-HAD) that were
selected for measurement (Table 3).
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Similar increases in MCT1 and MCT4 were observed after the prolonged
exercise session (Table 4). On average,
these two isoforms progressively increased through the initial 4 days
of recovery. At 6 days postexercise, the MCTs had regressed to
levels comparable to those on the 2nd day of recovery. No differences
in relative changes were observed between MCT1 and MCT4 at any time
point.
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DISCUSSION |
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The results of this study indicate that a single, extended, submaximal training session results in reductions in muscle lactate content during submaximal exercise that persist through the six days of recovery. The reductions in muscle lactate during the short-term exercise occurred independently of changes in muscle high-energy phosphate content, as determined by ATP and PCr concentrations, or in net glycogen depletion. As hypothesized, the reduction in muscle lactate was associated with an expansion of PV during all periods of recovery. The exercise session also increased both MCT1 and MCT4 expression in muscle during the 6 days of recovery. No changes in mitochondrial oxidative potential were observed, as indicated by the two representative enzymes, MDH and CS. Although it is tempting to conclude that the lower muscle lactate content is due to increased removal, particularly in view of the correlative evidence that is presented, such a conclusion is premature without appropriate lactate turnover measures.
The isolated effect of the training session on muscle lactate content is unique, because numerous studies, employing training, have reported a tight coupling between the adaptations occurring in the muscle phosphate energy system, glycogen depletion, and lactate levels during submaximal exercise (4, 6, 16, 18, 24). It has been proposed that the reduced disturbance in energy homeostasis observed in the working limbs after training results in a lower accumulation of some of the putative modulators of phosphorylase and PFK such as ADPf and Pi and, consequently, a reduced glycogenolytic and glycolytic flux rate (24, 42). As a consequence, glycogen depletion and lactate accumulation are downregulated during exercise. Although it has been relatively easy to demonstrate the effect of training on high-energy phosphate content and associated metabolites, it has been considerably more problematic to demonstrate that the attenuations in glycogen depletion and lactate accumulation are mediated by reductions in glycogenolysis and glycolysis, respectively.
Because muscle lactate concentration represents a balance between production and removal, it is conceivable that changes in either process could explain the lower lactate concentration observed in this study and characteristically observed in working muscle after training (12). Unfortunately, measurement limitations have so far precluded agreement as to which process dominates after training. Measurements of blood flow and arterial-venous concentration differences across the working limb(s) have confirmed training-induced reductions in lactate release (28, 35), whereas increased clearance rates have been reported with the use of the stable isotope L-[1-13C]lactate (8, 9, 31). Although these findings are interesting, they do not indicate the importance of removal mechanisms within the muscle, either in the contracting cell or in neighboring inactive cells, such as the conversion of lactate to pyruvate, in either the cytosol or mitochondria, and oxidation of the pyruvate by the mitochondria (3, 12, 28).
We have postulated that increases in blood flow to the working muscle mediated by increases in PV could effectively enhance clearance rates (17). Moderate increases in PV, induced either artificially or by training, have been shown to cause an increase in muscle blood flow (5, 37). The increased muscle blood flow hypothesis is supported by previous work from our group, where we have shown that induced expansion of PV results in findings identical to those of this study, namely a lower exercise lactate concentration in muscle (17).
It is also possible that the single exercise session elicited adaptations that would encourage increased muscle lactate disposal that would not be realized with induced hypervolemia. As an example, it has been found that training elicits increases in both MCT1 and MCT4 in human skeletal muscle (34). Moreover, the increases, at least in the case of MCT1, may occur early in training (1). The increases in MCT expression appear to facilitate lactate efflux from the muscle during exercise (26, 34). More recently, Brooks et al. (3) have found that mitochondria contain lactate dehydrogenase, which enables lactate oxidation to occur in mitochondria. Lactate oxidation either in the contracting muscle cells or in neighboring cells, could be an important source of lactate disposal.
The fact that the single exercise session did not alter the decrease in glycogen during the exercise would suggest that glycogenolysis and, consequently, glycolytic flux have not been altered. Teleologically, depressions in muscle lactate production could occur without alterations in net glycogen depletion via increased glucose utilization acting as a substrate for glycolysis or by gluconeogenesis (2). Such appears not to be the case, however, since with the induced hypervolemia, no effect on either glucose appearance or glucose disappearance rates were found with the use of the stable isotope [6,6-2H2]glucose (29). Five days of prolonged exercise training also failed to affect glucose production and utilization (33).
Further evidence that glycogenolytic flux was not altered by the single-session training comes from posttranslational cytosolic signals involved in PHOSPH regulation. Although not calculated, ADPf and AMPf would not be expected to be different during exercise, pre- and posttraining, since the levels of ATP and PCr were unchanged. Moreover, blood Epi levels, which have been shown to increase muscle lactate during exercise by increases in phosphorylase activity (25), were unaltered during recovery after the training protocol. However, decreases in muscle Pi, which are commonly observed with training and which have also been suggested to be important in the regulation of phosphorylase (6), could be involved, since we have found decreases in Pi during recovery in this study.
The single-exercise training session failed to elicit the classic adaptations observed with daily training, namely a more protected high-energy phosphate content during exercise (15, 24). Previously, we have shown that 3-5 consecutive days of training are needed to induce such metabolic adaptations (15). The mechanisms underlying these metabolic changes remain uncertain. The most dominant hypothesis, promoted by Holloszy and Coyle (24), is that increases in oxidative potential are required to realize improved cellular energy homeostasis during exercise. According to this hypothesis, increases in oxidative potential increase respiratory control sensitivity, allowing a given level of oxidation phosphorylation to occur in skeletal muscle at a lower concentration of the putative modulators ADPf and Pi (24, 45). Such a theory, however, cannot explain the resetting of the phosphate energy system to high levels during moderate steady-state exercise. We have previously reported that the resetting occurs during the non-steady-state phase (16) and appears to be mediated by increases in oxidative phosphorylation (30), secondary to a more rapid adjustment in blood flow (41). Conceivably, the increase in blood flow could be mediated by increases in PV (5, 37), which is commonly realized with our training model. Increases in muscle blood flow may be necessary to maintain arterial O2 delivery (38), given the dilutional reduction in arterial O2 content that occurs with PV expansion.
However, factors other than increases in blood flow must be operative, because with the induced hypervolemia, high-energy phosphate content was not altered during exercise (17). The single-training session used in this study was also without effect in altering any of the mitochondrial enzymes examined, namely CS, MDH, and 3-HAD. In earlier studies, it was shown that increases in oxidative potential are not necessary for increases in the O2 kinetics and for the muscle metabolic adaptations realized with the short-term training model (30, 32).
In summary, we have demonstrated that a single extended training session can promote an uncoupling between the phosphate energy system and lactate content in muscle working at light to moderate intensities. It is proposed that the lower lactate accumulation is a result not of decreased production but of increased removal. The increased removal is dependent on increases in blood flow, secondary to elevated PV, and increases in MCT levels. Experiments are presently in progress, examining the viability of this hypothesis.
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ACKNOWLEDGEMENTS |
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This research was supported by a grant from the Canadian Natural Sciences and Engineering Research Council.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. J. Green, Dept. of Kinesiology, Univ. of Waterloo, Waterloo, Ontario, Canada N2L 3G1 (E-mail: green{at}healthy.uwaterloo.ca).
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 7 March 2001; accepted in final form 21 August 2001.
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