Copenhagen Muscle Research Centre, Rigshospitalet section 7652, DK-2100 Copenhagen Ø, Denmark
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ABSTRACT |
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We hypothesized that
reliance on lactate as a means of energy distribution is higher
after a prolonged period of acclimatization (9 wk) than it is at sea
level due to a higher lactate Ra and disposal from active
skeletal muscle. To evaluate this hypothesis, six Danish lowlanders
(25 ± 2 yr) were studied at rest and during 20 min of bicycle
exercise at 146 W at sea level (SL) and after 9 wk of acclimatization
to 5,260 m (Alt). Whole body glucose Ra was similar at SL
and Alt at rest and during exercise. Lactate Ra was also
similar for the two conditions at rest; however, during exercise,
lactate Ra was substantially lower at SL (65 µmol · min1 · kg
body wt
1) than it was at Alt (150 µmol · min
1 · kg
body wt
1) at the same exercise intensity. During
exercise, net lactate release was ~6-fold at Alt compared with SL,
and related to this, tracer-calculated leg lactate uptake and release
were both 3- or 4-fold higher at Alt compared with SL. The contribution
of the two legs to glucose disposal was similar at SL and Alt; however, the contribution of the two legs to lactate Ra was
significantly lower at rest and during exercise at SL (27 and 81%)
than it was at Alt (45 and 123%). In conclusion, at rest and during
exercise at the same absolute workload, CHO and blood glucose
utilization were similar at SL and at Alt. Leg net lactate release was
severalfold higher, and the contribution of leg lactate release to
whole body lactate Ra was higher at Alt compared with SL.
During exercise, the relative contribution of lactate oxidation to
whole body CHO oxidation was substantially higher at Alt compared with
SL as a result of increased uptake and subsequent oxidation of lactate by the active skeletal muscles.
glucose; isotopes; [1-13C]lactate
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INTRODUCTION |
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CARBOHYDRATE AND LACTATE METABOLISM is altered by hypoxia. Carbohydrate oxidation under hypoxic conditions has been suggested to be the preferable metabolic pathway during exercise, because it provides the highest ATP yield per mole of oxygen (3, 15, 16). Thus any increase in the percentage of energy derived from carbohydrate sources will result in a more economical use of oxygen. Indeed, results from studies in high-altitude natives (17) and lowlanders exposed to high altitude (5, 27) show a shift toward increased blood glucose utilization relative to normoxic conditions. However, McClelland et al. (23) reported that rats acclimatized to severe hypoxia did not increase carbohydrate utilization compared with normoxic conditions. Moreover, women acclimatized for 10 days to 4,300 m had a tendency for a lower contribution of carbohydrate oxidation to total energy expenditure during exercise, and they had a similar blood glucose disposal compared with sea level (2). In addition, Young et al. (35) suggested that, after chronic hypoxia exposure, increased mobilization and use of free fatty acids during exercise resulted in sparing of muscle glycogen. Thus there is no consensus in the literature with regard to metabolic fuel selection under hypoxic conditions. Some of the differences observed in fuel utilization after altitude exposure have been attributed to cachexia and energy deficiency (5, 8), gender (2), or limited carbohydrate stores (23).
With regard to lactate, it is well known that the blood lactate concentration at a given submaximal workload is larger under acute exposure to hypoxia compared with sea level. After several weeks of acclimatization to hypoxia, the blood lactate response to a given workload is blunted, i.e., the "lactate paradox" (33), although this concept has been challenged (22, 32). So far, only one study is available describing in more detail whole body and muscle carbohydrate and lactate metabolism at rest and during exercise after a relatively short period of 3 wk of acclimatization to altitude (3, 4, 5). In addition, a careful evaluation of the data reveals that the field study suffered from variability in the measurements, which potentially might explain the "disbalance" in glucose and lactate whole body vs. leg glucose and lactate utilization/production (3). Despite these limitations, it was concluded that active skeletal muscle as a source of lactate was not affected by acclimatization, and it was suggested that other tissues besides active skeletal muscle participate in producing the blood lactate concentration responses described as the lactate paradox (7). In addition, it was concluded that blood lactate was less important as a means of distributing energy between glucose/glycogen and complete oxidation when acclimated (4). However, evidence has been presented that the blunted blood lactate concentration in the course of acclimatization is transient. After 7 wk of acclimatization to high altitude (5,400 m), the blood lactate concentration was similar to what was observed in acute hypoxia (22). Furthermore, during submaximal and maximal bicycle work, net lactate release from the active legs has been reported to be lower with acute compared with chronic exposure to hypoxia (32). Therefore, we hypothesized that, after a prolonged period of acclimatization, the reliance on lactate as a means of distributing carbohydrate potential energy is higher than it is at sea level due to a higher lactate appearance and disposal from active skeletal muscle.
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METHODS |
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Subjects. Six healthy, physically active subjects (5 males, 1 female, 25 ± 2 yr) residing in the Copenhagen area participated in the study. The subjects were informed about the possible risks and discomfort involved before their voluntary consent to participate was given. The study was performed according to the Declaration of Helsinki and was approved by the Ethics Committee of the Copenhagen and Frederiksberg Communities, Denmark.
Study periods.
Each subject underwent two moderate-intensity bicycle exercise tests on
a cycle ergometer, at 5,260 m after 9 wk of acclimatization (Chacaltaya, Bolivia) and at sea level (~0 m) in Copenhagen. The sea-level trial was performed 10 mo after return from Bolivia. The
reason for performing the trial at sea level a long time after the
sojourn was due to the following, in part ethical reasons. A slightly
larger number of subjects left for Bolivia than those finally studied.
Ahead of departure, it was difficult to foresee who would be able to
handle the exposure and primitive life at 5,260 m. This experiment, as
well as another study investigating the lactate paradox during
incremental exercise until exhaustion (32), was quite
invasive and should not be performed unless the results are going to be
used. Thus the studies at sea level had to be performed after a
prolonged period of deacclimatization and when the subjects had
returned to their normal habits, i.e., activity level. Therefore,
sea-level trials were performed in the same month as, but a year later
than, when they left for Bolivia. Physical activity level, maximal
oxygen uptake (O2 max), body weight,
and forearm venous blood lactate concentration at submaximal and
maximal work were similar compared with sea-level values before the
altitude studies (32).
Acclimatization. Upon arrival in Bolivia, the subjects spent ~5 days in La Paz (~3,700 m). Subsequently, they went up to the laboratory at Chacaltaya (5,260 m) for 1 day and returned to La Paz for the night, followed by ~2 days at a base camp (4,700 m) before climbing Mt. Potosi (6,088 m). The subjects then moved to the laboratory at Chacaltaya and, except for a 4-day climb of Mt. Illimani (6,462 m), stayed there until weeks 9-10, when they participated in the studies. All subjects were given oral iron supplementation during the first 5-6 wk following their arrival in La Paz.
Protocol for continuous cycle exercise at a constant moderate
workload.
Each subject underwent 20 min of cycle exercise (Monark 818, Varberg,
Sweden) at 146 ± 14 W at sea level breathing ambient air (Sea
Level) and 40 min of cycle exercise at the same workload at 5,260 m
after 9 wk of acclimatization (Altitude), the first 20 min breathing
ambient air, immediately followed by 20 min of breathing 47%
O2 in N2 (Altitude, normoxia). The
workload at sea level was 46 ± 2% of the sea level
O2 max. At altitude, the workload while
breathing ambient air was 82 ± 2% of the altitude
O2 max and an estimated 62 ± 4%
of the altitude
O2 max while breathing
47% O2 in N2.
O2 max was determined during an
incremental bicycle test, as described elsewhere (32). A relatively high workload at altitude and, as a consequence, a relatively short exercise time were chosen in the present study to get
relatively large arterial-femoral venous differences for concentration
and tracer measurements of lactate and glucose, thereby reducing
variability in the leg exchange data. This was especially important for
the Sea Level trial, carried out at the same absolute workload, because
leg net lactate release and leg lactate uptake and release can be
expected to be lower the lower the exercise intensity. On the day of
the experiment, the subjects reported to the laboratory at 8 AM. The
subjects changed clothes and remained supine for the next 3 h.
After 10 min in the supine position, catheters were placed in a
femoral artery and vein under local anesthesia (lidocaine, 20 mg/ml)
for blood sampling and blood flow measurements. The tip of the each
catheter was advanced 6 cm proximal to the inguinal ligament. The
arterial catheter was 20 G and 20 cm (Ohmeda, Swindon, UK), and
the venous catheter was a radiopack TFE catheter with side holes (Cook,
Bjaevershou, Denmark). A thermistor was inserted through the venous
catheter for blood flow measurements by the constant infusion
thermodilution technique (1). Thirty minutes after
placement of the catheters, breath and blood samples were obtained for
assessment of background enrichment of breath and blood CO2
and blood lactate and glucose. Immediately after the background samples
had been obtained, a primed constant infusion of
[1-13C]lactate (1.4 µmol · min
1 · kg
body wt
1, prime 22 µmol/kg body wt) and
[6,6-2H2]glucose (0.25 µmol · min
1 · kg
body wt
1, prime 17 µmol/kg body wt) was started, along
with a prime of bicarbonate (1.5 µmol/kg body wt). For each
individual, the actual rate of infusion for each tracer was determined
from the tracer concentration and infusion rate of the pump. All
isotopes were purchased from Cambridge Isotope Laboratories (Andover,
MA) and were dissolved in 0.9% sterile saline and passed through a
0.2-µm filter into a 250-ml sterile saline bag immediately before
infusion. At minutes 90, 105, and 120 after the
start of the constant infusion, blood samples were taken for analysis
of the concentration and enrichment of lactate and glucose, and the
blood flow was measured. In addition, the blood samples were analyzed
for hematocrit, hemoglobin, and O2 saturation (OSM3
hemoxymeter, Radiometer, Copenhagen, Denmark), and blood pH,
O2, and CO2 tension (ABL5, Radiometer). While
the blood samples were being taken, indirect calorimetry measurements were performed (Medgraphics, St. Paul, MN) and, in a separate 5-l bag
at rest or 20-l bag during exercise (Hans Rudolph, Kansas City, KS),
expired air was collected, from which a 20-ml vacutainer was filled via
a needle for measuring CO2 enrichment. At the start of
exercise, the infusion rate of [1-13C]lactate was
increased threefold (Sea Level) or fourfold (chronic hypoxia and acute
normoxia), whereas that for [6,6-2H2]glucose
was increased twofold for each of the three conditions. Blood and
breath samples were taken and blood flow measured every 5 min from the
start of exercise.
Analytical procedures.
Part of the blood sample was collected in ice-cold tubes that
contained 10 µl of 0.33 M EDTA per milliliter of blood. The blood
sample was collected in an ice-cold tube that contained 28 µl of 70%
perchloric acid (HClO4) per milliliter of blood. Blood
samples were vortex-mixed and centrifuged at 4°C for 10 min. The
HClO4 extract was stored at 50°C. Before analysis, the HClO4 extracts were neutralized with 22 µl of 2 M
potassium bicarbonate (KHCO3) per 100 µl of extract and
analyzed for the concentration and enrichment of lactate and glucose.
Lactate and glucose enrichments were measured by gas
chromatography-mass spectrometry (GC-MS, Finnigan Automass II and III,
Paris, France). In preparation of the GC-MS analysis, samples were
processed to make a trimethylsilyl derivative of lactate and a
butylboronic acid acetate derivative of glucose. For the preparation of
the trimethylsilyl derivative of lactate, 1 ml of ethanol was added to
200 µl of blood extracts and centrifuged for 10 min, and the
supernatant was transferred to a new screw-capped tube and evaporated
to dryness under a stream of nitrogen. For lactate enrichment, 50 µl
of pyridine and 50 µl of
N,O-bis(trimethylsilyl)trifluoroacetamide with 1%
trimethylchlorosilan (Pierce, Rockford, IL) were added, and the
solution was incubated for 30 min at room temperature. The lactate
enrichment was determined by split injection (ratio 1:25) of 1 µl
into the GC-MS (GC column, CP-SIL 8CB, Chrompack, Middelburg, The
Netherlands). The isotopic enrichment was determined using electron
impact ionization, with ions at mass-to-charge ratio
(m/z) 219 and 220, representing the molecular
ions of unlabeled and labeled derivatives, respectively.
Calculations. The measured pH, PO2, and PCO2 were corrected for temperature by using the blood temperature as measured in the femoral vein. Blood CO2 content was calculated according to Douglas et al. (11a).
Systemic and leg carbohydrate oxidation rates were calculated using stoichiometric equations (12, 26). Carbohydrate oxidation in micromoles per minute was determined by converting the rate of carbohydrate oxidation to its molecular equivalent by dividing it by the glucose molecular weight of 180 g/mol
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Whole body tracer measurements.
The whole body rate of appearance (Ra) at rest of lactate
and glucose was calculated using the steady-state equation
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Statistical analysis. All data are expressed as means ± SE of six subjects. The nonparametric Wilcoxon signed rank test was applied to determine differences between data obtained at each time point. Statistical significance was set at P < 0.05.
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RESULTS |
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Body mass, hemoglobin, and O2.
Body weight of the subjects at sea level was 74 ± 3 kg before
acclimatization and 76 ± 4 kg 10 mo after acclimatization when the Sea Level trials were carried out. Despite adequate and nutritional food supply, the subjects had undereaten, as they all lost weight (7.3 ± 1.0 kg) during their 9-wk stay at 5,260 m. Magnetic
resonance imaging revealed that the leg lean area was reduced by an
average of ~9% (36).
O2 max was 4.3 l/min at sea level and 2.8 l/min at altitude. The subject's maximal performance was
maintained at Altitude despite the loss in body weight. In fact,
performance was even increased when expressed per kilogram of body
weight, as indicated by the
O2 max with
acute exposure to hypoxia equivalent to 5,260 m (35 ml · min
1 · kg
body wt
1) and after 9 wk at 5,260 m (40 ml · min
1 · kg
body wt
1) (32). The 20 min of continuous
cycle work at 146 W was 46 ± 2% of sea level
O2 max. After 9 wk of acclimatization, the workload was 82 ± 2% of altitude
O2 max, and altitude breathing normoxia
was an estimated 62 ± 4% of the altitude breathing normoxia
O2 max. Hemoglobin concentration
increased from 14.3 ± 0.5 g/dl at sea level to 18.7 ± 0.5 g/dl at altitude with a corresponding increase in hematocrit.
Whole body and leg glucose metabolism.
The arterial glucose concentration at rest was significantly higher at
sea level than at altitude (Fig. 1).
After 10 min of exercise, however, this changed, and arterial
glucose concentration at sea level was lower than at altitude. Despite
the difference in arterial glucose concentration, the Ra
was similar, as was the net glucose uptake by the active leg.
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Whole body lactate metabolism.
At rest, arterial lactate concentration and lactate Ra were
similar at sea level and altitude (Fig.
2). At the onset of exercise at a
constant workload of 146 W, the arterial lactate concentration increased nearly twofold at sea level, whereas at altitude the lactate
concentration increased more than sixfold. The arterial lactate
concentration decreased with exercise duration, although quantitatively
more so at altitude. With normoxia, the arterial lactate concentration
immediately decreased substantially, and after 20 min of exercise under
this condition, lactate concentration was lower than after 20 min of
exercise at sea level. The same pattern of changes was observed for the
systemic lactate Ra; however, the absolute changes in
Ra from rest to exercise were far more pronounced, with 4- and 11-fold increases at sea level and at altitude, respectively. The
percentage of [1-13C]lactate that disappeared from the
circulation and was recovered as 13CO2 in the
breath at rest was similar with 52-63% at sea level and altitude.
During exercise at sea level, the amount of lactate leaving the
circulation was nearly completely oxidized; however, at altitude, this
was significantly lower (80%). Nearly the same differences were
observed for the amount of lactate taken up by the active leg and
recovered as 13CO2 in the blood, suggesting
that the active skeletal muscle was responsible for a lower percentage
of lactate being oxidized at altitude. In contrast, the relative
contribution of lactate oxidation to carbohydrate oxidation was
significantly higher during exercise at altitude than it was
at sea level (Table 2).
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Leg lactate metabolism.
At rest, no significant net uptake or release of lactate from the
leg could be observed (Fig. 3). During
exercise at sea level, the net lactate release gradually decreased with
exercise duration, and, after 20 min of exercise, a small net lactate
release was observed in three subjects and a small net lactate uptake
in the other three subjects. At altitude, a more than sixfold higher net lactate release from the leg was observed compared with sea level,
with a marked decrease from 5 to 20 min of exercise. However, the
decrease in net lactate release was not directly reflected in a fall in
the arterial lactate concentration in either condition. The
tracer-calculated lactate uptake and release were 0.16-0.18 mmol/min at rest under both conditions. With exercise, the leg lactate
uptake increased ~13-fold at sea level and ~32-fold at altitude.
The lactate uptake remained nearly constant during 20 min of exercise,
whereas leg lactate release decreased at sea level. At altitude, the
leg lactate uptake also decreased with exercise duration but to a far
less extent than the decrease in lactate release, as reflected by the
changes in net lactate release from the leg. At rest, only 16 and 32%
of the [1-13C]lactate taken up was released as
13CO2. At 5 min of exercise, on the other hand,
100% of the lactate taken up by the leg was oxidized. At rest,
oxidation is likely to be underestimated by underestimating
13CO2 production as a result of a
disequilibrium between the slow turnover of muscle bicarbonate pools
and the 13CO2 produced from lactate oxidation.
During the initial period of exercise, however,
13CO2 production is overestimated as a result
of 13CO2 "stored" at rest and appearing
during the initial period of exercise due to changes in the size and
turnover rates of the muscle bicarbonate pools (31).
During the last 15 min of exercise, an apparently steady oxidation rate
of ~90% was observed. The relative contribution of leg lactate
oxidation to the leg carbohydrate oxidation is higher at altitude
compared with sea level (Table 2); however, this was significant only
during exercise, despite a lower percentage of lactate taken up being
oxidized.
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Whole body vs. leg carbohydrate, glucose, and lactate metabolism and the relative contribution of lactate to carbohydrate oxidation. The contribution of the legs to whole body carbohydrate utilization was about one-third at rest and increased to ~80% with exercise, and no difference was observed between sea level and altitude (Table 2). The contribution of glucose uptake of the legs to Rd of glucose during exercise tended to be higher at altitude than at sea level. This was caused by a nonsignificantly higher leg glucose uptake, since Rd was similar in both conditions (Fig. 1). Both at rest and during exercise, the contribution of the lactate release of the legs to Ra of lactate was higher at altitude than it was at sea level. The relative contribution of lactate oxidation to carbohydrate oxidation was ~33% at whole body level and between 7 and 32% for the leg, no differences between sea level and at altitude. However, during exercise, the contribution of lactate oxidation to carbohydrate oxidation was significantly higher at altitude compared with sea level, caused by an increased contribution of lactate to carbohydrate oxidation of the active legs.
Catecholamine concentration.
During continuous bicycle exercise at moderate intensity, the
norepinephrine and epinephrine concentrations were about sixfold higher
at altitude than they were at sea level (Fig.
4). When switched acutely from ambient
air to normoxia, catecholamine concentrations immediately dropped but
were still threefold higher than sea level values.
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DISCUSSION |
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The major findings of the present study investigating carbohydrate and lactate metabolism in lowland natives at sea level and after a prolonged period of acclimatization to high altitude (9 wk at 5,260 m) are the following. 1) At rest, arterial lactate concentration and the Ra of lactate in blood were similar at sea level and after acclimatization to hypoxia. During exercise, however, the arterial lactate concentration and the rate of lactate appearance in blood were severalfold higher after acclimatization to hypoxia. 2) The contribution of skeletal muscle to blood lactate appearance and disposal was higher after acclimatization compared with sea level both at rest and during exercise. 3) The contribution of lactate oxidation to carbohydrate oxidation was substantially higher after acclimatization compared with sea level, due mainly to an increased uptake and subsequent oxidation of lactate by skeletal muscle.
The present study showed that, after 9 wk of acclimatization to 5,260 m, the lactate concentration and whole body lactate Ra and oxidation were increased during continuous exercise at the same absolute workload compared with sea level. These findings are similar to those after 3 wk at 4,300 m (4). However, in the present study, a severalfold increase during exercise of leg net lactate release, leg lactate uptake/release, leg lactate oxidation, and a higher contribution of the leg lactate release to whole body lactate Ra was observed at altitude compared with sea level. Previously, no change in the leg net lactate release (6, 7), lactate release, and contribution of leg lactate release to whole body lactate Ra was observed after 3 wk of acclimatization to 4,300 m compared with sea level (7). It was suggested that active skeletal muscle as a source of lactate was not affected by acclimatization and that other tissues besides active skeletal muscle participate in producing the blood lactate concentration responses described as the lactate paradox (7). Of note, no lactate paradox phenomenon was observed during incremental exercise in the same subjects of the present study; i.e., at submaximal and maximal exercise intensities, the lactate concentration was similar with acute exposure to hypoxia equivalent to 5,260 m compared with 5,260 m after 9 wk of acclimatization (32). Furthermore, at any absolute exercise intensity, the lactate concentration and leg lactate release were considerably higher at altitude compared with sea level. However, lactate concentration and leg lactate release were similar at any relative exercise intensity (32). The findings from the incremental maximal exercise study may imply that continuous submaximal exercise at the same relative exercise intensity as at sea level would have elicited similar lactate utilization at altitude compared with sea level. Thus the relative exercise intensity muscle lactate production relation was unchanged with prolonged acclimatization to high altitude. Whether the longer period and/or the higher altitude of acclimatization in the present study compared with the studies of Brooks and colleagues (4, 7) may have caused the differences in whole body and muscle lactate metabolism remains to be resolved.
Whole body vs. muscle lactate turnover: methodological considerations. In the present study, whole body lactate Ra was calculated from the dilution of the lactate tracer, infused in a forearm vein, in an artery (the a-v infusion/sample mode). However, lactate Ra is 20-30% higher when the generally accepted appropriate infusion in the aortic arch and blood sampled from the vena cava (the a-v infusion/sample mode) is used (21). With the underestimation in lactate Ra taken into account, lactate Ra would be 1.5 and 6.3 µmol/min at rest and during exercise at sea level, respectively. Total skeletal muscle mass is ~40% of the body weight (~30 kg) and the muscle mass of two legs ~14 kg. Therefore, under resting conditions, the rate of lactate uptake and release by total skeletal muscle is ~0.7 mmol/min at sea level. Thus ~45% of the systemic lactate Ra originates in skeletal muscle. The contribution of skeletal muscle to systemic lactate Ra is similar to the 41% previously reported when forearm lactate release was extrapolated to systemic lactate Ra (11). With exercise, the contribution of lactate release from the active legs to the corrected lactate Ra is ~65% at sea level. At rest 1.2 mmol/min and during exercise 2.2 mmol/min of lactate originate from nonleg tissues. This does not necessarily mean that other tissues than skeletal muscle have doubled in both lactate Ra and Rd. With bicycle exercise, not only the muscles in the legs directly involved in bicycling but also muscles in the rest of the body, such as the back, trunk, and, to some extent, arm muscles, will become more active.
Systemic lactate Ra or two-leg lactate release at rest was not significantly different at sea level and altitude. However, the corrected 65% contribution of the two-leg lactate release to lactate Ra at rest was significantly higher at altitude compared with sea level. During exercise, whole body lactate Ra, leg lactate release, and the relative contribution of the legs to whole body lactate Ra were higher at altitude compared with sea level. In fact, leg lactate release accounted for virtually all lactate appearing in the blood compared with ~65% at sea level. Thus, after acclimatization, lactate Ra during exercise is higher compared with sea level. In addition, resting and active skeletal muscles are more important in lactate Ra and Rd after acclimatization to hypoxia than at sea level. The aforementioned evaluation of the contribution of skeletal muscle to lactate Ra during exercise is based on the average of the 20 min of exercise (Table 2). However, it is clear from Fig. 3 that, with exercise duration, the decrease in lactate release from the legs is more pronounced than the decline in lactate Ra and that the leg lactate uptake decreased far less compared with the release. These changes are also reflected in the marked decrease in the net lactate release compared with a modest decline in arterial lactate concentration, as described previously (14, 19, 20). This implies that, with exercise duration, the active muscles become less important as a tissue for lactate clearance but maintain or even slightly increase their role in lactate clearance. Consequently, other tissues, including nonleg skeletal muscle, become more important in terms of lactate release. The decline in net lactate release and, as shown here, in lactate release as well has been suggested to originate from a shift in fiber type recruitment (25). The very early release of lactate upon the start of exercise may be due to activation of type II fibers with a high glycolytic capacity. During continued moderate-intensity exercise, these fibers may not be recruited, but rather type I fibers with a lower glycolytic capacity. However, most likely, the low workload of 146 W in the present study did not result in type II fiber recruitment. The higher lactate release during the initial phase of moderate-intensity exercise has also been attributed to a mismatch between the rate of pyruvate production and utilization in the tricarboxylic acid (TCA) cycle. However, the pyruvate dehydrogenase (PDH) activity and the TCA cycle intermediate concentration did not change between 1 and 15 min of moderate-intensity exercise, suggesting that optimal activation may have been reached shortly after the start of exercise (13). Recently, Parolin et al. (24) showed that PDH activity at rest was similar under normoxic and hypoxic conditions. After 1 min of exercise at the same absolute work intensity, PDH activity was lower in hypoxia compared with normoxia. After 15 min of exercise, PDH activity did not further increase in normoxia, but PDH activity in hypoxia further increased compared with 1 min, resulting in a significantly higher PDH activity in hypoxia compared with normoxia. Despite a higher PDH activity in hypoxia, muscle lactate was severalfold higher in hypoxia compared with normoxia. Therefore, it appears that pyruvate oxidation is not limited in hypoxia, supported by the observation in the present study that lactate uptake and subsequent oxidation by active skeletal muscle are already high at the onset of exercise at altitude, and no differences could be observed in carbohydrate oxidation between sea level and altitude. This may indicate that hypoxia elicits an upregulation of glycolysis far above the rate of pyruvate production needed for oxidation. Still another alternative that cannot be excluded is that, locally in muscle intracellular compartments, a lack of oxygenation exists, and supplementary ATP is generated from glycolysis.Contribution of lactate oxidation to carbohydrate oxidation. At rest, the contribution of lactate oxidation to whole body carbohydrate oxidation was 33% with sea level and at altitude. With exercise, the absolute rate of lactate oxidation increased more than sevenfold, but the relative contribution of lactate oxidation to carbohydrate oxidation decreased at sea level. In contrast, the relative contribution of lactate oxidation to carbohydrate oxidation at altitude was slightly higher compared with rest and significantly higher compared with sea level. The higher contribution of leg lactate oxidation to leg carbohydrate oxidation suggests that active skeletal muscle is responsible for the higher contribution of whole body lactate oxidation to whole body carbohydrate oxidation during exercise at altitude compared with sea level. If we assume that there is no net change in muscle glycogen at rest, about one-half of the carbon of glucose is converted to lactate at whole body level and by skeletal muscle. With exercise, leg lactate uptake was two- and sixfold higher than leg glucose uptake at sea level and at altitude, respectively. Thus lactate equals glucose in delivering carbon from the circulation to the muscle at sea level and threefold higher at altitude. Because lactate, especially during exercise, is nearly completely oxidized, this suggests that lactate is an important fuel for muscular activity. However, at rest, and certainly during exercise, a net lactate release is observed. This implies that, despite a substantial lactate uptake and oxidation by the leg, in a "net sense" lactate does not add carbon for oxidation, in contrast to glucose.
Carbohydrate and glucose utilization. Lowlanders acutely exposed to high altitude showed a shift toward increased blood glucose utilization relative to normoxic conditions (5, 28). After 3 wk of acclimatization, reliance on blood glucose increased even further (5) or decreased (28). In the latter case, blood glucose disposal and oxidation were decreased after acclimatization compared with an acute hypoxic condition, but still higher than at sea level. In the present study, total carbohydrate oxidation tended to be lower at altitude at rest but similar during exercise, whereas glucose Ra was similar at sea level and altitude, as was previously shown in diet- and weight-controlled women after 10 days at 4,300 m (2). Hypoxia causes severe disturbances of sea-level homeostasis at rest but a more profound disturbance under a metabolic challenge like exercise. On the basis of the present study and the study of Roberts et al. (27), one could argue that the enhanced utilization of carbohydrates and blood glucose seen in acute hypoxic conditions and in the 1st wk of acclimatization is overcome by a prolonged period of acclimatization and that glucose homeostasis is reestablished to the sea-level condition. However, we cannot exclude the possibility that energy imbalance (5, 8) and change in dietary carbohydrate and fat intake may have affected our findings. Noteworthy, however, is the much higher blood lactate Ra and net lactate release from the active leg at altitude compared with sea level, indicating that muscle glycogen stores were sufficient despite reduced body weight. Moreover, muscle glycogen availability was not limited either by energy deficiency or by change in diet, as the same subjects had similar lactate concentrations at submaximal and maximal work during graded incremental exercise when acutely exposed to hypoxia and after 9 wk at 5,260 m (32).
Brooks et al. (5) observed small differences in epinephrine and norepinephrine concentrations during exercise at sea level and during exercise acutely and after 3 wk at 4,300 m. The norepinephrine concentration correlated with glucose Ra. In the present study, more than sixfold higher epinephrine and norepinephrine concentrations were observed during exercise at Altitude without a change in glucose Ra. The role of adrenergic stimulation on hepatic glucose output during exercise is unclear; however, the data of the present study support the notion that hepatic adrenergic stimulation does not play a major role in glucose homeostasis during exercise (9, 10, 18).Altitude normoxia after 9 wk of acclimatization to 5,260 m. To get some insight into the effect of oxygen availability during exercise after acclimatization, the 20 min of breathing ambient air was immediately followed by 20 min of exercise while breathing a normoxic gas mixture (altitude normoxia) simulating sea-level conditions. Clearly, the comparison between normoxia and ambient air at altitude and sea level has its limitation. The values on carbohydrate, glucose, and lactate metabolism during normoxia are affected by the previous 20 min of exercise. The previous exercise (Altitude, ambient air) had caused a substantially enhanced arterial lactate concentration, thereby affecting lactate utilization, and furthermore, lipolysis had increased, thereby affecting carbohydrate utilization. In addition, because lactate release from an active limb decreases with exercise duration, as is clearly shown in the present study, it is difficult to discriminate between the effects of exercise duration and normoxia. However, with these limitations kept in mind, it seems that, after 20 min of exercise while subjects breathed a normoxic gas mixture, most parameters, such as arterial lactate concentration, lactate Ra, percent lactate Rd oxidized, leg lactate uptake and release, and leg lactate uptake being oxidized, reached values similar to those at sea level. Immediate normalization of lactate metabolism with supplementary oxygen to sea-level values may originate from oxygen per se and/or from oxygen and adaptive changes caused by acclimatization.
In summary, After 9 wk of acclimatization to 5,260 m, the lactate concentration and whole body lactate Ra are increased during exercise compared with sea level, as previously observed after 3 wk at 4,300 m (4). However, different from previous work (7) were the findings of a higher leg net lactate release, leg lactate release, and higher contribution of the leg lactate release to whole body lactate Ra at altitude compared with sea level. In addition, the relative contribution of lactate oxidation to whole body carbohydrate oxidation was substantially higher at altitude compared with sea level as a result of an increased uptake and subsequent oxidation of lactate by the active skeletal muscles. Whether the differences between the present study and previous work are due to the longer duration and/or higher altitude of acclimatization is unclear. ![]() |
ACKNOWLEDGEMENTS |
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We thank all the subjects who participated in the study, Birgitte Jessen and Harrieth Wagner for excellent technical assistance, and Göran Rådegran and Rob Roach for the organization of the study.
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FOOTNOTES |
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We also thank the Bolivian Academy of Science and the Instituto Boliviano Biologia de Altura (Bolivia) for invaluable help. We are grateful to Radiometer (Copenhagen, Denmark) and Monark (Varberg, Sweden) for placing valuable equipment at our disposal.
This study was supported by a grant of the Carlsberg Foundation (Denmark). The Copenhagen Muscle Research Centre has received a grant (Grant no. 504-14) from the Danish National Research Foundation.
Address for reprint requests and other correspondence: G. van Hall, Copenhagen Muscle Research Centre, Rigshospitalet, section 7652, 9 Blegdamsvej, DK-2100 Copenhagen Ø, Denmark (E-mail: gvhall{at}cmrc.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.
July 30, 2002;10.1152/ajpendo.00134.2001
Received 20 March 2001; accepted in final form 23 July 2002.
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