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Unité Mixte de Recherche 5578 Centre National de la Recherche Scientifique, Laboratoire de Physiologie, Faculté de Médecine, F-69373 Lyon cedex 08, France; Anatomisches Institut, Universität Bern, CH-3000 Bern; Departement de Physiology, Centre Médical Universitaire, 1211 Geneva 4, Switzerland; and Instituto Boliviano de Biologia de Altura, Casilla 717 La Paz, Bolivia
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Desplanches, D., H. Hoppeler, L. Tüscher, M. H. Mayet,
H. Spielvogel, G. Ferretti, B. Kayser, M. Leuenberger, A. Grünenfelder, and R. Favier. Muscle tissue adaptations of
high-altitude natives to training in chronic hypoxia or acute normoxia.
J. Appl. Physiol. 81(5):
1946-1951, 1996.
Twenty healthy high-altitude natives, residents
of La Paz, Bolivia (3,600 m), participated in 6 wk of endurance
exercise training on bicycle ergometers, 5 times/wk, 30 min/session, as
previously described in normoxia-trained sea-level natives (H. Hoppeler, H. Howald, K. E. Conley, S. L. Lindstedt, H. Claassen, P. Vock, and E. R. Weibel. J. Appl.
Physiol. 59: 320-327, 1985
[Medline]
). A first group of 10 subjects was trained in chronic hypoxia (HT; barometric
pressure = 500 mmHg; inspired O2
fraction = 0.209); a second group of 10 subjects was trained in acute
normoxia (NT; barometric pressure = 500 mmHg; inspired O2 fraction = 0.314). The
workloads were adjusted to ~70% of peak O2 consumption
(
O2 peak) measured
either in hypoxia for the HT group or in normoxia for the NT group.
O2 peak determination and biopsies of the vastus lateralis muscle were taken before and after
the training program.
O2 peak in the HT
group was increased (14%) in a way similar to that in NT sea-level
natives with the same protocol. Moreover,
O2 peak in the NT
group was not further increased by additional
O2 delivery during the training session. HT or NT induced similar increases in muscle
capillary-to-fiber ratio (26%) and capillary density (19%) as well as
in the volume density of total mitochondria and citrate synthase
activity (45%). It is concluded that high-altitude natives have a
reduced capillarity and muscle tissue oxidative capacity; however,
their training response is similar to that of sea-level residents,
independent of whether training is carried out in hypobaric hypoxia or
hypobaric normoxia.
muscle stereology; histochemistry; enzyme activities
INTRODUCTION THE ROLE OF LOCAL MUSCLE TISSUE HYPOXIA during exercise
as a stimulus for muscle cell adaptation is debated (11). Hypoxia has
long been assumed to play a role in muscle cellular adaptations observed with long-term endurance training (12). Two studies that used
hypoxia during endurance training sessions demonstrated that, in
addition to the changes usually seen with endurance training (i.e., an
increase in muscle oxidative capacity and capillarity), hypoxia
increased the myoglobin content (29) and fiber size (6) of skeletal
muscles fibers. In contrast, it is well documented that simulated (11)
or real exposure (14, 17) to permanent hypoxia results in a loss of
muscle mass as well as of muscle oxidative capacity, whereas the extent
of the capillary network is maintained. A loss in body mass due to an
initial loss of water and subsequently to a loss of muscle and fat mass
(4) is often described as a consequence of hypoxia.
As exercise training in environmental hypoxia is often used as an
ergogenic agent, one wonders about the mechanisms by which the
combination of mild permanent hypoxia with training could induce
organismic adaptations favoring athletic performance. Recently, Levine
et al. (21) suggested that an optimal strategy to improve performance
at sea level would entail low-altitude training with residency at high
altitude. The latter would improve cardiovascular O2 delivery due to an increased
hematocrit, whereas the former would allow for maintaining high
training intensities and thus stress on muscle tissue. To explore the
contention that reduced muscle stress during endurance training in
hypoxia could limit muscle adaptations, we hypothesized that
high-altitude residents subjected to a training with supplementary
O2 should show larger muscle
biochemical and structural adaptations than high-altitude residents
subjected to the same training protocol in hypoxia.
MATERIALS AND METHODS Subjects. The experiments were carried
out on 20 healthy male subjects, residents of La Paz, Bolivia (3,600 m
altitude). According to anthropological studies, these high-altitude
natives ranged from Ameridian to European, most of them being mestizos
(10). They were never exposed to a low altitude for >1 mo within 3 yr before the study. Moreover, they were not engaged in a training program
during the preceding months. Their weekly exercising time averaged 4 ± 0.5 h, with two subjects reporting no physical activity at all.
The subjects were fully informed about the possible risks involved in
the experiment. Their main physical characteristics are given in Table
1.
Table 1.
Anthropometric data and
O2 peak before and after
training in normoxia and hypoxia
Age, yr
Weight, kg
Height,
cm
O2 peak,
l/min
Normoxia
Hypoxia
Before
After
Before
After
HT
24.2 ± 0.7
62.0 ± 2.6
167 ± 1
2.64 ± 0.10
3.02 ± 0.13*
2.42 ± 0.10*
2.79 ± 0.13*
(n = 10)
(n = 10)
(n = 10)
(n = 8)
(n = 8)
(n = 8)
(n = 8)
NT
24.9 ± 1.2
60.3 ± 2.9
168 ± 2
2.46 ± 0.10
2.94 ± 0.15*
2.31 ± 0.11*
2.69 ± 0.15*
(n = 10)
(n = 10)
(n = 10)
(n = 10)
(n = 10)
(n = 10)
(n = 10)
Values are means ± SE; n, no. of subjects. HT, training
at 70% of peak O2 consumption
(
O2 peak) in chronic
hypoxia; NT, training at 70% of
O2 peak in acute normoxia.
*
Significantly different before and after training.
Significantly different from normoxia ( P < 0.05).
Performance tests. Peak
O2 consumption
(O2 peak) was
measured on a mechanically braked Fleisch bicycle ergometer with a conventional open-circuit system, as previously described (8). The
workload was increased stepwise by 30 W every 4 min until the subjects
were unable to maintain the pedaling rate at 70 revolutions/min. The
criterion for having reached
O2 peak was attaining
a plateau in O2 consumption
(<150-ml O2 consumption
increase) with an increase in power output, blood lactate > 7 mM, and a respiratory quotient >1.1. During the test and
training sessions in acute normoxia, the gas mixture was coming from a
vacuum cleaner providing air to which
O2 was added from a tank through a
flowmeter, this mixture being introduced in a 200-liter container
acting as a mixing chamber. The inspired
O2 fraction
[FIO2 = 0.314;
barometric pressure (PB) = 500 mmHg; inspired PO2 = 150 Torr]
was adjusted close to the respiratory valve (Hans Rudolph model
2700). Each subject completed two incremental cycle
ergometric tests separated at least by 24 h, inhaling either ambient
hypoxic gas (PB = 500 mmHg;
FIO2 = 0.209) or normoxic
gas (PB = 500 mmHg;
FIO2 = 0.314).
Training program. These 20 high-altitude natives underwent a training program as previously
described (9). A 6-wk exercise program was carried out by a first group
of 10 subjects on bicycle ergometers in chronic hypoxia (HT;
PB = 500 mmHg;
FIO2 = 0.209). Five training
sessions were performed per week for 30 min each. The same training
protocol was performed by a second group of 10 subjects but in acute
normoxia (NT; PB = 500 mmHg; FIO2 = 0.314). Workloads
were adjusted when necessary to maintain a workload corresponding to
~70% of O2 peak
measured either in hypoxia for the HT group or in normoxia for the NT
group.
Muscle biopsies and analysis by electron microscopy. Muscle biopsies of the vastus lateralis were taken at the midthigh level by using the technique of Bergström (1). A fraction of the muscle tissue was processed for electron microscopy. The tissues were immersion fixed in a 6.25% solution of glutaraldehyde in 0.1 M sodium cacodylate (adjusted to 430 mosmol with NaCl). After 1 h of fixation, samples were cut into small blocks and put into a solution of 1% osmic acid in 0.06 M veronal-acetate buffer for 2 h. After dehydration in increasing concentrations of ethanol, the samples were finally embedded in Epon (13).
For stereological analysis, ultrathin sections (60-90 nm), transverse with regard to the fiber axis, were cut with an ultramicrotome from four tissue blocks randomly chosen from each muscle. Sixteen micrographs per muscle were taken on 35-mm film with a Philips 300 electron microscope at a final magnification of ×1,500, allowing analysis of ~125 muscle fiber profiles in each muscle. The number of fibers and capillaries were counted directly. For mean fiber cross-sectional area, sampling was done by point counting in consecutive corners of the frames on 100-square mesh grids.
For analysis of the mitochondria and myofibrils, 20 micrographs/section (and thus 40 micrographs/muscle) were taken at a magnification of ×24,000. The volume density of interfibrillar mitochondria, subsarcolemmal mitochondria, and myofibrils was determined with a systematic sampling procedure in consecutive frames of 200-square mesh grids. The reference space was the total fiber volume. The mean total volume density of the mitochondria was calculated as the sum of the mean interfibrillar and subsarcolemmal mitochondrial volume densities for each muscle. Micrographs were projected on a screen fitted with a quadratic grid of lines: grid A100 (100 test points) for the low magnification and grid C16 (144 test points) for the high magnification (31). Morphological parameters are expressed in relative terms.
Histochemical analysis. The samples
were frozen in isopentane cooled in liquid nitrogen, mounted in an
embedding medium (TEK ACT compound), and stored at 
80°C
until analysis. Serial transverse sections (10 µm) were cut on a
microtome at 30°C and were stained by the myofibrillar
adenosinetriphosphatase (ATPase) method (2). After preincubation at pH
4.3, 4.35, and 4.4 in acid buffer (50 mM acetic acid) with 25 mM
CaCl2 for 4 min at 25°C, the
ATPase reaction was carried out in buffer (pH 9.4) with 18 mM
CaCl2 and 2.7 mM ATP at 37°C
for 20 min. Muscle fibers were classified into three major types (I,
IIA, and IIB) and an intermediate-type fiber (IIAB). With the myosin
ATPase reaction, type IIAB displays an intermediate behavior in pH
sensitivity between type IIA and IIB fibers.
Fiber type composition was expressed as the number of fibers of each type relative to the total number of fibers. Measurements were made on ~300 fibers on each section. The fiber cross-sectional areas were calculated by means of a computerized planimetry system coupled to a digitizer. The areas of 70 fibers were measured, and the mean was calculated.
Biochemical analysis. Muscle samples
(10 mg) were weighed and immediately homogenized (between 0 and
4°C) in 0.3 M phosphate buffer containing 0.05% bovine
serum albumin (pH 7.7) with a glass Potter-Elvehjem homogenizer. They
were frozen at 80°C and thawed three times to disrupt the
mitochondrial membrane. Enzyme activities were determined at 25°C.
For measuring phosphofructokinase (PFK; EC 2.7.1.11) activity, we used
a slightly different phosphate buffer (0.1 M K-phosphate buffer at pH
8.2, with 0.5 mM ATP, 5 mM MgSO4,
30 mM NaF, and 10 mM glutathione). The PFK activity was immediately
measured on this homogenate. PFK and 3-hydroxyacyl-CoA dehydrogenase
(HAD; EC 1.1.1.35) were determined by fluorimetric techniques as
previously described (22). Citrate synthase (CS; EC 4.1.3.7) was
measured spectophotometrically according to Srere (28). Enzyme
activities were expressed as micromoles of substrate per minute per
gram wet mass.
Statistical analysis. All data are expressed as means ± SE. A multifactorial analysis of variance was used for intergroup comparisons. The Fisher paired least significant difference was used to identify specific mean differences. In all cases, the level of significance was set at P < 0.05.
RESULTS
All subjects had been subjected to chronic hypoxia (living at 3,600 m)
all their lives. They were recruited to be similar concerning their
major anthropometric characteristics such as age, weight, and height
(Table 1). Training in chronic hypoxia (HT) or in acute normoxia (NT)
induced a similar significant increase in
O2 peak when measured
either in hypoxia (15 or 16%, respectively) or in normoxia (14 or
20%, respectively; Table 1).
O2 peak values were
always significantly lower by 6.1-8.5% when measured in hypoxia.
There was a statistically significant difference in the percent
distribution of type I and IIA fibers between the two groups before
training; however, neither fiber type distribution nor fiber
cross-sectional area changed significantly with either mode of training
(Table 2). Capillary density increased
significantly in both groups (21% in HT and 17% in NT;
Table 3). This increase was due to a
significant increase in the capillary-to-fiber ratio (26% in both
groups) at an unchanged fiber cross-sectional area (Tables
2 and 3). The volume density of total mitochondria was increased
similarly (by 47 and 43% in HT and NT groups, respectively; Table 3).
However, HT induced a greater increase in subsarcolemmal than in
interfibrillar mitochondria (109 vs. 38%), whereas NT had similar
effects on subsarcolemmal (58%) and interfibrillar (41%)
mitochondria. A significant decrease in myofibrils (7%) occurred after training with both exercise conditions, whereas the
volume density of lipids remained constant (Table 3). Both training
programs induced a significant 45% increase in CS activity but not in
the activity of HAD (Table 4). The PFK
activity also remained unchanged.
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DISCUSSION
We investigated the muscle structural composition and activity of key metabolic enzymes in 20 young lifelong residents of mixed ethnic origin of La Paz (3,600 m) before and after 6 wk of endurance exercise training either in environmental hypoxia or in artificial normoxia. Most of the subjects were medical or physical education students at the University of La Paz. They led an active lifestyle but were not enrolled in any systematic endurance exercise program previous to our study.
Comparing the ultrastructural composition of their vastus lateralis muscles to previous studies, we note most importantly that muscle oxidative capacity measured as volume density of total mitochondria or as CS activity was found to be reduced by some 20% compared with lowlanders of similar age and socioeconomic background (13, 14, 17). This finding is consistent with a number of studies that reported significantly reduced muscle tissue oxidative capacities in native highland populations (18, 19, 26) as well as in lowlanders after prolonged exposure to simulated or real hypoxia (11, 14, 23). The only study to our knowledge reporting on an increased muscle tissue oxidative capacity in high-altitude residents dates back to the 1960s (24). The results of that study reporting significantly higher activities of cytochrome c reductase in highlanders have been questioned, however, on the fact that physically active highlanders were compared with sedentary lowlanders. It therefore seems that a prominent and consistent effect of a hypoxic environment on human skeletal muscle tissue is a reduction in muscle oxidative capacity, i.e., peripheral O2 demand. Also noteworthy and consistent is the finding of a much reduced intramyocellular lipid content in biopsies from untrained permanent high-altitude residents (18, 19). Lipid substrate stores in muscle fibers of highlanders are barely one-half of those seen in young untrained lowlanders (13). Maintaining energy balance in chronic hypoxia seems difficult (4, 20). It is well known that altitude can lead to weight loss and possibly to substrate depletion in muscle cells. An increased reliance of muscle cells on glucose metabolism has been previously described at rest as well as during exercise (3). The low muscle lipid content in the group of young students investigated in this study seems related more to hypoxia than to diet because they were from a privileged socioeconomic background and can hardly have been described as malnourished. As shown in a previous paper (10; see Table 1), the anthropometric data of our population show that height, weight, body mass index (considered as a relatively good index of nutritional status), and percent fat are within the standard range.
With regard to the capillary supply of muscle fibers of high-altitude-exposed subjects, the literature data are varied. Some of this variability must be attributed to the technical difficulties involved in measuring fiber cross-sectional area in muscle biopsies when both the degree of fiber contraction and the alignment of muscle fibers cannot be controlled (33). By using young untrained lowlanders as a comparison (13), the present study indicates that muscle capillarity is reduced in close proportion to the reduction in oxidative capacity, whereas the reduction in capillary density is brought about by a reduction in the capillary-to-fiber ratio at a constant fiber size. Similar results have been obtained in a group of Quechuas, also natives of the high Andes (26), and in Sherpas native to the Himalayas (18). In permanent high-altitude residents, we thus find that the number of capillaries supplying similar-sized muscle fibers is reduced in proportion to the reduction of mitochondria within these fibers. In contrast, lowlanders exposed to simulated or real hypoxia are capable of improving muscle tissue O2 supply (11, 14, 23). This is achieved by maintaining a constant capillary-to-fiber ratio when fiber size is reduced. As a consequence, capillary density as well as capillary length per volume of mitochondria is significantly increased in lowlanders after long-term exposure to hypoxia (14).
Fiber type distribution as determined from ATPase staining characteristics showed a significantly lower value for type I fibers in one of the experimental groups (NT). This finding is likely a chance result. Taken together, both groups are well within fiber type distributions reported for the untrained human vastus lateralis muscle (8).
When subjected to exercise training for 6 wk on a bicycle ergometer, HT
and NT subjects were able to improve their
O2 peak similarly by
close to 15% whether measured in hypoxia or in normoxia [for a
detailed analysis of the functional results, see Favier et al.
(9)]. This increase in
O2 peak is of the same
magnitude as that observed in untrained lowlanders subjected to a
similar training regimen under near sea-level conditions (13, 25). In
particular, it appears that training in acute normoxia, i.e., at 19%
higher absolute exercise intensity, did not convey any functional
advantage.
In neither of the groups did we observe an increase in the type I fiber population and a decrease in the type IIB population as previously reported for this type of training in lowlanders (16). Because short-term endurance exercise training is not consistently observed to lead to fiber type shifts, we would not attribute much significance to the lack of fiber type plasticity in this study. Fiber size did not change significantly in either group whether measured globally (morphometry of electron micrographs) or by fiber type (morphometry of histochemistry). The difference in fiber size between measurements taken from fixed or frozen tissue is related to tissue shrinkage incurred when the tissue is processed for electron microscopy (7).
Whatever the O2 availability during training, we observed a similar increase in muscle tissue oxidative capacity of close to 45% in both groups whether measured morphometrically (volume density of total mitochondria) or biochemically (CS activity). These changes are entirely consistent with those observed in lowlanders subjected to the same training paradigm (13, 25). Supplementary O2, enabling the NT subjects to train at higher absolute workloads, did not seem to add to the training effect. Note that the NT group was always subjected to the environmental hypobaric hypoxia characteristic of La Paz except during the training periods. As protein synthesis is known to be sensitive to the intracellular oxygenation state (27, 30, 32), this may have affected muscle cell remodeling in the recovery period between exercise sessions for both groups. Acute normoxia during training did affect the response of specific subpopulations of mitochondria, however. A much larger increase in subsarcolemmal mitochondria could be observed in the HT group (109%), very much in line with the results obtained in lowlanders (13). In NT subjects, both subsarcolemmal and interfibrillar mitochondria increased in similar proportions. Because the functional significance of the subsarcolemmal vs. the interfibrillar location of mitochondria is currently being debated (5, 15), our findings merely support the concept that these two populations should indeed be distinguished, at least based on their capacity to respond differently to extrinsic stimuli.
Neither of the two experimental groups increased the volume density of intracellular lipid stores significantly with exercise training. Lipid concentrations in excess of 1% of the fiber volume are a consistent finding in lowlanders subjected to the same 6-wk training protocol as the subjects in this study (13). The lack of a structural adaptation of the lipid substrate stores in muscle cells is all the more surprising because pretraining values were very low indeed. As previously mentioned, either dietary influences or hypoxia-induced shifts in muscle fiber metabolism may be responsible for these findings, which need to be confirmed and expanded. An important finding in this context is the lack of an increase in the capacity to oxidize free fatty acids, as indicated by an unchanged HAD activity; this enzyme is usually observed to increase its activity with endurance exercise training (12). The increase in CS in parallel with total mitochondrial volume density supports the morphometric data. No change occurred in muscle glycolytic capacity as estimated by an unchanged activity of PFK.
The results of this study clearly suggest that, although NT subjects
were subjected to a 19% higher absolute training intensity, there were
no functional or structural improvements over those seen in the HT
group. The hypothesis of this study, namely, that training in hypoxia
reduces stress on muscle, thus limiting muscle tissue adaptations,
therefore has to be rejected. However, because improvement of athletic
performance as a consequence of high-altitude training possibly has
multiple causes, it does not mean that the contention that it may be
beneficial for athletes to live at altitude but to train at sea level
is necessarily wrong (21). For one, the major gain in
O2 peak and performance
in lowland athletes was brought about by an increase in hematocrit due
to altitude exposure, whereas in high-altitude residents, the increase
in O2 peak was the
consequence of exercise training at a constant but elevated hematocrit
in both NT and HT (9).
It is further worth mentioning that this study was carried out on
untrained subjects. It cannot be excluded that untrained subjects are
capable of maximally increasing structural and functional performance
parameters. Hence training at a reduced exercise intensity at altitude
may, in fact, be detrimental with regard to maintaining optimal
structural muscle capacities for aerobic metabolism in athletes. This
remains to be proven, however, with direct observations. With regard to
exercise intensity, it should also be considered that the reduction in
O2 peak and sustainable
work intensity is substantially larger in lowlanders exposed to acute
hypoxia than the gain in aerobic performance and
O2 peak of
permanent high-altitude residents on exposure to acute normoxia (10). This would result in a larger penalty of lowlanders training in hypoxia
compared with a smaller advantage of highlanders training in acute
normoxia.
In conclusion, this study lends further support to previous
observations that skeletal muscle tissue consistently responds to
permanent hypoxia by a decrease in oxidative capacity. In contrast to
lowlanders exposed to acute hypoxia, high-altitude residents seem to
reduce capillarity in proportion to oxidative capacity. The training
response of highlanders to a standard endurance exercise protocol is
similar to that of the lowlanders with regard to improving O2 peak, mitochondrial
content, oxidative enzyme activity, and capillary supply. In contrast,
neither HAD enzyme activity nor the low intramyocellular lipid stores
are increased with training in highlanders. Supplementary
O2 during training, allowing
subjects to work at higher absolute workloads, has no effect on the
magnitude of the training-induced functional or structural adaptations. The hypothesis that reduced muscle stress in hypoxia could limit muscle
adaptations in high-altitude training is therefore rejected for a
population of previously untrained permanent high-altitude residents.
ACKNOWLEDGEMENTS
The authors express their sincere gratitude to H. Claassen, E. Caceres and to the subjects who have consented to the biopsies.
FOOTNOTES
Address for reprint requests: D. Desplanches, UMR 5578 CNRS, Laboratoire de Physiologie, Faculté de Médecine, 8, Ave. Rockefeller, 69373 Lyon cedex 08, France.
Received 26 December 1995; accepted in final form 17 July 1996.
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