II. Morphological Adaptations of Human Skeletal Muscle to Chronic Hypoxia* H. Hoppeler' , E. Kleinert1 , C. Schlegei2 , H. Claassen1 , H. Howald2 , S. R. Kayar' , andP. Cerretel!

H. Hoppeler, E. Kleinert, C. Schiegel, H.

tissue adaptations to high altitude seem difficult to interpret due to limitations of the analytical procedures (1, 36), confounding variables such as differences in body weight in experimental and control animals (8), or simultaneous exposure

Claassen, H. Howald, S. R. Kayar, and P. Cerretelli, Mor-

of animals to cold and hypoxia (see 2). Banchero (3), thus, con-

phological Adaptations of Human Skeletal Muscle to

cludes that chronic normothermic hypoxia has no influence on skeletal muscle capillarity in sedentary laboratory animals and that exercise or cold exposure must further challenge the


Chronic Hypoxia. mt j Sports Med, Vol 11, Suppi 1, pp S3— S9, 1990.

oxygen delivery system to force muscle structural adaptations.

Muscle structural changes during typical mountaineering expeditions to the Himalayas were

With regard to human skeletal muscle struc-

assessed by taking muscle biopsies from 14 mountaineers before and after their sojourn at high altitude (> 5000 m for over 8 weeks). M. vastus lateralis samples were analyzed morphometrically from electron micrographs. A significant reduction (—10%) of muscle cross-sectional area was found on CT scans of the thigh. Morphologically this loss in muscle mass appeared as a decrease in muscle fiber size

tural adaptations to high altitude, experimental data are

mainly due to a loss of myofibrillar proteins. A loss of

measured in biopsies of m. vastus lateralis in five subjects (39). The almost complete lack of structural data on adaptations of

muscle oxidative capacity was also evident, as indicated by a decrease in the volume of muscle mitochondria (—25 %). In contrast, the capillary network was mostly spared from catabolism. It is therefore concluded that oxygen availabil-

ity to muscle mitochondria after prolonged high-altitude exposure in humans is improved due to an unchanged capillary network, supplying a reduced muscle oxidative capacity. Key words

high altitude, hypoxia, stereology, mitochondna, myofibnils, computed tomography, capillaries, fiber size


Little is known about structural adaptations of skeletal muscle as a consequence of prolonged high-altitude exposure. From animal experimentation it would appear that chronic exposure to hypoxia leads to an increase in muscle tissue capillarity (see 25) and oxidative capacity (20). These generally held assertions have been questioned seriously (3, 34). Some of the "classic" studies on the effects of muscle Int.J Sports Med. ll(1990)S3—S9 GeorgThieme VerlagStuttgart. NewYork

sparser still. Reynafarje (30) reports 14% higher myoglobin concentrations and 20 % higher oxidative enzyme activities in biopsies of M. sartorius of nine young natives of the high Andes as compared with nine sea-level subjects. More recent evidence suggests that shorter exposure to 4300 m (18 days) has no effect on oxidative and glycolytic enzyme activities

human skeletal muscle tissue to continued exposure to the stresses of high altitude in a natural environment led us to perform the present study. Materials and Methods

Informed consent was obtained from 14 male subjects participating in one of two expeditions to the Hima-

layas in 1981 and 1986 (for details of expedition characteristics, acclimatization profiles, timing of measurements, etc., consult 10). Briefly, VO2max tests, computed tomographies (CT), and muscle biopsies were obtained before and 10— 15 days after the return of an 8-to 10-week stay at a base camp between 5200 and 5350 m with several exposures to altitudes in excess of 8000 m of all participants. VO2max was assessed during an incremental cycloergometric test as described in detail in an accompanying paper (14). It may be noted that this study reports on seven subjects in each of the expeditions, from which matching sets of structural and functional data could successfully be obtained. The accompanying paper (14) reports on six subjects only due to technical problems related to the measurements of cardiac output. This explains minimal differences in some of the functional variables reported betweenthese studies (Table 1).

* This work was supported by grant 3.036.084 from Swiss National Science Foundation

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'Department of Anatomy, University of Berne, Berne, Switzerland 2Research Institute of the Swiss School for Physical Education and Sports, Magglingen, Switzerland 3Department of Physiology, University of Geneva, CMU, I rue Michel Servet, Genève, Switzerland

mt. J. Sports Med. 11(1990)

H. Hoppeler, E. Kleinert, C. Schiegel, H. Claassen, H. Howald, S. R. Kayar, and P. Cerretelli

Table 1 Physical and physiologic characteristics of subjects. (means SD; b = before expedition; a after expedition; * = significantly different P < 0.05, two-sided, paired t-test)

Age (years)

Lhotse ( n = 7)

Everest (n = 7)




31.6 2.9

Bodymass 69.7 (kg)

VO2max (I 02/minI

67.4 8.1

73.6 5.7

3.26 4.67 0.42* 0.38

All (n = 14) b

38.2 8.7

7.2 3.62 0.45



34.9 7.1 70.1


71.7 6.6

4.57 4.14 0.43 0.68

68.8 7.0* 3.91


The cross-sectional area of the left thigh muscles was determined by computed tomography (SOMATOM SF, Siemens, Erlangen, Germany). Scans were taken on approximately 8-mm thick slices at 2/3 of the distance be-

tween the upper border of the patella and the greater trochanter, where the circumference of the thigh is nearly maximal (15).

Muscle biopsies of vastus lateralis were taken at mid-thigh level using the technique of Bergstrom (4). The muscle samples were processed for electron microscopy by fixation in a 6.25% solution of glutaraldehyde, as previously described (22). Morphometry of these samples was carried out on cross sections from four randomly chosen tissue blocks from each biopsy. Capillary number, fiber number, and fiber area were estimated at a final magnification of x 1 500 (16 micrographs) analyzing more than 100 muscle fiber profiles in each biopsy, as described in detail by Zumstein et al. (40; Fig. 1). A final magnification of x 24000 (40 micrographs) was

used to estimate the volume of mitochondria, intracellular lipid deposits, myofibrils, and sarcoplasm per volume of muscle fiber (22; Fig. 1). Systematic sampling was used for all stereologic procedures. Point counting was performed with a grid AI00 (100 test points) for the lower and with a grid B36 (144 test points) for the higher magnification. All stereologic

variables were estimated according to standard procedures



Fig. 1 Representative electron micrographs of transverse sections of m. vastus lateralis as used for morphometry of fiber size and capillarity and muscle ultrastructural components (inset). Arrows in-

dicate capillaries; EC = erythrocyte; N = nucleus of endothelial cell; f = myofibrils; I = lipid; m = mitochondria.

in detail by Kayar et al. (27). Ten fibers per muscle (5 fibers x 2

(37, chapters 4 and 6).

blocks, before and after) were selected randomly from the seven subjects on the Everest expedition. The location desig-

Absolute values of mitochondrial -and myofibrillar volumes were obtained by multiplying the volume densities of the skeletal muscle tissue components with the muscle

nated as zone I was at the fiber border and included a corner of a capillary. Zone II was halfway into a fiber, and zone III was at the fiber center. Zone IV was at the fiber border, halfway between the capillary in zone I and the next capillary to appear

volume (calculated for a slice of muscle of 1 cm thickness). Ab-

solute values for capillary length were also calculated for a slice of muscle of 1 cm thickness by multiplying the capillary density data with muscle volume, assuming a factor for capillary tortuosity of 1.25. This procedure has been decribed and justified in detail by Conley et al. (12). An important assumption was made for the assessment of absolute values of morphometric data: all muscles of the thigh are equally affected by

the stress of high altitude and, hence, the structural changes observed in vastus lateralis are representative for all thigh muscles. Volume densities of subsarcolemmal and interfibrillar mitochondria as well as subsarcolemmal substrate space were additionally calculated for four specific locations within muscle fibers (Fig. I) according to a method described

clockwise around the fiber. At the magnification used (x 36000), a zone represented a circular area of approximately 10 pm in diameter.

For statistical comparisons of group means (before and after the expeditions), the Student's t test for paired samples was used; the level of statistical significance was set at 5 %. Linear least-squares regression analysis (with the assumption of a normal distribution of errors) was used to describe relationships between parameters. Results

Physiologic Characteristics of Subjects Basic physical and physiologic variables of the subjects are reported in Table 1. The characteristics of the two

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mt. J. Sports Med. 11(1990) S5

II. MorphologicalAdaptations of Human Skeletal Muscle to Chronic Hypoxia Table 2 Computed tomography, capillary, and fiber size data. (symbols, see Table 1; + , n = 6 or n = 12) Fat tissue crosssectional area

C/F ratio








Mean fiber area

Fiber area


supplied by one capillary (im2)























±0.36* ±73

±89* ±710 ±580











±870 ±620





± 53*

± 510 ± 520**

(n=14) 170 ±23 (n = 7)

Capillary density

±21* ±17





30.8 ±9.1




±0.32 ±0.21 ±98




± 23**

± 22

± 18

Everest (n=7) 184 ± 23





± 0.32 ± 0.45 ± 36





± 150*

± 150

Table 3 Ultrastructural composition of muscle fibers (symbols, see Table 1)


(n = 14)

Volume density central mitochondria

Volume density subsarc. mitochondria

Volume density total mitochondria

Volume density intracellular lipid

Volume density myofibrils

















4.23 ± 0.53*









± 050

± 0.21 *

± 1.2

± 0.64* ± 0.53

± 0.44

± 2.7

± 2,4*

4.34 ± 0.48





± 1.0

486 ± 0.57


± 0.17

0.52 ± 0.14


± 0.86

± 0.39

± 0.59

± 2.2

± 2.0













±0.28** ± 1.2





78.9 ± 1.3

± 0.81 Lhotse


(ri = 7)

(n = 7)


expeditions were rather similar (10), and it was therefore decided to analyze the expeditions jointly as well as individually. On each occasion complete sets of structural measurements were obtained from seven subjects.

Considering both expeditions together, the participants lost 5%—l0% of their body mass and maximal oxygen uptake capacity (VO2max). Measurements done at the base camp indicated that the weight losses were already partially compensated by the time the second set of measurements could be obtained.

Computed Tomography Muscle cross-sectional area was significantly reduced by close to 10% after both expeditions (Table 2). We observed a reduction in fat tissue cross-sectional area of similar magnitude; however, this reduction reached statistical significance only for the Lhotse expedition.

Fiber Size and Capillarity

As would be expected from the loss in total muscle cross-sectional area, the mean fiber cross-sectional area of M. vastus lateralis was significantly reduced (Table 2). This decrease was on the order of 20% for both expeditions an-

alyzed jointly. The capillary to fiber ratio was significantly reduced, but only by some 10% (both expeditions together). As a consequence of the relatively larger decrease in muscle fiber cross-sectional area than capillary to fiber ratio, the capillary density was still increased significantly for the members of the Everest expedition as well as for all subjects taken together. As a consequence of the decrease in fiber size and the increase in capillary density, we found that the fiber volume supplied by one capillary was also significantly reduced (all subjects and members of the Everest expedition).

Muscle Ultrastructure The volume density of total mitochondria (volume of mitochondria per volume of muscle fiber) was sig-

nificantly reduced by almost 20% in the joint analysis of all subjects (Table 3). This decrease was the result of a decrease both in interfibrillar and subsarcolemmal mitochondria. The relative decreases in volume densities of mitochondria were somewhat larger for the Everest expedition, for which the starting values were higher (not statistically significant). The volume densities of intracellular lipids showed no significant changes with high altitude exposure, while the volume density of myofibrils was slightly but significantly increased by 3.5%. When muscle fibers were analyzed in specific zones (Fig. 2), it

was found that the volume density of mitochondria did not

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Muscle tissue cross-sectional area

S6 mt. J. Sports Med. 11(1990)

H. Hoppeler, E. Kleinert, C. Schiegel, H. Claassen, H. Howald, S. R. Kayar, and P. Cerretelli Fig. 2 Relative distribution of subsarcolemmal mitochondria (ms), interfibrillar mitochondria (mc), and subsarcolemmal glycogen (ssgly) in specific regions of fibers of m. vastus lateralis before and after an expedition to Mt. Everest (n 7). Zone! is at the fiber border near a capillary; zone II is half way into a fiber; zone Ill is at the fiber center; zone IV is at the fiber border between two capillaries ( indicates significant difference after the expedition, p 0.05)



00) U)



Zone I










change after the expedition in the inner regions of the muscle

fibers. All the loss of subsarcolemmal and interfibrillar mitochondria and intracellular glycogen stores occurred at the outermost edges ofthe fibers, in zones I and IV. Discussion

Body Composition A prominent finding of the current series of studies is the considerable weight loss incurred by all subjects as a consequence of their stay at altitudes in excess of 5000 m.


Weight loss after a prolonged sojourn at high altitude is frequently reported (6, 18). It has been recognized that the loss in body mass is due both to a loss of muscle mass and a loss of

total body fat (7). These findings are supported by the computer tomographic data of the current analysis (Table 2). Differences in the relative decrease of muscle mass and fat tissue seem related to a number of factors such as initial body weight, habits of food intake, fat absorption, duration and level of high-altitude exposure, and intensity of muscular exercise (6, 18). The somewhat smaller body tissue losses in the current as compared to some previous studies (e. g., 7) seems related to the fact that the body mass and computed tomography data were obtained 10—15 days after the subjects had returned to normal altitudes (360 m). Further, we have to consider that muscle tomographic and biopsy data were obtained from a leg muscle certainly stressed and may be even trained to some extent by the expedition-related, day-to-day activities. Muscles less used, such as arm muscles, may have undergone an even more pronounced reduction in size (31).

Fiber Size In line with the finding of a decrease in thigh muscle cross-sectional area, we found a decrease in average muscle fiber cross-sectional area. As no histochemical analysis was peformed, we do not know whether all fiber types were af-

fected to a similar degree by high-altitude exposure, or whether fiber type changes also occurred which have been re-

ported for rats and guinea pigs (26, 33) and possibly for humans (29). The finding of a significant decrease in fiber

Fig. 3 Lipofuscin accumulations (Ip) as evidence of fiber catabolism in subsarcolemmal location of a muscle fiber in a biopsy obtained after return from the Everest expedition (IS = interstitial space; mf myofibrils; ms = subsarcolemmal mitochondria).


area in humans is at variance with evidence

from a study which exposed caged rats for 5 weeks to a simulated altitude of 6100 m, and we found no significant changes in fiber cross-sectional area in m. gastrocnemius and the diaphragm (35). Likewise, no fiber size changes were observed in m. soleus an m. gastrocnemius when caged guinea pigs were exposed to a simulated altitude of 5100 m for up to 14 weeks (34). It is currently unclear whether these desparate results are a consequence of species-specific differences in muscle fiber response to hypoxia or whether they are due to differences in locomotor activity, cold exposure, or other uncontrolled variables.

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mt. J. Sports Med. 11(1990) S7

II. MorphologicalAdaptations of Human Skeletal Muscle to Chronic Hypoxia 10



















0.113- V02max-0.55


0,702 (pO 05)











V02 max/Mb (ml 02- min kg1)

V02 max/Mb (mI02mir1 k) Fig. 4b

Fig. 4a

Fig. 4a and b Relationship between VO2max/Mb and volume density of mitochondria in m. vastus lateralis before (4a) and after (4b) highaltitude exposure (heavy line). They intercept and slope of this relationship is not significantly different from previously reported values (21, 23).

Capillarity The capillary to fiber ratio was significantly reduced after the Lhotse expedition and when both expeditions are considered together. As is the case for fiber size, this result is at variance with the bulk of data gained from comparable animal experimentation in which capillary to fiber ratio is found to be unchanged (33, 34, 35). However, in the current experiment the relatively larger loss of fiber size than of capillary to fiber ratio still led to a significant increase in capillary density, at least in the members of the Lhotse expedition and when the data of all subjects were analyzed jointly. From the previous discussion it is evident that the increase in capillary density can solely be a result of the loss in muscle fiber cross-sectional area

and does not represent capillary neoformation. In fact, the decrease in capillary to fiber ratio would indicate that some capillaries might have been lost. Possible consequences of the reorganization of the capillary network with regard to oxygen supply of muscle tissue in humans after high-altitude exposure are further discussed below.

of myofibrils is directly related to the drop in volume density of

mitochondria with all other components of the muscle cell maintaining essentially constant fractions of the total cell volume.

Comparing the morphometric estimates of muscle tissue components after high-altitude exposure of the present investigation to values previously obtained with identical techniques on a group of six world-class high-altitude climbers (29), we found a remarkable match between these two sets of data. In both cases mitochondrial volume densities were in the upper range for untrained people, whereas fiber

cross-sectional areas were reduced significantly. As a consequence of the decrease in fiber size with a "normal" capillary to fiber ratio, we found a significantly increased capillary density in both cases. The data on world-class climbers were ob-

tained 2—12 months after their last high-altitude exposure. From this it could be speculated that possibly not all of the observed acute structural changes in the current study might be completely reversible.

Muscle Ultrastructural Changes

From a survey of the literature, it would appear that the efficiency of oxidative phosphorylation in mitochon-

Muscle tissue oxidative capacity estimated by

dna is not changed after prolonged exposure to moderate

volume density of total mitochondria was significantly decreased by almost 20% after exposure to high altitude when

considering all subjects together (Table 3). The decrease in volume density of mitochondria observed was due to a relatively large decrease in the smaller fraction of subsarcolemmal (—43%) than in the larger fraction of interfibrillar (—13%) mito-

chondria. The analysis of fibers in specific zones (Fig. 2)

further confirms that the losses of mitochondrial material and residual components (primarily intracellular stores of glyco-

gen granules, which are often found in high concentration among the subsarcolemmal mitochondria) seemed to occur from the fiber periphery. In line with these quantitative finding, we observed qualitative evidence of fiber degradation (lipofuscin accumulations) in subsarcolemmal locations particularly in post-experiment biopsies (Fig. 3). In contrast to exercise training in which the intracellular lipid content of muscle fibers is usually increased (23), this variable remained unchanged in the current study (Table 2). The small but significant increase in volume density

levels of altitude (16,20), while acute exposure to elevations in

excess of 6000 m seems to inhibit mitochondrial oxidation (38). For the following discussion it is assumed that the maximal amount of oxygen consumed by a unit volume of mitochondria per unit time (24) remained unchanged after returning from the expedition.

If the pre-expediton volume density of mitochondriato VO2max relationship for all subjects of the current analysis is plotted (Fig. 4a), we find a significant linear regression with aslope and y intercept similar to those observed in earlier studies (see 21, 23). This indicates that the subjects of

the current analysis, before the expeditions, were similar to previously investigated populations with regard to the relationship of central ('O2max) to peripheral (muscle mitochondrial volume) descriptors of aerobic capacity. However, if the same variables are plotted after the return from the expeditions (Fig. 4b), we no longer find a statistically significant re-

lationship. The obvious reason for this change in the mito-

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S8 Int.J. Sports Med. 11(1990) MYOFIBRILLAR VOLUME

H. Hoppeler, E. Kleinert, C. Schiegel, H. Claassen, H. Howald, S. R. Kayar, and P. Cerretelli



The total capillary length and, hence, also the total capillary volume and surface area (assuming constant capillary diameters) were found to be unchanged with highaltitude exposure when both expeditions are analyzed jointly (Fig. 5). For the calculation of absolute muscle capillary length, we assumed the capillary tortuosity to remain constant with high-altitude exposure. For pigeon flight muscle capillary tortuosity has been shown to increase with exposure for 5

months to an altitude of 3800 m (28). Unfortunately, due to technical limitations, human biopsy material does not allow an assessment of capillary tortuosity (40). Had the capillary tortuosity of our subjects increased as suggested by the findings of Mathieu-Costello (28), we would have found an inFig. 5 Absolute volumes of myofibrils and mitochondria in a slice of vastus lateralis of 1-cm thickness before and after high-altitude exposure (average of both expeditions SE; s significant, 2P O.05(.

chondria to VO2max relationship is that a large decrease in volume density of mitochondria in vastus lateralis is combined with a quite small decrease in whole body VO2max. There are a

number of reasons why peripheral and central determinants of aerobic work capacity might change independently under the

particular conditions that our subjects experienced. As previously mentioned, one might be concerned about the representativeness of the response of m. vastus lateralis to high-alti-

tude exposure. Vastus lateralis is a superficial muscle and

After high-altitude exposure a constant capil-

lary length or volume thus supplies a reduced quantity of skeletal muscle mitochondria. In that sense we can state that the capillary supply of the remaining mitochondria is improved, not because of an adaptation of the capillary network, but because of a reduction of the mitochondrial mass. There are at least two additional important factors that augment oxygen availability to skeletal muscle mitochondria under hypoxia that must be considered in this context:

a) As commonly found in high-altitude exposure, we observed an increase in hemoglobin concentration (5). As a consequence of the higher hemoglobin concentration, there is (for a given oxygen pressure head) more oxygen

available to muscle tissue at any one time per unit capillary might respond in a complex manner to the combined stresses volume, which, at least partially, compensates for the enof high altitude and possibly cold exposure in a situation of vironmental hypoxia. An increase in hemoglobin has pregeneral catabolism. It will certainly be necessary to look into viously been found in athletic as compared with inactive structural adaptations of muscles of different functions and mammalian species (12), and is thought to be part of the fiber type composition in future expeditions. Moreover, one is adaptive response of the oxygen delivery system to the reminded that it is generally held that there is no simple cause greater oxygen demand of the periphery in athletic animals. and effect relationship between single muscle oxidative capac- b) If, in fact, the myoglobin concentration of human muscles ity and whole body VO2max (17, 32) and that both variables is increased after high-altitude exposure (30), then this have been shown to vary independently under various expericould also improve oxygen conductance to skeletal muscle mental conditions (13, 19). mitochondria during hypoxia (11).

Absolute Changes in Structural Components of Muscle Tissue

In conclusion, we found that the prolonged exposure to high altitude as experienced during typical Hima-

Tables 2 and 3 report morphometric data ob-

skeletal muscle tissue. Foremost, there is a significant loss of muscle tissue as a consequence of an enhanced catabolism.

tained with reference to a unit volume of muscle tissue. It is important to consider that due to body mass and muscle wasting incurred by the prolonged high-altitude exposure, the muscle

volume decreases significantly by 10%. The total quantity of muscle tissue available to the subjects was therefore likewise globally reduced. By multiplying the volume density of tissue component with the organ volume, absolute values for structural quantities can easily be calculated. Figure 5 reports data

on absolute myofibrillar and mitochondrial volume calculated for 1-cm thick muscle slices of our subjects before and after the expedition. It is evident that despite the significant increase in volume density of myofibrils, the muscle and fiber cross-sectional area and, hence, the absolute quantitiy of contractile protein was significantly reduced by close to 10% due to the overriding effect of the loss of muscle mass. Likewise,

the decrease in absolute volume of mitochondria of close to 30% is due to the multiplicative effects of the loss in volume density and in muscle mass.

laya expeditions has profound effects on the structure of

Morphometrically, the loss in muscle mass appears as a decrease in muscle fiber size. In quantitative terms this decrease is mostly due to a loss of myofibrillar proteins. The smaller fraction of respiratory organelles, the mitochondria, suffers an even grater reduction in volume. The loss of myofiber material was occurring preferentially at the fiber periphery. Thus, the oxidative capacity of muscle tissue is reduced both in relative and absolute terms. On the oxygen supply side, the capillary network seems spared from catabolism. This leads to a situation of an unchanged capillary network supplying a smaller muscle oxidative capacity. Acknowledgment

The authors express their sincere gratitude to L. TUscher, K. Babi, and B. Krieger for excellent technical assistance.

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crease of the absolute size of the capillary network upon return from the expeditions.

II. MorphologicalAdaptations of Human Skeletal Muscle to Chronic Hypoxia



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H. Hoppeler

Department of Anatomy BUhlstrasse 26

CH-30l2 Bern Switzerland

Heruntergeladen von: National University of Singapore. Urheberrechtlich geschützt.

Banchero N.: Long term adaptation of skeletal muscle capillarity.

fin. J. Sports Med. 11(1990) S9

Morphological adaptations of human skeletal muscle to chronic hypoxia.

Muscle structural changes during typical mountaineering expeditions to the Himalayas were assessed by taking muscle biopsies from 14 mountaineers befo...
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