Acta

Physiol Scand 1991, 142, 421427

Operation Everest II : structural adaptations in skeletal muscle in response t o extreme simulated altitude J. D. M A c D O U G A L L ~H. , J. GREEN?, J. R. SUTTON*, G. COATESX, A. CYMERMANS, P. YOUNG$, and C. S. HO US T O N § Departments of Physical Education and Medicine, McMaster University, Hamilton, Ontario; Department of Kinesiology, University of Waterloo, Waterloo, Ontario and ; $ Altitude Research Division, Department of the Army, U S . Army Research Institute of Environmental Medicine, Natick, Massachusetts

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MACDOUGALL, J.D., GREEN, H.J., SUTTON, J.R., COATES, G., CYMERMAN, A,, YOUNG, C.S. 1991. Operation Everest 11: structural adaptations in skeletal P. & HOUSTON, muscle in response to extreme simulated altitude. Acta Physiol Scund 142, 421-427. Received 18 September 1990 accepted 6 December 1990. ISSN 00014772. Departments of Physical Education and Medicine, McMaster University, Hamilton, Ontario, Canada. Alterations in skeletal muscle structure were investigated in 6 male subjects who underwent 40 days of progressive decompression in a hypobaric chamber simulating an ascent to the summit of Mount Everest. Needle biopsies were obtained from vastus lateralis of 5 subjects before and immediately after confinement in the chamber, and were examined for various structural and ultrastructural parameters. In addition, total muscle area was calculated in 6 subjects from C T scans of the thighs and upper arms. Muscle area at these sites was found to decrease significantly (by 13 and 15%) as a result of the hypobaric confinement. This was substantiated by significant (25 %) decreases in cross sectional fibre areas of the Type I fibres and 26% decreases (non significant) in Type I1 fibre area. Capillary to fibre ratios remained unchanged following hypoxia as did capillary density although there was a trend (non significant) towards an increase in capillary density. There were no significant increases in mitochondrial volume density or other morphometric parameters. These data indicate that chronic, severe hypoxia on its own does not result in an increase in absolute muscle capillary number or a de nova synthesis of mitochondria. The trends toward an increase in capillary density and mitochondrial volume density were interpreted as being secondary occurrences in response to the pronounced muscle atrophy which occurred. Key words : capillarization, hypobaric hypoxia, muscle ultrastructure.

INTRODUCTION

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T h e progressive decline in and physical work capacity which occurs with ascent to increasing altitudes is well known and documented (Buskirk et al. 1967, Saltin et al. 1968, West et al. 1983). It is also known that, at a given altitude, these changes can be modified by Correspondence : Dr. J.D. MacDougall, Department of Physical Education, McMaster University, Hamilton, Ontario, L8S 4K1, Canada.

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acclimatization. For example, following 10 or more days of exposure to moderate altitude, a significant improvement is found in physical work capacity (Billings et al. 1971, Maher et al. 1974) and a reduction in plasma lactate accumulation is observed when subjects exercise at the same power output (Maher et a/. 1974). There is, however, little or no change in VO~,,,, over this time (Adams et al. 1975, Saltin et al. 1968). This disproportionately large increase in work capacity and apparent decrease in. lactate production, despite minimal change in V O ~ , , ~ ~ ,

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is commonly interpreted as evidence of adaptation having occurred at the muscle level, as opposed to evidence of improved oxygen delivery. Theoretically a number of adaptations could occur at the tissue level which might improve 0, utilization and exercise capacity in conditions of chronic hypoxia. Among these would be: an increase in muscle capillarity; an increased mitochondria1 volume fraction within the fibre and an increase in myoglobin concentration. While each of these adaptations has been documented in earlier studies using animal models (Yaldiva, 1958, Reynafarje, 1962, Ou & Tenny 1970), they have been questioned by more recent investigation (Sillau et al. 1980) and generally have not been substantiated in humans exposed to moderate altitude (Boutellier et al. 1983, Mizuno et a / . 1985, Terrados et al. 1985). Interpretation of data from human subjects is often more difficult because of wide variations in the degree of hypoxia and the duration of the exposure. Moreover, when such data are collected during climbing expeditions, interpretation may be further complicated by variations in exercise patterns, hypothermia, hydration and nutritional status which usually accompany such ventures. T h i s paper will examine the structural adaptations in human skeletal muscle to severe progressive chronic hypoxia in a controlled environment achieved by a large 'live-in ' hypobaric chamber.

MATERIALS A N D IIETHODS The data presented in this paper were collected as part of the Operation Everest I1 project conducted at the US Army Research institute of Environmental hledicine in Natick MA In this stud!, subjects experienced SO00

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progressive gradual decompression over 40 days to a final inspired oxygen tension (Pro,) of 43 Torr as would simulate an ascent to the summit of Mt Everest. Details of the chamber, project design, ascent profile and characteristics of the volunteer subjects have been previously published (Houston et al. 1987). The study was conducted according to the ethical approval of the Research Advisory Group of XWMaster University and the Human Use Review Committee at the US Army Research Institute of Environmental Medicine. During their confinement in the chamber, subjects were exposed to a Pro, of 80 Torr and lower for at least 30 days ; a Pio, of 73 Torr and lower for at least 25 days; a Pro, of 63 Torr and lower for at least 15 days and a Pio, of 49 T o n and lower for at least 10 days (Fig. 1). In addition subjects w r e taken to a Pro, of 43 Torr on several occasions over the final 10-day period for short durations of usually less than 2 h. At night the chamber pressure was increased to give a P I O , of 55 Torr to enable subjects to sleep. Using the Bergstrom technique (1962) needle biopsies were obtained from the vastus lateralis of 5 healthy male subjects (21-31 years) before and immediately after 40 days in the hypobaric chamber and at several points between (Green et al. 1989). The structural data presented in this paper are confined to the tissue taken during the resting state before and after completion of the study. Tissue samples were divided into a portion to be utilized for histochemical analysis and a portion for electron microscopy. Tissue for electron microscopy was immediately fixed in 2 oo glutaraldehyde, washed in 0.2 M cacodylate buffer, post-fixed in osmium tetroxide, dried in ethanol and imbedded in epoxyresin. Serial ultrathin sections were then made at a slightlv oblique (75") angle to the fibres and mounted on copper/rhodian grids. These sections were photographed at approximately 50000 x magnification under a Philips EIL1200. Where possible, 4&60 fibres were randomly selected per biopsy and for each, a photographic field for the interior of each fibre was randomly selected and photographed. In situations where samples were too small to permit random selection of fibres, it was necessary to photograph all available fibres. Stereological analysis was performed on each micrograph by means of a 168-point short line test system (Weibel, 1979) according to the method as previously described by Hoppeler and colleagues (1973). An average of 42 fibres (R, 27-60) were analyzed per biopsy and volume densities calculated for myofibrils ( V,.m).uf), interior mitochondria ( V,,,,), lipid and cytoplasm (V,.cyt). Tissue for histochemical analysis was mounted in embedding medium and frozen in isopentane cooled in liquid nitrogen. Cryostat sections were mounted onto glass slides which then underwent preparations to be utilized for determination of: fibre type, fibre

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Structural adaptations to hypoxia area, and muscle capillarization. Sections stained for NADH-TR were used for calculations of fibre area, with differentiation being made according to the pH lability of myofibrillar ATPase. Cross-sectional fibre area was determined by planimeter, by measuring an average of 122 Type I fibres and 112 Type I1 fibres per biopsy. For capillary identification, 16 pm sections were stained by the periodic acid Schiff procedure, following partial digestion with amylase. Muscle capillarization was then calculated from projected photographs of the PAS stained tissue and expressed as capillaries in contact with each fibre, capillaries relative to fibre area and capillaries per mm2 of muscle tissue. Further details of the histochemical preparation techniques appear elsewhere (Green et al. 1989). In one subject, there was not adequate tissue in the post study sample for ultrastructural analysis, so tissue from the resting biopsy at day 33 of exposure was utilized as representing his post exposure sample. This was also the case for 2 subjects for histochemical analysis. Changes in total muscle area (and, presumably, volume) were assessed in 6 subjects by computerized tomography of the upper arms and thighs before beginning decompression and within 4 h after emerging from the chamber. Five 1 cm thick slices were scanned in each limb. The centre slice in the thigh was positioned mid point between the tibiale and anterior superior iliac crest. The centre slice in the upper arm was positioned 60% of the distance down from the acromium to the medial condyle of the humerus. These regions are the thickest parts of the thigh and upper arm respectively. The total cross sectional areas for bone, muscle and subcutaneous fat were obtained from each slice with a planimeter interfaced to an IBM PC computer. T o correct for any changes in magnifications of the C T scanner between studies, the area of fat and muscle in each slice was divided by the area of bone to obtain a muscle/bone and fat/bone ratio. It was assumed that any changes in these values would reflect changes in muscle and fat since a change in humerus and femur diameter was considered unlikely during the 42 days between measurements. The data from all 10 slices from both limbs was pooled for each individual to obtain a mean muscle/ bone and fat/bone ratio. Statistical analysis was performed by analysis of variance and Student t test in order to assess differences between the pre and post hypoxia conditions. In all cases a 95% level of confidence was chosen as denoting statistical significance.

RESULTS Muscle volume. All subjects displayed a decrease in total muscle volume of the upper arm and thigh. T h e magnitude of this change was approximately 13% in the arms and 15% in

thighs (Fig. 2 ) and was statistically significant (P > 0.002) for both sites. I n addition, subcutaneous fat volume was decreased by approximately 12% in the arms and thighs, but the change was only significant (P > 0.05) for the arm measurement. Further details of changes in body composition have been published elsewhere (Rose et al. 1988). Fibre areas and capillarazataon. Fibre type distribution (49f4y0 Type I, pre hypoxia) was unchanged (51 f6% Type I, post-hypoxia). T h e effects of the hypoxic confinement on fibre area and capillarization have also been summarized in a previous paper (Green et al. 1989) but have been included in greater detail in the present paper (Table 1) because of their implications to the alterations in muscle ultrastructure. Following the hypoxic exposure, mean fibre area of the T y p e I fibres decreased by approximately 25% and mean fibre area of the T y p e I1 fibres decreased by approximately 26 yo. T h e change in type I area was statistically significant (P > 0.05) but that for the T y p e I1 fibres was not. T h e number of capillaries in contact per fibre and the capillary to fibre ratio did not change as a result of the hypoxic exposure (Table 1). When the number of capillaries per fibre was expressed relative to muscle fibre area, however, the post hypoxia sample indicated a 19 yoincrease for the T y p e I fibres and a 20% increase for the T y p e I1 fibres. Again these changes were only significant for the T y p e I fibres. When capillary density was expressed as the number of capillaries per m m 2 it was approximately 9% greater following hypoxia but this difference was not statistically significant.

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J. D.MacDougall et ai. Muscle ultrastructure. Muscle ultrastructure components are summarized in Table 2. The hypoxic condition resulted in an 8% increase in mitochondria density and a 14% increase in the mitochondria to myofibrillar volume density ratio, however, neither change was statistically significant. Values for myofibrillar, lipid and cytoplasm volume density remained remarkably consistent following hypoxia. DISCUSSION

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Muscle area. The 13 and 15% decrease in total muscle cross sectional area of the arms and thighs, respectively, was consistent with the 9% decline in body weight, as previously reported (Rose et al. 1988) and suggests that loss of muscle mass was largely responsible for this change in body weight. Loss of weight and muscle size is a common complaint of high altitude climbers (Pugh & Ward 1956) and is sometimes attributed to a decreased appetite and difficulty of preparing adequate or palatable food under such conditions. In the present study, subjects had free access to excellent, nutritionally balanced and varied food, yet all experienced a loss in appetite with advanced decompression. Mean caloric intake decreased by 42% from approximately 3 100 kcal day-' to approximately 1800 kcal day-' at 282 Torr (Rose et al. 1988). Despite this, the extent to which the subjects may have been in negative caloric balance is questionable since there was also a progressive decline in daily exercise time and estimated energy expenditure as the study progressed (Rose et al. 1988). Thus, while it is possible that some of the loss in lean tissue may have been the result of a negative caloric balance-protein catabolic state, we do not consider this to be the major factor since weight loss considerably exceeded that which could be accounted for by comparisons of caloric intake to energy expenditure (Rose et al. 1988). Two other possibilities remain : (1) that the loss in muscle was simply caused by disuseatrophy due to reduced physical activity with chamber confinement; or (2) that the protein cataboiic/anabolic processes were affected by hypoxia and that the atrophy which we found does indeed represent an adaptive response. In the present study it is difficult to disassociate the two. While subjects were encouraged to attempt to

425

Structural adaptations to hypoxia

Table 2. Muscle morphometry before and after severe chronic hypoxia. Data are given for volume density of myofibrils ( Vvmyuf), mitochondria (~,,,,), lipid (b&) and cytoplasm ( V\crt)

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maintain their normal sea-level exercise patterns using a treadmill or cycle ergometer, total daily exercise time decreased dramatically with decompression below 350 Torr (Rose et al. 1988). It is thus probable that the progressive decrease in daily exercise in a previously very physically active group of subjects (Houston et al. 1987) contributed, in part, to a loss in muscle size over the duration of the experiment. The magnitude of the decrease in fibre areas, however, is considerably greater than what one would expect to see with deconditioning, and resembles that which one finds following a similar period of joint immobilization (MacDougall et al. 1980). Moreover, since subjects had been previously active in cycling or running, our finding that similar decreases in total muscle size occurred in the arms, as well as the legs, suggests a more generalized response which may have been only minimally related to their reduced physical activity. The mechanism(s) by which chronic hypoxia might result in muscle atrophy cannot be determined from the present study. It has been shown, however, that acute hypoxia suppresses the rate of protein synthesis in skeletal muscle, resulting in a net loss of amino acids (Rennie et al. 1983), which over time could cause muscle wasting. Further detailed studies of protein synthesis under conditions of chronic hypoxia need to be performed in order to investigate this possibility. Musclejbre area. The 25 and 26% decrease in cross section fibre area found in Type I and Type I1 fibres (Table 1) is consistent with, but considerably exceeds the change in total muscle

area noted from the C T scans. We have no single explanation for this discrepancy, although it may reflect a greater relative atrophy of vastus lateralis (compared to other thigh muscles). Although the 26y0 decrease in Type I1 fibre area was not statistically significant, possibly due to the small number of subjects, we think it reasonable to assume that atrophy occurred in these fibres as was the case for the Type I fibres. Capillarization. An increase in muscle capillary density is generally accepted as occurring in humans in response to physical training (Anderson, '975, Brodal et al. 1977). Such an adaptation could be expected to facilitate 0, diffusion by reducing the diffusion distance between the capillary and the cell and, during exercise, by delaying muscle transit time for the same total flow (Saltin 1985). For these reasons, an increase in muscle vascularity, such as occurs due to physical training, should constitute a neaningful adaptive response to chronic hypoxia. Whether or not chronic hypoxia, without an additional exercise stimulus, stimulates increased capillarity remains controversial. Earlier reports of increased capillary proliferation in skeletal muscle of guinea pigs exposed to chronic hypoxia (Valdivia 1958, Cassin et al. 1971) have been criticized by Sillau and co-workers (1980) on the grounds that these studies did not control for the change in capillary density which accompanies normal growth. A recent review of the physiological characteristics of world-class high-altitude climbers (Oelz et al. 1986) notes higher than normal muscle capillary densities, but it is unknown whether this adaptation may be due to hypoxia or to physical training.

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I n the present study, our findings that no change occurred in capillary contact per fibre or capillary/fibre ratio (Table 1) following hypoxia, indicates no synthesis of new capillaries. On the other hand, the decrease in muscle fibre area resulted in a trend towards an increase in capillary density. Again, while such changes did not achieve statistical significance (possibly due to sample size) they may have considerable biological significance. Muscle morphometry. Morphometric characteristics of vastus lateralis (Table 2) before decompression are consistent u-ith those found in health! but untrained subjects (Howald 1982, Hoppeler 1986). T h e 4.90n volume density for interfibrillar mitochondria is similar to the 4.2 O o yalue found in elite climbers by Oelz and coworkers (1986) but is considerably less than that found in endurance-trained athletes (Hoppeler 1986, Alvr-ay et al. 1988). Since an increased mitochondrial fraction would result in a decreased diffusion distance for 0, from cell membrane to mitochondria, such an adaptation would be beneficial in an hypoxic condition. I n the present study it is apparent, however, that chronic severe hypoxia was not a stimulus for the increased synthesis of new mitochondria. Our finding that mitochondrial volume density and the mitochondrial to myofibrillar volume ratio tended to increase only slightly (by 8 and 14”, respectively) while muscle fibre area decreased by approximately 25 O n indicate that the absolute number of mitochondria did not increase, but may even have decreased slightly in response to severe hypoxia. I t thus appears that chronic severe hypoxia, on its own, results in minimal structural adaptation in human skeletal muscle. T h i s finding is not surprising when one considers that skeletal muscle may be very resistant to hypoxia, with mitochondria able to function during exercise at Po2’sas 10%- as 2 T o r r (Gayeski et a / . 1985). It is conceivable that, in the resting state at least, the hypoxia imposed by decompression could have been offset by autoregulated increases in flow, thus minimizing the stimulus for an adaptive response. Whether or not hypoxia in combination with exercise results in a greater stimulus for enzymatic and structural adaptation than occurs with exercise in normoxia (Terrados et al. 1990) remains controversial. In summary, we conclude that chronic severe hypoxia does not result in a net increased

synthesis of capillaries or mitochondria. Slight increases in muscle concentration of these structures may occur, however, as a result of the muscle atrophy which appears to be mediated by se\-ere hypoxia. This paper is one of a series entitled ‘Operation Everest I1 ’, describing a project which was sponsored by the Arctic Institute of North America and U.S. -4rmy Research Institute of Environmental Medicine and funded by the U.S. Army Research and Derelopment Command (Contract N o . DAMD1785-(305206). Principal investigators were Charles S. Houston, John R. Sutton and Allen Cymerman. The ultrastructural portion of this study was supported by the Natural Sciences and Engineering Research Council of Canada.

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Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude.

Alterations in skeletal muscle structure were investigated in 6 male subjects who underwent 40 days of progressive decompression in a hypobaric chambe...
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