Journal Logo


Muscle Protein Turnover and the Molecular Regulation of Muscle Mass during Hypoxia


Author Information
Medicine & Science in Sports & Exercise: July 2017 - Volume 49 - Issue 7 - p 1340-1350
doi: 10.1249/MSS.0000000000001228
  • Free


More than 140 million people live at altitudes of 2500 m above sea level and higher (35), and millions more visit high altitudes every year for recreation or work. Thus, research concerning human adaptations to acute hypoxia and altitude acclimatization has practical application for understanding the health of people living and sojourning above sea level. In general, the effects of acute hypoxia and altitude acclimatization are known, and it is generally well accepted that lowlanders sojourning at high altitude experience negative energy balance and the loss of both total body mass and fat-free mass. Less appreciated, however, are the mechanisms accounting for the loss of fat-free mass.

Body mass lost by lowlanders sojourning at high altitude reflects loss of total body water, body fat, and residual lean mass, primarily body protein and glycogen stores (47) (see Table 1). During the first few days at high altitude, diuresis is usually experienced, and respiratory- and sweating-associated water losses may be increased, all of which could contribute to reduced body water if water intake is not adequate (6,16); however, a reduction in total body water is not always observed during high-altitude sojourns (31,64). Losses of body fat and fat-free mass have been documented during high-altitude sojourns in people eating ad libitum (6,16,42,68), and it is widely presumed that negative energy balance is the principal cause of weight loss in lowlanders sojourning at high altitude. Anorexia is common among sojourning lowlanders (9), especially among those experiencing symptoms of altitude sickness, but appetite suppression can persist even after acclimatization alleviates these symptoms (63). In addition, food availability can be constrained while sojourning at high altitude in austere, real-world scenarios. Total daily energy expenditure usually increases during high-altitude sojourns, as lowlanders sojourning at high-altitude under real-world conditions typically engage in longer, more frequent, and more strenuous physical activities (e.g., trekking and climbing) over harsher terrain, steeper grades, and carrying heavier loads, compared with activities typically completed at sea level. In addition, basal metabolic rate increases during altitude sojourns, and the increase is most pronounced over the first 2–3 d after arrival (10,28) but remains higher than at sea level for at least 3 wk (10).

A summary of acute and chronic high altitude, body composition, and protein balance studies.

Negative energy balance may present a much greater challenge to skeletal muscle mass during sojourn at high altitude than at sea level. Interestingly, although fat-free mass accounts for approximately 25% of total body mass lost during energy deficits commonly used at sea level to induce weight loss, reports suggest that fat-free mass accounts for as much as 60%–70% of total body mass lost during high-altitude sojourns (74). Several studies have reported reductions in skeletal muscle cross-sectional area up to 25% with exposure to high altitude (33,48,53). In the Operation Everest II study (48), the 40-d simulated ascent to the summit of Mount Everest (8848 m) reduced type I and type II muscle fiber cross-sectional by 25% and 26%, respectively. Others have reported that in addition to reductions in muscle cross-sectional area, vastus lateralis muscle protein content was reduced by as much as 37% in response to 5 wk at altitudes at or above 5200 m (5). However, not all studies have reported reductions in skeletal muscle cross-sectional area with high-altitude exposure (18,26,38,45). It is likely that the discrepancies in muscle cross-sectional area responses to high altitude are because of differences in hypoxic exposure (17), diet, activity, sleep, and water metabolism across studies (30,41). It is also possible that the overall hypoxic dose, which takes into account both the elevation of exposure and the duration of exposure in hours (km·h−1 = (m/1000) × h), was insufficient in some studies (18,26,38) to elicit measurable changes in cross-sectional area (17). D'Hulst and Deldicque (17) recently suggested that, based on the hypoxic dose theory (25), an exposure of 5000 km·h−1 was the “cutoff” point above which muscle loss starts to occur, and studies that failed to observe decrements in fat-free mass did not achieve that hypoxic dose (3,21,29,38,40,65,68,70,73,76). However, not all studies that do report decrements in fat-free mass or cross-sectional area (or negative nitrogen balance) achieve the threshold suggested by D'Hulst and Deldicque (4,10,39,47,51,75,76). Therefore, the trigger for skeletal muscle loss during sojourns at high altitude may be more complex than only a function of elevation and time. Regardless, when fat-free mass is lost during sojourns at high altitude, the predominant source of that loss is myofibrillar protein (14,33), but how this occurs is largely unknown.

Thus, this review examines the physiological basis for disrupted skeletal muscle mass during acute and chronic hypoxia, and the mechanisms by which negative energy balance may modulate those effects and exacerbate loss of muscle mass in lowlanders sojourning at high altitude. Gaps in existing knowledge will be identified and future research directions, particularly the exploration of nutritional interventions to preserve muscle mass during energy deficit at high altitude, will be discussed.

Skeletal Muscle Protein Synthetic Response to High Altitude

Researchers have attempted to address whether the loss of muscle mass at high altitude is, in part, attributable to hypoxia and/or physical activity-induced changes in muscle protein synthesis. In one study (37), volunteers were randomly assigned to a passive (hypoxia alone) or active (physical activity and hypoxia) ascent group. Passive ascent volunteers were flown to 3480 m by helicopter, stayed overnight, and flown to 4559 m the following day. Active ascent volunteers traveled by cable car up to 3220 m, walked approximately 1.5 h up to 3611 m, where they stayed overnight, and then walked approximately 5 h up to 4559 m on the following day. Resting muscle protein synthesis was quantified once at sea level (normoxia) and 48 h after arriving at 4559 m. Urinary nitrogen and 3-methylhistidine excretion were measured as indices of whole-body and myofibrillar protein degradation. Low-altitude muscle protein synthesis (i.e., baseline) was the same between the passive and the active ascent groups; however, muscle protein synthesis increased above measures at low altitude in the active ascent group but not in those who passively ascended to high altitude. Urinary measures of whole-body and myofibrillar protein degradation were not different from sea level in either group. These findings suggest that acute high-altitude exposure itself has no measurable effect on muscle protein turnover, and that any change in protein turnover during sojourns to high altitude can be largely attributed to physical activity. The authors argue that because the increase in muscle protein synthesis observed in the active ascent group was lower than what others have reported after similar prolonged bouts of endurance exercise at sea level (66), the stimulation of protein synthesis after exercise was likely blunted by hypoxia. It is important to acknowledge that although this could be true, drawing conclusions by comparing muscle protein kinetic data from different studies is tenuous given the interindividual and interlaboratory (and study) variability in the measure (67).

The hypothesis that hypoxic stress leads to muscle being partially resistant to an anabolic stimulus is feasible and, if proven true with new research, could provide a mechanistic rationale that, in part, helps explain loss of fat-free mass during prolonged exposure to high altitude. The possibility that acute hypoxia elicits an anabolic resistance is also suggested by findings reported by Etheridge et al. (22), who studied resting and postresistance exercise myofibrillar protein synthesis after a 3.5-h normobaric hypoxia exposure (12% inspired O2 to achieve 80%–90% blood oxygen saturation, similar to exposure to 4300 m). The authors hypothesized that acute hypoxia would blunt muscle protein synthesis, particularly in response to resistance exercise. Their hypothesis was based partly on the observations of Preedy et al. (59), as well as results reported by Rennie et al. (60), both of whom observed marked reductions in protein turnover with hypoxia (~4300–4600 m), particularly during conditions causing negative net protein balance. In the Etheridge et al. (22) study, acute hypoxia (3.5 h) did not affect resting myofibrillar protein synthesis but attenuated myofibrillar protein synthetic responses to resistance exercise, the extent of which was predicted by peripheral oxygen desaturation. That myofibrillar protein synthesis was largely resistant to the anabolic stimulus of resistance exercise, and that this anabolic resistance was dependent on the severity of hypoxemia, supports the hypothesis suggested by Imoberdorf et al. (37) (i.e., hypoxia-dependent anabolic resistance) and suggests one potential mechanism by which skeletal muscle may be lost during sojourns at high altitude. Perhaps, under hypobaric hypoxic conditions, muscle is also resistant to other anabolic stimuli (e.g., protein/amino acids alone or combined with exercise) and more sensitive to conditions that downregulate muscle protein synthesis and, to a lesser extent, upregulate muscle proteolysis, such as negative energy balance. These factors could contribute to diminished muscle protein accretion and increased myofibrillar protein loss with hypoxia.

Holm et al. (32) sought to determine mechanisms by which fat-free mass is lost after a longer exposure (i.e., acclimatization) to high altitude by twice measuring resting whole-body protein turnover, myofibrillar and sarcoplasmic muscle protein synthesis: at sea level and 7–9 d after actively ascending to 4559 m. Sarcoplasmic protein synthesis rates did not change after 7–9 d of altitude exposure, whereas myofibrillar protein synthesis rates doubled. Whole-body protein breakdown increased, albeit only by 9%, after high-altitude exposure, but neither whole-body protein oxidation nor whole-body protein synthesis rates were affected by altitude. These data show that 7–9 d of high-altitude exposure upregulated contractile protein synthesis and whole-body protein breakdown, effects probably largely attributable to hypoxia rather than physical activity, since measurements occurred after 7–9 d of high-altitude acclimatization under highly controlled physical activity and dietary intake (i.e., matched activity and diet between sea level and altitude) to establish energy balance and maintain body weight (32).

To account for the loss of fat-free mass that often occurs during high-altitude exposure, Holm et al. (32) speculated that the increase in myofibrillar protein synthesis must be accompanied by an even greater increase in myofibrillar protein breakdown. The small increase in whole-body protein breakdown provides some support for that theory, yet measures of muscle protein breakdown were not performed. However, altitude exposure did not alter fat-free mass in the Holm et al. study, nor did altitude diminish myofibrillar actin concentrations, suggesting that the increase in muscle protein synthesis occurred with the same increase in muscle protein breakdown (72). The net effect in this scenario would favor conservation of skeletal muscle during high-altitude exposure in those that consumed sufficient food to maintain energy balance, regardless of any changes in myofibrillar protein turnover. However, maintaining energy balance is highly unlikely during high-altitude sojourns under nonresearch conditions, and no study to date has examined the effects of acute and chronic high-altitude exposure on muscle protein synthesis, breakdown, and whole-body protein balance at rest and in response to exercise while in a persistent state of negative energy balance. Therefore, studies examining acute and prolonged effects of hypoxia on integrated measures of skeletal muscle and whole-body protein turnover and the molecular regulation of muscle mass in response to a combination of physiologically relevant (i.e., real-world) exercise and nutritional stressors are needed.

The Molecular Regulation of Skeletal Muscle Protein Turnover at High Altitude

Any observed decrements in muscle mass relating to high-altitude exposure are inherently a result of cellular-level antianabolic and/or catabolic processes exceeding rates of synthesis. Hypoxia-inducible factor-1α (HIF-1α) is the central regulator of skeletal muscle adaptations to hypoxic stress and may modulate the mechanistic target of rapamycin (mTORC1) signaling and subsequent changes in muscle protein synthesis (1,11,34). In cell culture, hypoxia stabilizes the HIF-1α subunit, allowing for dimerization with HIF-1β and resultant transcriptional regulation (54). Hypoxia also results in an increase in human muscle mRNA expression of Regulated in Development and DNA Damage Responses 1 (REDD1), which is a negative regulator (i.e., inhibitor) of mTORC1 signaling (19). REDD1 competitively binds the tuberous sclerosis complex-2 (TSC2) inhibitor 14-3-3, thereby releasing TSC2, which allows it to slow mTORC1 activity (11,19,20,71). For example, REDD1 protein expression and TSC2 inhibitor coupling were significantly increased in soleus muscle of rats exposed to 3 wk of hypobaric hypoxia (6300 m), relative to pair-fed controls (23). The resulting TSC2 inhibition of mTORC1 signaling was illustrated by significant decreases in protein expression and phosphorylation/activation of Akt, mTOR, and ribosomal protein S6. These intracellular changes resulted in significant muscle loss in hypoxic rats, with ~60% of that loss independent of hypophagia. These findings are similar to those observed in hypoxemic chronic obstructive pulmonary disease (COPD; PaO2 < 60 mm Hg) patients (23). Akt and S6 phosphorylation status were markedly lower in hypoxemic COPD patients than in nonhypoxemic COPD counterparts. In addition, REDD1 coupling to the TSC2 inhibitor was higher in hypoxemic COPD patients relative to nonhypoxemic counterparts (23). Thus, hypoxia may allow for a net catabolism of muscle protein via HIF-1α-mediated increases in REDD1 inhibition of mTORC1 signaling and, ultimately, muscle protein synthesis.

Hypoxia may also inhibit muscle protein synthesis by mechanisms independent of HIF-1α-mediated dysregulation of mTORC1. Humans living at 4559 m for 7–9 d showed diminished mTOR protein expression relative to sea level, despite no change in HIF-1α protein levels (72). The phosphorylation state of the translation initiation factor eukaryotic initiation factor-2α (eIF2α) was also not affected by 7–9 d of high-altitude exposure in humans (72), although in cell culture models (43) hypoxia appears to modulate eIF2α activity via rapid phosphorylation (i.e., increased eIF2α phosphorylation inhibits muscle protein synthesis). It is possible that endoplasmic reticulum-related stress may be a significant contributor to the apparent HIF-1α-independent inhibition of mTORC1 signaling mediated by hypoxia-induced phosphorylation of the eIF2α kinase PERK. Cells expressing a dominant-negative PERK allele show diminished eIF2α phosphorylation and smaller reductions in muscle protein synthesis under hypoxic conditions (43).

Although the existing literature provides a general understanding of how hypoxia may alter the intracellular regulators of muscle mass, the specific mechanisms involved in this regulation may be affected differently depending on extent of hypoxia (i.e., the elevation), energy status, and physical activity. Studies with multiple measures across time and elevations (i.e., increasing doses of hypoxic exposure) could allow for the determination of both expression and activity changes in intracellular anabolic machinery. Researchers may also choose to focus on designing studies at physiologically relevant altitudes for populations most susceptible to muscle loss during sojourns at high altitude. For example, military service members operating in mountainous areas across the globe (~3000–5000 m) are likely to perform high levels of physical activity with limited access to food (49,50), while under severe psychological stress, during missions at high altitude, resulting in decrements in fat-free mass and performance. Such studies could provide valuable mechanistic data necessary to design targeted approaches to prevent muscle wasting and sustain performance in service members operating at high altitude.

Skeletal Muscle Proteolytic Responses to High Altitude

The fat-free mass loss that commonly occurs during high-altitude sojourns suggests that muscle proteolytic activity exceeds muscle protein synthesis. In laboratory animals exposed to hypobaric hypoxia (7620 m), Chaudhary et al. (14) observed that muscle protein breakdown increased in relation to the duration of exposure (3, 7, or 14 d), when compared with pair-fed, normoxic controls. More specifically, muscle proteolysis measured using tyrosine release increased 2.5-, 3-, and 5-fold in hind limb muscles after 3, 7, and 14 d of altitude exposure, respectively. Accordingly, the ratio of gastrocnemius muscle weight-to-tibial length decreased by 25% and 34% for 7 and 14 d of high altitude, respectively, with histological analysis showing greater muscle fiber atrophy (i.e., smaller fiber size and more space between fibers) as the duration of hypoxia exposure increased. The reduction in total protein content was more pronounced in the myofibrillar subfraction, with a 30% reduction after 14 d, compared with just a 7% reduction in the sarcoplasmic subfraction (14).

Chaudhary et al. (14) further illustrated elevated skeletal muscle proteolysis at the molecular level. In their experiments, ubiquitin proteasome proteolytic enzyme activities were fivefold higher in rats exposed to high altitude for 14 d, relative to normoxic controls. Calpain activity was also elevated threefold and acid phosphatase activity, an indicator of lysosomal activation, was 20% higher after 2 wk of high-altitude exposure (14). Similarly, μ-calpain protein expression was 2.7-fold higher and total protein ubiquitylation was fivefold higher after high-altitude exposure relative to normoxic controls. By contrast, Favier et al. (23) showed no changes in atrogin-1 or muscle ring finger 1 (MuRF1) mRNA expression, nor in levels of protein ubiquitylation, despite significantly lower muscle weight and fiber cross-sectional area in rats exposed to high altitude (6300 m) for 21 d. The activity of the 26S proteasome did not change with hypoxia exposure, nor did lysosomal enzyme activity or calpain protein expression (23).

It is well known that the relative hyper-metabolism of rodents can complicate the interpretation and extension of gene expression and enzymatic activity data derived from small animals to humans. Similarly, there are limited data demonstrating the effects of high-altitude exposure on human muscle-specific proteolysis. D'Hulst et al. (19) assessed the molecular regulation of muscle proteolysis in humans exposed to 4 h of normoxia and hypoxia (5000 m) using a randomized, crossover design. Muscle samples were taken 1 and 4 h after consuming a fixed breakfast meal in both conditions. Postprandial Bnip3 mRNA expression, representative of lysosomal activation, was not affected by either time or hypoxia, and cathepsin L and calpain activities were also not different between normoxic and hypoxic conditions (19). Interestingly, postprandial 26S proteasome activity increased 19% from 1 to 4 h during normoxia but was unchanged during hypoxic conditions. The phosphorylation of the transcription factors forkhead box O1/3a (FoxO1/3a) increased over time during normoxia but not during hypoxia. The phosphorylation of the FoxO transcription factors results in their sequestration in the cytoplasm, thereby preventing upregulated atrogene (e.g., muscle-specific ubiquitin ligases atrogin-1 and MuRF1 expression in the nucleus). Atrogin-1 mRNA levels did decrease over time, but more so during hypoxia, and MuRF1 expression actually increased over time, but only during hypoxia (19). These data are difficult to interpret because the measures were performed in the postprandial state, when levels of insulin, which downregulate proteolysis by activating the PI3K-Akt pathway (13), are not constant. Insulin concentrations decreased over time, but to a much greater extent during normoxia (19). The lower circulating insulin observed by D'Hulst et al. (19) during normoxia may partially explain the relative increase in cathepsin L and calpain activities and the smaller decrease in atrogin-1 mRNA expression for normoxia relative to hypoxia. It is important to recognize that assessment of muscle proteolytic activity via biopsy allows for illustration of changes at specific time points, which may not always accurately reflect temporal changes gene expression, enzyme activity, and protein breakdown occurring over time. Although the difficulties in assessing human muscle protein breakdown rates are well known, assessments of muscle proteolysis via stable isotope methods (i.e., flooding dose, oral deuterium oxide, tracee release, or pulse tracer injection) could broaden the examination window and limit the reliance snap-shot assessments of intramuscular proteolysis (56). This would provide an opportunity to better understand the meaningful changes, if any, in proteolysis during sojourns to high altitude.

Despite observations suggesting the ubiquitin proteasome system may not be uniformly activated by hypoxia, it remains an important regulator of the genotypic response to altitude (54). HIF acts as a transcriptional regulator during hypoxic conditions, creating expression patterns that allow for adaptation to an oxygen-depleted environment. HIF-1α is normally unstable under normoxic conditions, being targeted for degradation after oxygenation by prolyl-hydroxylase domain–containing protein 2 (PHD2) (8,54). The von Hippel–Lindau tumor suppressor protein binds to prolyl-hydroxylated HIF-1α, tagging the protein for ubiquitylation and subsequent proteasomal degradation (52,54,69). Hypoxia leads to diminished PHD2 activity, thereby increasing the life span of HIF-1α. This increased longevity allows for dimerization with HIF-1β, and increased transcriptional activation of hypoxia-related genes, which may ultimately mediate altitude-related changes in muscle protein synthesis and overall muscle mass.

Nutritional Approaches to Counteract High-Altitude Muscle Loss

Energy intake

Several nutritional strategies have been investigated to minimize the loss of body mass and fat-free mass of high-altitude sojourners. Butterfield et al. (10) showed that loss of body mass and fat-free mass can be significantly, but not completely, attenuated in sojourners at 4300 m by closely balancing energy intake with energy expenditure, thereby minimizing or eliminating negative energy and nitrogen balance. However, investigators in that study took meticulous care to monitor energy intake, physical activity, and changes in metabolic rate, making adjustments to the prescribed diet for each subject after 7 d at altitude to account for increases in basal metabolic rate and enforcing consumption of all study food to maintain energy balance. In another study, body mass loss was attenuated by increasing energy intake from 3340 kcal·d−1 at sea level to ~3600 kcal·d−1 during 21 d at high altitude (−0.8 ± 0.7 kg); however, a significant decrease in fat-free mass persisted (−1.4 ± 0.5 kg; +0.05 ± 0.8 kg fat mass) (3). Nevertheless, in nonresearch settings, high-altitude sojourners consuming a typical ad libitum diet are unlikely to achieve energy balance (9); therefore, investigators have explored other nutritional countermeasures to preserve fat-free mass during high-altitude sojourns.

Protein intake

A recent study by Wing-Gaia et al. (75) reported no differences in the loss of body mass or fat-free mass between mountaineers provided a leucine-enriched protein supplement and mountaineers provided an isocaloric, isonitrogenous placebo during a 13-d trek at high altitude in the Himalayas (range, 2810–5364 m). However, substantial subject attrition limited the resolution to detect body composition differences between groups in that study.

At sea level, our laboratory (57) and others (2) have studied the effects of manipulating dietary macronutrient distribution on changes in muscle protein turnover and fat-free mass resulting from negative energy balance (58). In our study, a 40% energy deficit for 21 d caused significantly less fat-free mass loss when the diet provided 1.6 or 2.4 g·kg−1·d−1 of protein, as compared with 0.8 g·kg−1·d−1 protein. During the energy deficit, subjects consuming the lower-protein diet also exhibited a blunted postprandial muscle protein synthesis response after consuming 20 g of milk protein as part of a mixed meal. By contrast, subjects consuming the moderate or high protein diets exhibited normal (i.e., the same as during energy balance) protein synthesis responses to the high-quality protein, as well as simultaneous attenuation of ubiquitin proteasome system-mediated muscle proteolysis (12). The observation that increasing dietary protein intake during negative energy balance can preserve muscle protein synthesis has since been confirmed by others (2). As discussed previously, acute high-altitude exposure may blunt postexercise muscle protein synthesis and chronic exposure to hypoxia appears to increase myofibrillar protein turnover during energy balance (14,32). This may occur with a concomitant increase in muscle proteolysis (14).

Higher protein diets have been used to promote weight loss at sea level due to, in part, the satiating effect of protein relative to carbohydrates (44). As such, higher protein intakes at higher elevations might exacerbate altitude-related anorexia and prove counterproductive to maintaining energy balance. Nevertheless, no study has determined the cumulative effects of exercise, dietary protein level, and sustained negative energy balance on fat-free mass and the mechanisms regulating muscle protein turnover at high altitude. There also is no evidence that directly supports the efficacy of consuming high protein diets for the preservation of fat-free mass during high-altitude sojourns. This unexplored area of nutrition, muscle, and environmental physiology warrants further study, especially considering the focus on metabolic advantages of dietary protein during negative energy balance (55).

Carbohydrate intake

Nutritional recommendations for high-altitude sojourns typically include advice to increase carbohydrate intake (>60% of energy) before and during ascent to maximize substrate availability, ensure adequate glycogen stores, and optimize performance (24). The basis for this recommendation is that individuals have an increased dependence on glucose as a fuel source at high altitude, especially during exercise (7,61,62). Glycogen depletion could, in part, explain the increase in protein degradation at high altitude. Howarth et al. (36) showed that glycogen depletion before endurance exercise at sea level can lead to increased protein breakdown and decreased muscle protein synthesis, likely because of a need for glucogenic amino acids as substrate for tricarboxylic acid cycle (TCA) cycle intermediates and a consequence of the concurrent reduction in circulating insulin concentrations.

A study by Macdonald et al. (47) failed to observe any significant difference in the loss of body mass and fat-free mass in two groups of people eating ad libitum and receiving either a carbohydrate supplement or a placebo during a 21-d trek at high altitude (5100 m) in the Himalayas, although the carbohydrate-supplemented group consumed 500–700 kcal·d−1 more than the placebo group. However, in both groups, an energy deficit persisted (−38.4 ± 19.7 at sea level vs −24.9 ± 11.8 kcal·kg−1·d−1 at high altitude) and dietary protein consumption fell below the recommended dietary allowance (0.7 ± 1.3 g·kg−1·d−1) during the high-altitude sojourn. Thus, whether increasing carbohydrate intake during negative energy balance at high altitude can mitigate losses of body mass and fat-free mass requires further study.


It is generally accepted that individuals will lose fat-free mass during sojourns to high altitude. Factors that contribute to fat-free mass decrements discussed in this review include hypoxia-induced anorexia, an elevated metabolic rate, and increased physical activity levels, which lead to a negative energy balance. Whether the total hypoxic dose (i.e., elevation–duration) also is an important factor contributing to the loss of functional muscle protein at high altitude requires further study. These factors do not explain the mechanisms by which hypoxia alters the regulation of muscle mass. There is some evidence to suggest that muscle protein synthesis is resistant to external anabolic stimuli during acute hypoxia exposure. Under basal conditions, acute exposure has no effect on muscle protein synthesis. However, with acclimatization the opposite occurs, and myofibrillar protein turnover may double, which could elicit a net catabolic state if energy balance is not achieved. The catabolic response to hypoxia is likely mediated, in part, by an upregulation in intramuscular proteolysis and dysregulation of anabolic signaling resulting from both HIF-1α-dependent and -independent mechanisms. Future studies are needed to evaluate the efficacy of dietary manipulation during negative energy balance on muscle protein turnover and fat-free mass during sojourns to high altitude.

The authors thank Dr. Scott J Montain for his critical review of this manuscript.

This work was supported by the U.S. Army Medical Research and Materiel Command.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. Any citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement of approval of the products or services of these organizations. The results of the studies referenced in this review are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The authors have conflicts of interest to declare.


1. Ameln H, Gustafsson T, Sundberg CJ, et al. Physiological activation of hypoxia inducible factor-1 in human skeletal muscle. FASEB J. 2005;19(8):1009–11.
2. Areta JL, Burke LM, Camera DM, et al. Reduced resting skeletal muscle protein synthesis is rescued by resistance exercise and protein ingestion following short-term energy deficit. Am J Physiol Endocrinol Metab. 2014;306(8):E989–97.
3. Barnholt KE, Hoffman AR, Rock PB, et al. Endocrine responses to acute and chronic high-altitude exposure (4,300 meters): modulating effects of caloric restriction. Am J Physiol Endocrinol Metab. 2006;290(6):E1078–88.
4. Bharadwaj H, Malhotra MS. Body composition changes after 4 week acclimatization to high altitude: anthropometric and roentgenogrammetric evaluation. Z Morphol Anthropol. 1974;65(3):285–92.
5. Boutellier U, Howald H, di Prampero PE, Giezendanner D, Cerretelli P. Human muscle adaptations to chronic hypoxia. Prog Clin Biol Res. 1983;136:273–85.
6. Boyer SJ, Blume FD. Weight loss and changes in body composition at high altitude. J Appl Physiol Respir Environ Exerc Physiol. 1984;57(5):1580–5.
7. Brooks GA, Butterfield GE, Wolfe RR, et al. Increased dependence on blood glucose after acclimatization to 4,300 m. J Appl Physiol (1985). 1991;70(2):919–27.
8. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–40.
9. Butterfield GE. Nutrient requirements at high altitude. Clin Sports Med. 1999;18(3):607–21, viii.
10. Butterfield GE, Gates J, Fleming S, Brooks GA, Sutton JR, Reeves JT. Increased energy intake minimizes weight loss in men at high altitude. J Appl Physiol (1985). 1992;72(5):1741–8.
11. Cam H, Easton JB, High A, Houghton PJ. mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol Cell. 2010;40(4):509–20.
12. Carbone JW, Margolis LM, McClung JP, et al. Effects of energy deficit, dietary protein, and feeding on intracellular regulators of skeletal muscle proteolysis. FASEB J. 2013;27(12): 5104–11.
13. Carbone JW, McClung JP, Pasiakos SM. Skeletal muscle responses to negative energy balance: effects of dietary protein. Adv Nutr. 2012;3(2):119–26.
14. Chaudhary P, Suryakumar G, Prasad R, Singh SN, Ali S, Ilavazhagan G. Chronic hypobaric hypoxia mediated skeletal muscle atrophy: role of ubiquitin–proteasome pathway and calpains. Mol Cell Biochem. 2012;364(1–2):101–13.
15. Consolazio CF, Johnson HL, Krzywicki HJ, Daws TA. Metabolic aspects of acute altitude exposure (4,300 meters) in adequately nourished humans. Am J Clin Nutr. 1972;25(1):23–9.
16. Consolazio CF, Matoush LO, Johnson HL, Krzywicki HJ, Isaac GJ, Witt NF. Metabolic aspects of calorie restriction: hypohydration effects on body weight and blood parameters. Am J Clin Nutr. 1968;21(8):793–802.
17. D'Hulst G, Deldicque L. Human skeletal muscle wasting in hypoxia: a matter of hypoxic dose? J Appl Physiol. 2017;122(2):406–8.
18. D'Hulst G, Ferri A, Naslain D, et al. Fifteen days of 3,200 m simulated hypoxia marginally regulates markers for protein synthesis and degradation in human skeletal muscle. Hypoxia. 2016;4:1–14.
19. D'Hulst G, Jamart C, Van Thienen R, Hespel P, Francaux M, Deldicque L. Effect of acute environmental hypoxia on protein metabolism in human skeletal muscle. Acta Physiol (Oxf). 2013;208(3):251–64.
20. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008;22(2):239–51.
21. Ermolao A, Bergamin M, Rossi AC, Dalle Carbonare L, Zaccaria M. Cardiopulmonary response and body composition changes after prolonged high altitude exposure in women. High Alt Med Biol. 2011;12(4):357–69.
22. Etheridge T, Atherton PJ, Wilkinson D, et al. Effects of hypoxia on muscle protein synthesis and anabolic signaling at rest and in response to acute resistance exercise. Am J Physiol Endocrinol Metab. 2011;301(4):E697–702.
23. Favier FB, Costes F, Defour A, et al. Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia. Am J Physiol Regul Integr Comp Physiol. 2010;298(6):R1659–66.
24. Friedlander AL, Braun B, Marquez J. Making molehills out of mountains: maintaining high performance at altitude. ACSM Health Fitness J. 2008;12(6):15–21.
25. Garvican-Lewis LA, Sharpe K, Gore CJ. Time for a new metric for hypoxic dose? J Appl Physiol. 2016;121(1):352–5.
26. Green H, Roy B, Grant S, et al. Downregulation in muscle Na(+)-K(+)-ATPase following a 21-day expedition to 6,194 m. J Appl Physiol. 2000;88(2):634–40.
27. Green HJ, Sutton JR, Cymerman A, Young PM, Houston CS. Operation Everest II: adaptations in human skeletal muscle. J Appl Physiol. 1989;66(5):2454–61.
28. Grover RF. Basal oxygen uptake of man at high altitude. J Appl Physiol. 1963;18:909–12.
29. Guilland JC, Klepping J. Nutritional alterations at high altitude in man. Eur J Appl Physiol Occup Physiol. 1985;54(5):517–23.
30. Hamad N, Travis SP. Weight loss at high altitude: pathophysiology and practical implications. Eur J Gastroenterol Hepatol. 2006;18(1):5–10.
31. Hannon JP, Chinn KS, Shields JL. Effects of acute high-altitude exposure on body fluids. Fed Proc. 1969;28(3):1178–84.
32. Holm L, Haslund ML, Robach P, et al. Skeletal muscle myofibrillar and sarcoplasmic protein synthesis rates are affected differently by altitude-induced hypoxia in native lowlanders. PLoS One. 2010;5(12):e15606.
33. Hoppeler H, Kleinert E, Schlegel C, et al. Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 1990;11(1 Suppl):S3–9.
34. Hoppeler H, Vogt M. Muscle tissue adaptations to hypoxia. J Exp Biol. 2001;204(Pt 18):3133–9.
35. Hornbein TF, Schoene RB. An Exploration of Human Adaptation. 1st ed. Boca Raton (FL): CRC Press; 2001. pp. 968.
36. Howarth KR, Phillips SM, MacDonald MJ, Richards D, Moreau NA, Gibala MJ. Effect of glycogen availability on human skeletal muscle protein turnover during exercise and recovery. J Appl Physiol (1985). 2010;109(2):431–8.
37. Imoberdorf R, Garlick PJ, McNurlan MA, et al. Skeletal muscle protein synthesis after active or passive ascent to high altitude. Med Sci Sports Exerc. 2006;38(6):1082–7.
38. Jacobs RA, Lundby AK, Fenk S, et al. Twenty-eight days of exposure to 3454 m increases mitochondrial volume density in human skeletal muscle. J Physiol. 2016;594(5):1151–66.
39. Johnson HL, Consolazio CF, Matoush LO, Krzywicki HJ. Nitrogen and mineral metabolism at altitude. Fed Proc. 1969;28(3):1195–8.
40. Kasprzak Z, Śliwicka E, Hennig K, Pilaczyńska-Szcześniak Ł, Huta-Osiecka A, Nowak A. Vitamin D, iron metabolism, and diet in alpinists during a 2-week high-altitude climb. High Alt Med Biol. 2015;16(3):230–5.
41. Kayser B. Nutrition and high altitude exposure. Int J Sports Med. 1992;13(1 Suppl):S129–32.
42. Kayser B, Acheson K, Decombaz J, Fern E, Cerretelli P. Protein absorption and energy digestibility at high altitude. J Appl Physiol (1985). 1992;73(6):2425–31.
43. Koumenis C, Naczki C, Koritzinsky M, et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol. 2002;22(21):7405–16.
44. Leidy HJ, Clifton PM, Astrup A, et al. The role of protein in weight loss and maintenance. Am J Clin Nutr. 2015;101(6):1320S–9.
45. Levett DZ, Radford EJ, Menassa DA, et al. Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J. 2012;26(4):1431–41.
46. Lundby C, Pilegaard H, Andersen JL, van Hall G, Sander M, Calbet JA. Acclimatization to 4100 m does not change capillary density or mRNA expression of potential angiogenesis regulatory factors in human skeletal muscle. J Exp Biol. 2004;207(22):3865–71.
47. Macdonald JH, Oliver SJ, Hillyer K, et al. Body composition at high altitude: a randomized placebo-controlled trial of dietary carbohydrate supplementation. Am J Clin Nutr. 2009;90(5):1193–202.
48. MacDougall JD, Green HJ, Sutton JR, et al. Operation Everest II: structural adaptations in skeletal muscle in response to extreme simulated altitude. Acta Physiol Scand. 1991;142(3):421–7.
49. Margolis LM, Murphy NE, Martini S, et al. Effects of supplemental energy on protein balance during 4-d arctic military training. Med Sci Sports Exerc. 2016;48(8):1604–12.
50. Margolis LM, Murphy NE, Martini S, et al. Effects of winter military training on energy balance, whole-body protein balance, muscle damage, soreness, and physical performance. Appl Physiol Nutr Metab. 2014;39(12):1395–401.
51. Mawson JT, Braun B, Rock PB, Moore LG, Mazzeo R, Butterfield GE. Women at altitude: energy requirement at 4,300 m. J Appl Physiol (1985). 2000;88(1):272–81.
52. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.
53. Mizuno M, Savard GK, Areskog NH, Lundby C, Saltin B. Skeletal muscle adaptations to prolonged exposure to extreme altitude: a role of physical activity? High Alt Med Biol. 2008;9(4):311–7.
54. Palmer BF, Clegg DJ. Ascent to altitude as a weight loss method: the good and bad of hypoxia inducible factor activation. Obesity (Silver Spring). 2014;22(2):311–7.
55. Pasiakos SM. Metabolic advantages of higher protein diets and benefits of dairy foods on weight management, glycemic regulation, and bone. J Food Sci. 2015;80(1 Suppl):A2–7.
56. Pasiakos SM, Carbone JW. Assessment of skeletal muscle proteolysis and the regulatory response to nutrition and exercise. IUBMB Life. 2014;66(7):478–84.
57. Pasiakos SM, Margolis LM, McClung JP, et al. Whole-body protein turnover response to short-term high-protein diets during weight loss: a randomized controlled trial. Int J Obes (Lond). 2014;38(7):1015–8.
58. Pasiakos SM, Vislocky LM, Carbone JW, et al. Acute energy deprivation affects skeletal muscle protein synthesis and associated intracellular signaling proteins in physically active adults. J Nutr. 2010;140(4):745–51.
59. Preedy VR, Smith DM, Sugden PH. The effects of 6 hours of hypoxia on protein synthesis in rat tissues in vivo and in vitro. Biochem J. 1985;228(1):179–85.
60. Rennie MJ, Babij P, Sutton JR, et al. Effects of acute hypoxia on forearm leucine metabolism. Prog Clin Biol Res. 1983;136:317–23.
61. Roberts AC, Butterfield GE, Cymerman A, Reeves JT, Wolfel EE, Brooks GA. Acclimatization to 4,300-m altitude decreases reliance on fat as a substrate. J Appl Physiol (1985). 1996;81(4):1762–71.
62. Roberts AC, Reeves JT, Butterfield GE, et al. Altitude and beta-blockade augment glucose utilization during submaximal exercise. J Appl Physiol (1985). 1996;80(2):605–15.
63. Rose MS, Houston CS, Fulco CS, Coates G, Sutton JR, Cymerman A. Operation Everest. II: nutrition and body composition. J Appl Physiol (1985). 1988;65(6):2545–51.
64. Sawka MN, Young AJ, Rock PB, et al. Altitude acclimatization and blood volume: effects of exogenous erythrocyte volume expansion. J Appl Physiol (1985). 1996;81(2):636–42.
65. Schena F, Guerrini F, Tregnaghi P, Kayser B. Branched-chain amino acid supplementation during trekking at high altitude. The effects on loss of body mass, body composition, and muscle power. Eur J Appl Physiol Occup Physiol. 1992;65(5):394–8.
66. Sheffield-Moore M, Yeckel CW, Volpi E, et al. Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise. Am J Physiol Endocrinol Metab. 2004;287(3):E513–22.
67. Smith GI, Patterson BW, Mittendorfer B. Human muscle protein turnover—why is it so variable? J Appl Physiol. 2011;110(2):480–91.
68. Surks MI, Chinn KS, Matoush LR. Alterations in body composition in man after acute exposure to high altitude. J Appl Physiol. 1966;21(6):1741–6.
69. Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel–Lindau tumor suppressor protein. EMBO J. 2000;19(16):4298–309.
70. Tanner DA, Stager JM. Partitioned weight loss and body composition changes during a mountaineering expedition: a field study. Wilderness Environ Med. 1998;9(3):143–52.
71. Vadysirisack DD, Ellisen LW. mTOR activity under hypoxia. Methods Mol Biol. 2012;821:45–58.
72. Viganò A, Ripamonti M, De Palma S, et al. Proteins modulation in human skeletal muscle in the early phase of adaptation to hypobaric hypoxia. Proteomics. 2008;8(22):4668–79.
73. Westerterp KR, Kayser B, Wouters L, Le Trong JL, Richalet JP. Energy balance at high altitude of 6,542 m. J Appl Physiol (1985). 1994;77(2):862–6.
74. Wing-Gaia SL. Nutritional strategies for the preservation of fat free mass at high altitude. Nutrients. 2014;6(2):665–81.
75. Wing-Gaia SL, Gershenoff DC, Drummond MJ, Askew EW. Effect of leucine supplementation on fat free mass with prolonged hypoxic exposure during a 13-day trek to Everest Base Camp: a double-blind randomized study. Appl Physiol Nutr Metab. 2014;39(3):318–23.
76. Zaccagni L, Barbieri D, Cogo A, Gualdi-Russo E. Anthropometric and body composition changes during expeditions at high altitude. High Alt Med Biol. 2014;15(2):176–82.


© 2017 American College of Sports Medicine