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Respiratory System Illness and Hypoxia

  • Manuela BartesaghiEmail author
  • Giuseppe Miserocchi
Chapter
Part of the Sports and Traumatology book series (SPORTS)

Abstract

Exposure to hypobaric hypoxia results in a reduction of the passage of O2 from the alveoli to the blood, reducing the amount of circulating oxygen and requires physical adaptations and physiological changes in every people.

The duration and degree of hypoxic exposure are critical to the metabolic response of skeletal muscle, with the response to acute hypoxia during exercise. Many changes in the pathways of oxygen delivery have been characterized in hypoxic humans at real or simulated altitude. In contrast, relatively little is understood about changes in tissue oxygen utilization in humans at altitude.

12.1 Hypobaric Hypoxia

During flights at high altitude or mountain climbing, people are subjected to the effect of reduced air pressure and, consequently, to lower partial pressure of O2. The concentration of oxygen in air remains constant so, as the barometric pressure decreases, the partial pressure of oxygen decreases proportionately, challenging oxygen delivery to the tissues. This condition is referred to as hypobaric hypoxia.

Exposure to hypobaric hypoxia results in a reduction of the passage of O2 from the alveoli to the blood, reducing the amount of circulating oxygen.

The exposition to high altitude requires physical adaptations and physiological changes in every people.

The positive aspects of high-altitude acclimatization, most notably decreased susceptibility to acute mountain sickness, also contrast with the less well-understood phenomenon of high-altitude deterioration, which occurs with prolonged exposure to extreme high altitude (>5500 m) and is characterized by lethargy, fatigue and muscle wasting [1, 2, 3, 4, 5, 6, 7, 8, 9].

High-altitude physiology may be divided into short-term changes that occur with exposure to hypobaric hypoxia (the acute response to hypoxia) and longer-term acclimatisation and adaptation. Acute exposure to the ambient atmosphere at extreme altitude (e.g., above 8000 m) is rapidly fatal [10]. Acclimatisation is the set of beneficial processes whereby lowland humans respond to a reduced inspired partial pressure of oxygen, and it begins already at 2500 m above sea. These changes tend to reduce the gradient of oxygen partial pressure from ambient air to tissues (classical oxygen cascade) and are distinct from the pathological changes that lead to altitude illness. High-altitude illness may be divided into the acute syndromes (AMS) that affect lowland ascending to altitudes and the chronic conditions that affect individual resident at high altitude for long periods. The AMS, if not recognized and treated, could degenerate into high-altitude pulmonary oedema (HAPE) and high-altitude cerebral oedema (HACE).

The incidence and severity of acute mountain sickness, HAPE, and HACE are related to the speed of ascent and the maximum height gained, suggesting a dose–response type of relationship in susceptible individuals [2]. A number of studies also suggest, however, that inflammation may be contributory in the pathogenesis of altitude illness [2].

The physiological response to acute hypobaric hypoxia serves to increase oxygen delivery to the tissues: ventilation, cardiac output and haemoglobin concentrations increase (haemoglobin concentration increases initially by the haemoconcentration and later as a result of increased erythropoiesis). Similarly, the textbook paradigm of acclimatisation to hypobaric hypoxia emphasises the development of mechanisms to increase oxygen flux (increase in ventilation, cardiac output, oxygen carriage and capillarity) [10].

These observations, however, do not adequately explain the observed differences between individuals in their tolerance of hypobaric hypoxic environments. Neither the baseline cardiorespiratory performance (maximal oxygen consumption) nor changes in the response to chronic hypoxia account for differences between individuals in acclimatisation to prolonged hypoxia [3] or performance at altitude [4]. Maximal oxygen consumption, maximal heart rate and stroke volume are all reduced [5] after acclimatisation despite normalisation of the blood oxygen content to sea-level values (by an increase in haemoglobin concentration) [6]. Furthermore, pure oxygen breathing by acclimatised individuals (which results in an oxygen content greater than that at sea level) does not return maximal oxygen consumption to sea-level values [7]. These surprising findings suggest that oxygen carriage is not a limiting factor for maximal oxygen consumption at altitude. This could be consistent with central nervous system limitation of the maximal exercise capacity, with limitation of oxygen flux within the tissues or with a downregulation of cellular metabolism [10].

An alternative model supported by empirical evidence suggests that mechanisms not related to oxygen delivery may play an even greater role: this alternative model proposes that acclimatisation is achieved not solely by increasing the oxygen flux but also by decreasing utilisation. Acclimatisation may therefore be mediated in part by alterations in oxygen delivery, but also by reductions in cellular oxygen demand, perhaps through hibernation/stunning or preconditioning pathways or through improvements in efficiency of use of metabolic substrates.

Hypoxia is not, however, the only stress encountered at altitude. Temperature falls with increasing elevation, whilst absolute humidity is extremely low and exposure to solar/ultraviolet radiation high. Visitors frequently experience gastrointestinal upset and appetite loss, which could result from the hypoxia itself, but may be exacerbated by infection, particularly in developing countries [11]. In addition, activity levels are often altered, as oxygen delivery limits exercise capacity and motivation falls; thus, individuals may undergo detraining [12].

12.2 Hypobaric Hypoxia and Exercise in Alpine Sky

In some period of training, also Italian skiing team is exposed to high altitude. Indeed, in the USA, many sky resorts provide access to mountain as high as 3050–4270 m. During the USA transfers in November (usually in Colorado), athletes stay for more than 2 weeks around 3000 m.

The duration and degree of hypoxic exposure are critical to the metabolic response of skeletal muscle, with the response to acute hypoxia during exercise or relatively [8].

Many changes in the pathways of oxygen delivery have been characterized in hypoxic humans at real or simulated altitude. In contrast, relatively little is understood about changes in tissue oxygen utilization in humans at altitude [13, 14].

Tissue hypoxia may be due to decreased tissue oxygen delivery associated with microcirculatory dysfunction or may occur via alterations in cellular energy pathways and mitochondrial function, resulting in a decreased ability to utilise the available oxygen [12].

In hypobaric hypoxia, mitochondrial respiration and aerobic capacity are thus limited, whilst reactive oxygen species (ROS) production increases [15].

Skeletal muscle, like all oxidative tissues of the body, is critically dependent on a supply of oxygen to maintain energetic and redox homeostasis. ATP can be synthesised in the skeletal muscle in an oxygen-dependent manner in the mitochondria via oxidative phosphorylation, utilising substrates such as glycolytically derived pyruvate, fatty acids, amino acids and ketone bodies, but also in an oxygen-independent manner in the cytosol, via glycolysis with the resulting pyruvate converted to lactate [16].

At moderate high altitude, even with prolonged exposure, no such loss in mitochondrial volume density occurs, although notably, lower muscle mitochondrial densities have been reported [17]. Even if literature describe changes in muscle respiratory function occur also at moderate altitudes, but again this may be dependent on the extent of exposure. Two similar high-resolution respirometry studies by Lundby and co-workers described a loss of respiratory capacity and improved coupling following 28 days at 3454 m, but no changes after 9–11 days at 4559 m [11, 12, 13, 14, 18, 19, 20, 21, 22, 23].

Despite changes in resting metabolites, however, muscle PCr recovery half-times following an exercise challenge were remarkably well preserved in subjects returning either from Everest Base Camp or the summit, indicating that muscle capacity for ATP synthesis may in fact be spared [19].

Many of the metabolic changes reported in humans at altitude have also been observed in hypoxic cells in culture and are associated with stabilization of the hypoxia-inducible factor (HIF) family of transcription factors [9], which controls the expression of hundreds of survival genes related to energy metabolism.

An alternative possibility to low muscle PO2 per se could be reactive oxygen species (ROS)-mediated effects, because mitochondrial ROS production increases in hypoxia and is modelled to increase sharply in muscle in altitudes. Reactive oxygen species have sometimes been described as indiscriminate mediators of damage to lipids, protein and DNA, and this may be the case when generated in large quantities, but at more moderate concentrations, they play an important signalling role within the cell and can, for instance, bring about stabilization of HIF-1α. This might suggest that transient production of ROS during training (possibly as a result of acute hypoxia due to high rates of muscle O2 consumption) may elicit training-induced changes, in agreement with a signalling role. Moreover, as outlined elsewhere in this issue of Experimental Physiology by Lundby [23], the response to hypoxia may in fact mediate some aspects of endurance training in muscle [8].

This is an important factor for not giving oxygen at intermediate altitudes, such as 3000 meters, during aerobic training workouts not maximal, because it may have more disadvantages than advantages.

Indeed restoration of PaO2 with supplementary O2 does not fully restore aerobic capacity in acclimatised individuals, possibly indicating a peripheral impairment [15].

Qualitative changes in mitochondrial function also occur and do so at more moderate high altitudes with shorter periods of exposure. Electron transport chain complexes are downregulated, possibly mitigating the increase in ROS production. Fatty acid oxidation capacity is decreased, and there may be improvements in biochemical coupling at the mitochondrial inner membrane that enhance O2 efficiency. Creatine kinase expression falls, possibly impairing high-energy phosphate transfer from the mitochondria to myofibrils. In climbers returning from the summit of Everest, cardiac energetic reserve (phosphocreatine/ATP) falls, but skeletal muscle energetics are well preserved, possibly supporting the notion that mitochondrial remodelling is a core feature of acclimatisation to extreme high altitude [15].

At altitude, however, creatine kinase is downregulated, potentially impairing high-energy phosphate transfer [15]. Muscle fibre wasting may mitigate this to some extent, by decreasing average diffusion distances, but it is possible that with a compromised capacity for PCr synthesis, the preferred maintenance of mitochondria in intermyofibrillar regions circumvents some of the resulting limitations of high-energy phosphate delivery to myosin.

Notably, however, protein levels of pyruvate dehydrogenase were also lower in these subjects following ascent of Everest, perhaps arguing against as witch towards glucose oxidation and instead supporting a possible increased role for glycolytic ATP production and lactate production instead, bypassing the mitochondria.

With the downregulation of oxidative enzymes and loss of mitochondrial density, it is conceivable that anaerobic glycolysis might make a greater contribution to muscle ATP demands at extreme altitude, particularly during exercise. In humans, however, the evidence to support increased glycolysis at altitude is limited [21]. Indeed, in muscle biopsies from humans returning from extreme altitude, the levels of several glycolytic enzymes were decreased as was hexokinase activity. These observations might reflect the so-called ‘lactate paradox’. In this phenomenon, acute exposure to high altitude is accompanied by greater blood lactate levels ([Lab]) at a given submaximal workload than at sea level, although following acclimatisation over a period of weeks, the same exercise challenge results in a lower [Lab], more comparable with that at sea level [8]. Thus, acclimatisation may decrease the initial dependence on glycolysis to meet cellular ATP demand, perhaps through multiple adjustments that optimise O2 delivery and utilisation or through better coupling of pyruvate production and oxidative phosphorylation. Some studies, however, have suggested that the ‘lactate paradox’ is a more transient feature of acclimatisation and not applicable to those spending longer durations at extreme altitude [15].

Whilst oxidative processes are selectively downregulated in the skeletal muscle following exposure to environmental hypoxia, in contrast to studies in cultured cells, glycolytic markers appear to remain largely unchanged. It is noteworthy, however, that there has been a distinct lack of direct measurements of glycolytic flux in vivo or ex vivo following hypoxic exposure [16].

Today, the lactate paradox is more commonly defined as the phenomenon in which an acute sojourn at altitude induces an increase in blood lactate accumulation during exercise in the short term, yet this decreases after chronic exposure. However, whilst this may reflect some aspect of metabolic remodelling following hypoxic acclimation, current explanations for this phenomenon remain controversial and probably involve factors beyond the mere capacity for substrate utilisation [24].

Taken together, the literature is not clear on whether a hypoxia-induced substrate switch from fatty acid oxidation to glucose oxidation occurs within the mitochondria of skeletal muscle as it does in the hypoxic rat heart, for instance. Environmental hypoxia does however induce a selective attenuation of whole muscle fatty acid oxidation, whilst glucose uptake is maintained or increased, perhaps to support glycolytic flux in the face of a downregulation of oxidative metabolism, optimising the pathways of ATP synthesis for the hypoxic environment [18].

Metabolism is reprogrammed in response to sustained exposure to hypoxia to increase the capacity for anaerobic metabolism and lower that for fatty acid oxidation, which is less O2 efficient than glycolysis/pyruvate oxidation [16].

In summary, literature report time-dependent changes in gene and protein expression that appear to underlie the mitochondrial response to subacute and sustained hypobaric hypoxia in human skeletal muscle. Following subacute hypoxia exposure, increased uncoupling may serve to protect the mitochondria, particularly the intermyofibrillar mitochondria, but at the cost of impaired efficiency of ATP synthesis [13].

To facilitate adaptation at high altitude is helpful to follow the traditional guidelines for the high altitude, so to expose gradually to high altitude and once achieved hydrated a lot during the stay (useful antioxidant and energy supplements), promoting quality and healthy foods reducing coffee that interfere with rest and then with sleep, already difficult at altitude [25]. About utility of using supplemental O2 in between heats to facilitate recovery, literature is very discordant and needs further investigations to be able to say with certainty of its usefulness, which at the moment remains doubtful.

Athletes sojourning to high altitude for ski camps can train on immediate ascent but should slowly increase training volume over the first 3 days. Athletes should expect improvements in balance and reaction time 3–6 days into acclimatization. Coaches and athletes should expect about 20% of youth lowlander athletes to have signs and symptoms of AMS during the first 3 days of altitude exposure for alpine lift access sports at altitudes of up to 3800 m [26].

References

  1. 1.
    Hill AB (1965) The environment and disease: association or causation? Proc R Soc Med 58:295–300PubMedPubMedCentralGoogle Scholar
  2. 2.
    Hackett PH, Roach RC (2001) High-altitude illness. N Engl J Med 345:107–114CrossRefPubMedGoogle Scholar
  3. 3.
    Cymerman A, Reeves JT, Sutton JR, Rock PB, Groves BM, Malconian MK, Young PM, Wagner PD, Houston CS (1989) Operation Everest II: maximal oxygen uptake at extreme altitude. J Appl Physiol 66:2446–2453CrossRefPubMedGoogle Scholar
  4. 4.
    Howald H, Hoppeler H (2003) Performing at extreme altitude: muscle cellular and subcellular adaptations. Eur J Appl Physiol 90:360–364CrossRefPubMedGoogle Scholar
  5. 5.
    Sutton JR, Reeves JT, Groves BM, Wagner PD, Alexander JK, Hultgren HN, Cymerman A, Houston CS (1992) Oxygen transport and cardiovascular function at extreme altitude: lessons from operation Everest II. Int J Sports Med 13(Suppl 1):S13–S18CrossRefPubMedGoogle Scholar
  6. 6.
    Calbet JA, Boushel R, Radegran G, Sondergaard H, Wagner PD, Saltin B (2003) Why is VO2 max after altitude acclimatization still reduced despite normalization of arterial O2 content? Am J Physiol Regul Integr Comp Physiol 284:R304–R316CrossRefPubMedGoogle Scholar
  7. 7.
    Cerretelli P (1976) Limiting factors to oxygen transport on Mount Everest. J Appl Physiol 40:658–667CrossRefPubMedGoogle Scholar
  8. 8.
    West JB et al (2007) High altitude medicine and physiology. Hodder Arnold, LondonGoogle Scholar
  9. 9.
    Murray AJ (2016) Energy metabolism and the high-altitude environment. Exp Physiol 101(1):23–27. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UKCrossRefPubMedGoogle Scholar
  10. 10.
    Ward MP, Milledge JS, West JB (2000) High altitude medicine and physiology. Arnold, LondonGoogle Scholar
  11. 11.
    Margaria R, Edwards HT, Dill DB (1933) The possible mechanisms of contracting and paying the oxygen debt and the role of lactic acid in muscular contraction. Am J Physiol 106:689–715Google Scholar
  12. 12.
    Grocott M (2007) Review: high-altitude physiology and pathophysiology: implications and relevance for intensive care medicine. FASEB J, Crit Care 11(1):203CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Levett DZ, Radford EJ, Grocott W (2012) Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J 26:1431–1441. www.fasebj.orgCrossRefPubMedGoogle Scholar
  14. 14.
    Murray, A. J. (2009) Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies. Genome Medicine 1:117CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Murray AJ, Horscroft JA (2016) Mitochondrial function at extreme high altitude. J Physiol 594(5):1137–1149. Department of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UKCrossRefPubMedGoogle Scholar
  16. 16.
    Horscroft JA, Murray AJ (2014) Skeletal muscle energy metabolism in environmental hypoxia: climbing towards consensus. Extrem Physiol Med 3:19CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kayser B et al (1996) Muscle ultrastructure and biochemistry of lowland Tibetans. J Appl Physiol 81(1):419–425CrossRefPubMedGoogle Scholar
  18. 18.
    Horscroft JA, Burgess SL, Hu Y, Murray AJ (2015) Altered oxygen utilisation in rat left ventricle and soleus after 14 days, but not 2 days, of environmental hypoxia. PLoS One 10(9):e0138564CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Edwards LM, Murray AJ, Tyler DJ, Kemp GJ, Grocott CJ, Clarke K, Caudwell Xtreme Everest Research Group (2010) The effect of high-altitude on human skeletal muscle energetics: P-MRS results from the Caudwell Xtreme Everest expedition. PLoS One 5:e10681.  https://doi.org/10.1371/journal.pone.0010681CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gladden LB (2004) Lactate metabolism: a new paradigm for the third millennium. J Physiol 558:5–30CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Horscroft JA, Murray AJ (2014) Skeletal muscle energy metabolism in environmental hypoxia: climbing towards consensus. Extrem Physiol Med 3:19CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Jacobs RA, Boushel R, Wright-Paradis C, Calbet JA, Robach P et al (2013) Mitochondrial function in human skeletal muscle following high-altitude exposure. Exp Physiol 98:245–255CrossRefPubMedGoogle Scholar
  23. 23.
    Jacobs RA, Siebenmann C, Hug M, Toigo M, Meinild AK et al (2012) Twenty-eight days at 3454-m altitude diminishes respiratory capacity but enhances efficiency in human skeletal muscle mitochondria. FASEB J 26:5192–5200CrossRefPubMedGoogle Scholar
  24. 24.
    Noakes TD (2009) Last word on viewpoint: evidence that reduced skeletal muscle recruitment explains the lactate paradox during exercise at high altitude. J Appl Physiol (1985) 106:745CrossRefGoogle Scholar
  25. 25.
    Chapman RF, Stickford JL, Levine BD (2010) Altitude training considerations for the winter sport athlete. Exp Physiol 95(3):411–421CrossRefPubMedGoogle Scholar
  26. 26.
    Hydren JR, Kraemer WJ, Volek JS, Dunn-Lewis C, Comstock BA, Szivak TK, Hooper DR, Denegar CR, Maresh CM (2013) Performance changes during a weeklong high-altitude alpine ski-racing training camp in lowlander young athletes. J Strength Cond Res 27(4):924–937CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Italian Winter Sports FederationMilanoItaly
  2. 2.Ambulatory of Clinic Physiology and SportUniversity of Medicine Milan-BicoccaMonzaItaly
  3. 3.Ambulatory of Sport MedicinePentavisLeccoItaly

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