How hypoxia/altitude works




Below is a paper I wrote for school on a hypothetical training situation.  I thought I'd share it because it gives the underlying science of how altitude/hypoxia works.  Remember that it's a hypothetical, so it doesn't mean that I think intermittent hypoxic training works.  Generally, the exposure is way too short for a lot of long term adaptations.  Enjoy:



Altitude training is increasingly being thought of as a necessity for performance in a variety of endurance sports. The interest extends from athletes and coaches to the research community. In recent years there has been an emphasis on living at high altitudes and training at lower altitudes. This process has proved to be highly beneficial to performance in many studies (Wilber et al. 2007). However, due to the challenge of finding an ideal place to follow such a procedure, or the costly and time consuming procedure of spending 10+ hours a day in a stimulated altitude tent, other researchers are trying to find a way around this. The two main options seem to be living and training at high altitude for periods of time before spending the next block of training at sea level, or performing some workouts in a simulated hypoxic environment. Both of these options require training in hypoxic environments. Therefore, in this paper, the goal will be to discern the mechanisms behind intense aerobic training (done around the lactate threshold) in a hypoxic environment on the major hypoxic induced change that seems to elicit improvements in performance, an increase in red blood cell (RBC) mass via an increase in EPO.


Going to a hypoxic environment, whether natural or artificial, puts a new stress on the body causing the various systems of the body to react and adapt to its new environment. Training, even at sea level, similarly causes numerous changes to occur within the body as it attempts to react to the stress of the particular training load. Therefore, when exercising at altitude, the body not only has to respond and adapt to one stimulus, it has to respond to two, a training and hypoxic one. When these two stressors combine, the body’s primary objective becomes insuring adequate oxygen delivery to the working muscles. It accomplishes this through a variety of mechanisms.


First, let’s look at some of the larger changes that occur when training in a hypoxic environment. Two main factors will determine the physiologic and metabolic response; the intensity of the exercise and the level of hypoxia. Both of these factors will affect the amount of oxygen delivered to the muscles through a variety of factors. The level of hypoxia will first affect the hemoglobin oxygen saturation due to the decrease in the pressure gradient which occurs because of the reduction in the partial pressure of oxygen at altitude (Rusko 2004). This greatly affects VO2max, as each 1% drop in oxygen saturation below 95%, decreases VO2max by 1-2% (Dempsey and Wagner, 1999). This drop in oxygen saturation even occurs at moderate to low intensities, as was demonstrated in well trained athletes seeing drops even when training at 60-85% VO2max (Peltonen 1999). The drop in oxygen saturation is linearly related to the drop in maximal heart rate that occurs at altitude (Rusko 2004). Due to this drop in HR max, cardiac output is reduced at altitude.
The nervous system also plays a role in controlling the response to hypoxic conditions. Due to the decrease in oxygen concentration, muscle activity is reduced in hypoxic conditions (Peltonen 1997). This reduction in muscle recruitment may be a way of the CNS governing performance. It has been suggested that the decrease in VO2max at altitude is the result of the CNS controlling exercise, instead of the decreased recruitment being a cause of the reduction in VO2max (Noakes et al. 2001). What the exact controlling mechanism of the response of the CNS to hypoxic conditions is remains unknown, but the CNS does play a role in the overall response to training in hypoxic conditions.


All of these changes that occur while training in hypoxic conditions lead to an eventual decrease in oxygen levels in the blood, and a decrease in the muscles themselves. This reduction in oxygen concentration in the blood and at the muscular level is the stimulus for the mechanisms behind our eventual desired outcome, an increase in RBC mass. A reduction in oxygen concentration of the blood activates the Hypoxia Inducible Factor-1 (HIF-1) pathway in tissues where EPO production can take place (i.e. kidney, liver, the brain) (Stockmann et al. 2006).




HIF-1 is a main oxygen homeostasis regulator in the body. Two subunits, HIF-1α and HIF-1β, make up the HIF-1 complex. Under normal conditions, HIF-1β is present, but HIF-1α is constantly being degraded by the proteasome (Dery 2005). When oxygen levels are lowered, the degradation of HIF-1α is inhibited, this stabilizes HIF-1α. The stabilization allows for HIF-1α to bind to transcriptional coactivators and enter the nucleus of the cell. Here, HIF-1α binds to HIF-1β, forming an HIF-1 transcriptional complex (Marzo et al. 2008). This HIF-1 complex then binds to the Hypoxia Response Element (HRE) on the EPO gene. This in turn leads to EPO expression (Stockmann et al. 2006).


EPO then needs to be transported to and bind with EPO receptors. EPO receptors can be found on erythroid stem cells in bone marrow (Marzo et al. 2008). The binding to the receptor on the cell membrane results in a signaling cascade that results in the activation of the transcription factor STAT-5 and two enzymes, PI3K and MAPK. These enter the nucleus and induce transcription of specific genes that result in the inhibition of apoptosis, programmed cell destruction (Marzo et al. 2008, Jelkmann 2004). The end result is that this prevention of destruction of developing RBC results in an increase in RBC.


A larger RBC mass means a larger oxygen carrying capacity, which ultimately results in increased oxygen delivery to the muscles. Oxygen delivery has been shown to be a major limiter of VO2max (Bassett & Howley 2000). In studies done on blood transfusion of RBC in elite endurance athletes, increases in endurance performance and in some cases VO2max have been significant (Calbet et al. 2006). In one particular study done on elite athletes with an average VO2max of 80 ml kg−1 min−1, time to exhaustion in an endurance test and VO2max were both significantly increased (Buick et al. 1980). Therefore, increased oxygen delivery results in increased aerobic capacity and the functional change of improved endurance.
This leads to reasoning behind the selection of the training intensity. The idea behind the selection of a training intensity around lactate threshold is due to our desired outcome. In order to elicit the reduction in oxygen levels in the blood and muscles, the intensity needs to be high enough that it will do this. As was stated earlier, Peltonen et al. found that oxygen saturation was reduced at even submaximal intensities of between 60-85% of VO2max (1999). In well trained individuals, this intensity corresponds well to that of LT. Secondly, the intensity has to be low enough to allow for a significant volume of training to take place. The duration spent training has to be long enough to allow for activation of the pathway responsible for the desired adaptations. The signaling of the HIF-1 pathway under hypoxic conditions has been shown to already show increases in HIF-1α in the first 2 minutes. However, maximum HIF-1α did not occur until 1 hour of hypoxia, with max half times occurring at between 12 and 13 minutes. In addition, the reduction of HIF-1α with reoxygenation occurred quickly, also within 2 minutes, and was back to normal within 32minutes (Jewell 2001). These results suggest that a sufficient duration is necessary to elicit maximum gains via the HIF-1 pathway. Lastly, in a study by Zoll et al. they found that training at an intensity that corresponded to the ventilatory threshold increased mRNA concentrations of the HIF-1α, giving credence to the theory discussed above (2005).


In looking at the research and the pathways involved in EPO production and RBC increase, it can be seen that in order for hypoxic training to increase RBC mass a sufficient intensity and duration is needed. The intensity must be high enough so that a drop in oxygen saturation occurs, while being low enough so that sufficient time can be spent training at that intensity for the pathway to be activated. The selection of intensity and duration of training, along with the level of altitude, might explain why mixed results have been seen in hypoxic training.



Bassett, D. R. & Howley, E. T. (2000). Limiting factors for maximum oxygen uptake and determinants of endurance performance. Medicine and Science in Sports and Exercise, 32, 70–84
Buick, F. J., Gledhill, N., Froese, A. B., Spriet, L., & Meyers, E. C. (1980). Effect of induced erythrocythemia on aerobic work capacity. J Appl Physiol, 48(4), 636-642.
Calbet, J. A., Lundby, C., Koskolou, M., & Boushel, R. (2006). Importance of hemoglobin concentration to exercise: acute manipulations. Respir Physiol Nerubiol, 151(2-3), 132–140.
Dempsey, J. A., & Wagner, P. D. (1999). Exercise-induced arterial hypoxemia. J Appl Physiol, 87(6), 1997–2006.
Dery, M. C., Michaud, M. D., Richard, D. E. (2005). Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. The International Journal of Biochemistry & Cell Biology, 37, 535–540.
Jelkmann, W. (2004). Molecular biology of erythropoietin. Internal Medicine, 43, 649–659.
Jewell, U. R., Kvietikova, I., Scheid, A., Bauer, C., Wenger, R. H., Gassmann, M. (2001). Induction of HIF-1 alpha is response to hypoxia is instantaneous. FASEB J, 15(7), 1312-1314.
Marzo, F., Lavorgna, A., Coluzzi, G., Santucci, E., Tarantino, F., Rio, T., Conti, E., Autore, C., Agati, L., & Andreotti, F. (2008). Erythropoietin in heart and vessels: focus on transcription and signalling pathways. J Thromb Thrombolysis, 26, 183–187.
Noakes, T. D., Peltonen, J. E., Rusko, H. K. (2001). Evidence that a central governor regulates exercise performance during acute hypoxia and hyperoxia. J Expl Biol, 204(18), 3225–3234.

Peltonen, J. et al. (1997). Effects of oxygen fraction in inspired air on force production and electromyogram activity during ergometer rowing. European Journal of Applied Physiology, 76, 495– 503.

Peltonen, J. E., Leppavuori, A. P., Kyro, K. P., Makela, P., & Rusko, H. K. (1999). Arterial haemoglboin oxygen saturation is affected by F(I)O2 at submaximal running velocities in elite athletes. Scand J Med Sci Sports, 9(5), 265-271.
Rusko, H. K., Tikkanen, H. O., & Peltonen, J. E. (2004). Altitude and endurance training. Journal of Sports Sciences, 22:10, 928 — 945.
Stockman, C. & Fandrey, J. (2006). Hypoxia induced erythropoietin production: a paradigm for oxygen-regulated gene expression. Clinical and Experimental Pharmacology and Physiology, 3, 968–979.
Wilber, R. L., Stray-Gunderson, J., Levine, B. D. (2007). Effect of Hypoxic "Dose" on Physiological Responses and Sea-Level Performance. Medicine and Science in Sports and Exercise. 39 (9):1590–1599
Zoll, J., Ponsot, E., Dufour, S., Doutreleau, S., Ventura-Clapier, R., Vogt, M., Hoppeler, H., Richard, R., & Fluck, M. (2006). Exercise training in normobaric hypoxia in endurance runners. III. Muscular adjustments of selected gene transcripts. J Appl Physiol, 100, 1258–1266.

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3 comments:

  1. Solid paper, Mags- got a question, though.

    Do you have any theories one why some people respond highly to altitude and some people don't? I know Chapman has discussed responders and non-responders. What are some of the physiological implications?

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  2. Good stuff. Does the Oregon house still use the modified air? I am guessing as pioneers there was a lot of trial and error.

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  3. Craig - The responders v non-responders debate still continues. Interestingly, although some athletes do not display a meaningful improvement in haematological parameters post-altitude exposure, this does not mean that performance does not improve. There are a number of beneficial non-haematological adaptations (

    Additionally, some recent evidence indicates that the HIF-2a gene may be the primary gene responsible for increasing EPO production in response to hypoxia, not just HIF-1a as originally thought (see Kapitsinou et al, 2010). However, further research is needed to confirm this and HIF-1a is still essential as it mediates numerous other adaptations to hypoxia.

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