NEURO AND MUSCULAR ADVANCES ON HIGH

ALTITUDE PHYSIOLOGYTYRLL ADOLF ITONG

BIO 220: CHEMICAL PHYSIOLOGY

WHAT IS HIGH ALTITUDE?

defined as:

intermediate altitude: 1500–2500 m

High Altitude: 2500–3500 m

very High Altitude: 3500–5800 m

extreme altitude: above 5800 m (Barry & Pollard, 2003)

Recently, there is an increase of lowlanders reaching

heights previously reserved for veteran climbers

For these climbers, higher risk of high altitude sickness,

leading to increase in injuries and fatalities

2014 Mt. Everest death tally: 16 deaths

HIGH ALTITUDE SICKNESS

Brought about by hypoxia, among other factors

Deprivation of adequate oxygen supply in the body

reduced O2 in the atmosphere due to lower total

barometric pressures

Lower partial pressure of gases, including oxygen

Creates “death zones” – oxygen pressure cannot sustain

human life

Symptoms include edema and physiological damage to

cognitive and cerebral areas of brain

Sleep and mood stage changes (Harris, et al., 2009)

neurobehavioral capacities impairment (Hornbein, et al., 1989)

Psychomotor ability and mental efficiency (Abraini, et al., 1998)

learning deficits and perceptive and memory retention (Kramer, Coyne, & Strayer, 1993)

Some authors argue the opposite

No cognitive changes found using brain imagery and

neuropsychological testing (Anooshiravani, et al., 1999)

No decline in neurophysiological tests of subjects exposed up

to 7500 m (Jason et al., 1989)

Resolved in recent high-altitude neurological research

Using saccadic eye performance, no significant effects on

cognitive performance in well-acclimatized climbers (Merz, et al.,

2013)

cognitive skills are affected in casual climbers (Lemos, et al., 2012)

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MUSCLE AND MITOCHONDRIAL PHYSIOLOGY

Muscles are highly plastic (Guggenheim, 1991)

Hypoxia has long been known to play a role in muscle

cellular changes, particularly harmful for skeletal muscle

mass (Holloszy and Coyle, 1984)

Significant muscle atrophy in m. quadriceps femoris and m. biceps

brachii and subsequent weight loss (Mizuno, et al., 2008)

Cardiac muscles are altered in response to altitude exposure (Holloway, et al., 2011)

Disproportionate change in left ventricular surface area

reduction of filling rate and stroke volume

cardiac phosphocreatine/ATP ratio decrease

How the body produces and responds to these structural

changes remains unclear

Phenotypic alterations of muscle tissue, including loss of

mitochondria previously believed to be the cause (Howald and

Hoppeler, 2003)

Decreased density of subsarcolemmal and intermyofibrillar

mitochondria (Levett, et al., 2012)

Brought about by increased production of lipofuscin

Reduction in capillarity and muscle tissue oxidative

capacity, thus aerobic capacity (Desplanches, 1996; Howald and Hoppeler,

2003)

Recent research suggest gene expression and protein levels

explains previously described changes (Levett, et al., 2012)

Plasticity of mitochondria facilitates these adaptations (Lynn, 2007)

up-regulation of UCP3, believed to be mitochondria’s main defense

against ROS (Brand, et al., 2002)

suppression of oxidative metabolism and mitochondrial biogenesis through down-regulation of complex I, IV, and PGC1α

Despite significant atrophy and weight loss, muscle function

is still maintained (Edwards, 2010)

Phosphocreatine recovery and inorganic phosphate

concentrations higher in veteran than in casual climbers

Changes in mitochondrial function a long term effect of

hypoxia

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Mitochondrial function remains largely unaltered despite

these extreme enzymatic changes (Jacobs, et al., 2013)

no significant change in skeletal muscle mitochondrial density after

19 days (Levett, et al., 2012)

Increased muscle turnover rate largely counterbalanced by elevated

myocontractile protein synthesis rate (Holm, 2010)

Capacity of complex I or II to oxidize fat and individually respire not

affected

WHERE DO WE GO FROM HERE?

Research continues on effects of high-altitude changes

possibility of cognitive impairment or long-term cerebral

damage occurring

long-term effects on mitochondria

Regulation of protein synthesis rates in mitochondria

Recovery of muscle atrophy after long-term hypoxic exposure

Normobaric vs hypobaric hypoxia (Girard, 2012)

LITERATURE CITED

Abraini, J., Bouquet, C., Joulia, F., Nicolas, M., & Kriem, B. (1998). Cognitive performance during a simulated climb of Mount Everest: implications for brain function and central adaptive processes under chronic hypoxic stress. Pflugers Arch., 436(4), 553-9.

Anooshiravani, M., Dumont, L., Mardirosoff, C., Soto-Debeuf, G., & Delavelle, J. (1999). Brain magnetic resonance imaging (MRI) and neurological changes after a single high altitude climb. Med Sci Sports Exerc., 31(7), 969-72.

Barry, P. W., & Pollard, A. J. (2003). Altitude illness. The British Medical Journal, 326(7395), 915-919.

Desplanches, D., Hoppeler, H., Tüscher, L., Mayet, M. H., Spielvogel, H., Ferretti, G., & Favier, R. (1996). Muscle tissue adaptations of high-altitude natives to training in chronic hypoxia or acute normoxia. Journal of Applied Physiology, 81(5), 194.

Edwards, L., Murray, A., Tyler, D., Kemp, G., & Holloway, C. (2010). The Effect of High-Altitude on Human Skeletal Muscle Energetics: 31P-MRS Results from the Caudwell Xtreme Everest Expedition. PLoS ONE, 5(5), e10681. doi:10.1371/journal.pone.0010681

Girard, O., Koehle, M. S., Guenette, J. A., Verges, S., Chapman, R. F., Conkin, J., . . . Taylor, B. J. (2012). Comments on Point:Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia. J Appl Physiol, 112, 1788-1794.

Guimarães-Ferreira, L., Nicastro, H., Wilson, J., & Zanchi, N. E. (2013). Skeletal Muscle Physiology. Scientific World Journal. doi:10.1155/2013/782352

Holloway, C. J., Montgomery, H. E., Murray, A. J., Cochlin, L. E., Codreanu, I., Hopwood, N., & Andr. (2011). Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp. The FASEB Journal, 25, 792-796.

Holm, L., Haslund, M. L., Robach, P., van Hall, G., Calbet, J. A., Saltin, B., & Lundby, C. (2010). Skeletal Muscle Myofibrillar and Sarcoplasmic Protein Synthesis Rates Are Affected Differently by Altitude-Induced Hypoxia in Native Lowlanders. PLoS ONE, 5(12), e15606. doi:10.1371/journal.pone.0015606

Hornbein, T. F., Townes, B. D., Sutton, J. R., & Houston, C. S. (1989). he cost to the central nervous system of climbing to extremely high altitude. N Engl J Med, 1714-1719.

Howald, H., & Hoppeler, H. (2003). Performing at extreme altitude: muscle cellular and subcellular adaptations. Eur J Appl Physiol., 90(3-4), 360-4.

LITERATURE CITED

Jacobs, R. A., Boushel, R., Wright-Paradis, C., Calbet, J. A., Robach, P., Gnaiger, E., & Lundby, C. (2013). Mitochondrial function in human skeletal muscle following high-altitude exposure. Exp Physiol, 98(1), 245–255.

Jason, G., Pajurkova, E., & Lee, R. (1989). High-altitude mountaineering and brain function: neuropsychological testing of members of a Mount Everest expedition. AviatSpace Environ Med, 60(2), 170-173.

Kramer, A. F., Coyne, J. T., & Strayer, D. L. (1993). Cognitive function at high altitude. Human Factors, 35(2), 329-344.

Lemos, V. d., Antunes, H. K., Vagner, R., Santos, T. d., Lira, F. S., Tufik, S., & de Mello, M. T. (2012). High altitude exposure impairs sleep patterns, mood, and cognitive functions. Psychophysiology, 49(9).

Levett, D. Z., Radford, E. J., Menassa, D. A., Graber, E. F., Morash, A. J., Hoppeler, H., . . . Murray, A. J. (2012). Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J., 26, 1431–1441.

Lynn, E., Lu, Z., Minerbi, D., & Sack, M. (2007). The regulation, control, and consequences of mitochondrial oxygen utilization and disposition in the heart and skeletal muscle during hypoxia. Antioxid Redox Signal. 2007 Sep;9(9):1353-61., 9(9), 1351-61.

Mason, N. (2000). The physiology of high altitude: an introduction to the cardio-respiratory changes occurring on ascent to altitude. Current Anaesthesia and Critical Care, 11, 34-41.

Merz, T. M., Bosch, M. M., Barthelmes, D., Pichler, J., Hefti, U., Schmitt, K.-U., . . . Schwarz, U. (2013). Cognitive performance in high-altitude climbers: a comparative study of saccadic eye movements and neuropsychological tests. European Journal of Applied Physiology, 113(8), 2025–2037. doi:10.1007/s00421-013-2635-6

Rodway, G. W., Hoffman, L. A., & Sanders, M. H. (2003). High-altitude-related disorders—part I: pathophysiology, differential diagnosis, and treatment. Heart & Lung: The Journal of Acute and Critical Care, 32(6), 353–359.

San, T., Polat, S., Cingi, C., Eskiizmir, G., Oghan, F., & Cakir, B. (n.d.). Effects of High Altitude on Sleep and Respiratory System and Theirs Adaptations. The Scientific World Journal. doi:10.1155/2013/241569

Xu, L., Wu, Y., Zhao, T., Liu, S., Zhu, L., Fan, M., & Wu, K. (2014). Effect of high altitude hypoxia on cognitive flexibility. Chinese Journal of Applied Physiology, 30(2), 106-9, 118.