Survival at Extreme Altitude: Protective Effect of Increased Hemoglobin-Oxygen Affinity

Eaton, John W.; Skelton, Tracer; Berger, E.

doi:10.1126/science.183.4126.743

Cited by 122 publications

(49 citation statements)

References 8 publications

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“…Even at low altitude, a left-shifted curve might be advantageous when the rate of O 2 transfer across the blood-gas interface is diffusion limited, as is the case during intense exercise (Bencowitz et al, 1982). In rats, a pharmacologically increased Hb-O 2 affinity was shown to greatly enhance metabolic performance and survival under conditions of extreme hypoxia (Eaton et al, 1974;Turek et al, 1978a;Turek et al, 1978b), and human subjects with mutant Hbs that exhibit increased O 2 affinity (Hb Andrews-Minneapolis) maintain normal arterial O 2 saturation and undiminished aerobic capacity at high altitude (3100m) relative to subjects with wild-type Hb (Hebbel et al, 1978). It therefore appears that the DPG response of lowlanders might be maladaptive at high altitudes.…”

Section: Blood-o 2 Affinitymentioning

confidence: 99%

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

Storz

Scott

Cheviron

2010

Journal of Experimental Biology

354

343

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SummaryHigh-altitude environments provide ideal testing grounds for investigations of mechanism and process in physiological adaptation. In vertebrates, much of our understanding of the acclimatization response to high-altitude hypoxia derives from studies of animal species that are native to lowland environments. Such studies can indicate whether phenotypic plasticity will generally facilitate or impede adaptation to high altitude. Here, we review general mechanisms of physiological acclimatization and genetic adaptation to high-altitude hypoxia in birds and mammals. We evaluate whether the acclimatization response to environmental hypoxia can be regarded generally as a mechanism of adaptive phenotypic plasticity, or whether it might sometimes represent a misdirected response that acts as a hindrance to genetic adaptation. In cases in which the acclimatization response to hypoxia is maladaptive, selection will favor an attenuation of the induced phenotypic change. This can result in a form of cryptic adaptive evolution in which phenotypic similarity between high-and low-altitude populations is attributable to directional selection on genetically based trait variation that offsets environmentally induced changes. The blunted erythropoietic and pulmonary vasoconstriction responses to hypoxia in Tibetan humans and numerous high-altitude birds and mammals provide possible examples of this phenomenon. When lowland animals colonize high-altitude environments, adaptive phenotypic plasticity can mitigate the costs of selection, thereby enhancing prospects for population establishment and persistence. By contrast, maladaptive plasticity has the opposite effect. Thus, insights into the acclimatization response of lowland animals to high-altitude hypoxia can provide a basis for predicting how altitudinal range limits might shift in response to climate change.

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Section: Blood-o 2 Affinitymentioning

confidence: 99%

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

Storz

Scott

Cheviron

2010

Journal of Experimental Biology

354

343

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“…In one study, Eaton et al (1974) investigated how increased Hb-O 2 affinity influences rat survival after exposure to extreme and sudden hypoxia. The ODCs of the experimental rats were shifted leftward by their ingestion of sodium cyanate.…”

Section: Benefits Of a Leftward Shiftmentioning

confidence: 99%

“…They posited that this decreased affinity plays an important role in the acclimatization of lowlanders to altitude, and in the genetic adaptations of those native to altitude. Eaton et al (1974) wished to test the hypothesis that decreased Hb affinity for O 2 is advantageous at altitude. They manipulated Hb-O 2 affinity of rats, via carbamylation of the Hb, to create high and low affinity groups.…”

mentioning

confidence: 99%

The in-vivo oxyhaemoglobin dissociation curve at sea level and high altitude

Balaban

Duffin

Preiss

et al. 2013

Respiratory Physiology & Neurobiology

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Some animals have adapted to hypoxia by increasing their haemoglobin affinity for oxygen, but in vitro studies have not shown any change of haemoglobin affinity for oxygen in human high altitude natives or lowlanders acutely acclimatized to high altitude. We conducted the first in vivo study of the oxyhaemoglobin dissociation curve by progressively reducing arterial PO 2 while maintaining normocapnia in lowlanders at sea level, lowlanders sojourning at 3600m for two weeks and native Andeans at the same altitude. We found that the in vivo PO 2 at which haemoglobin is half-saturated (P 50 ) is higher in lowlanders at sea level (32 mmHg) than that measured in vitro (27 mmHg) and that lowlanders and highlanders do significantly increase the in vivo affinity of their haemoglobin for oxygen with exposure to high altitude. These results indicate the value of an in vivo approach for studying the oxyhaemoglobin dissociation curve.iii

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“…For example, a reduced erythrocytic concentration of DPG would produce an increased blood-O 2 affinity that helps safeguard arterial O 2 saturation under hypoxia, and this could be reversed upon a return to normoxic conditions. Under conditions of severe hypoxia, theoretical and experimental results indicate that it is generally advantageous to have an elevated blood-O 2 affinity because of the increased premium on pulmonary O 2 loading (Turek et al, 1973;Eaton et al, 1974;Turek et al, 1978a;Turek et al, 1978b;Bouverot, 1985;Samaja et al, 1986;Samaja et al, 2003;Scott and Milsom, 2006). Consistent with this expectation, elevated blood-O 2 affinities are commonly recorded in terrestrial vertebrates that are native to high altitude environments, and in subterranean mammals that cope with the hypoxic and hypercapnic conditions of closed burrow systems (Jelkmann et al,CA, USA (-60m), and also on the summits of the highest peaks in the Sierra Nevada and Rocky Mountains (4350m) where the partial pressure of O 2 (P O2 ) is less than 60% of the sea level value.…”

Section: Introductionmentioning

confidence: 99%

“…In air-breathing vertebrates, changes in blood-O 2 affinity provide an important line of physiological defense against low O 2 availability (environmental hypoxia) (Eaton et al, 1974;Penny and Thomas, 1975;Monge and León-Velarde, 1991). Fine-tuned adjustments in blood-O 2 affinity may be mediated by changes in the intrinsic O 2 binding affinity of hemoglobin (Hb), changes in the sensitivity of Hb to allosteric effectors that modulate Hb-O 2 affinity, and/or changes in the concentration of allosteric effectors within the erythrocyte (Nikinmaa, 2001;Weber, 2007;.…”

Section: Introductionmentioning

confidence: 99%

Genetic differences in hemoglobin function between highland and lowland deer mice

Storz

Runck

Moriyama

et al. 2010

Journal of Experimental Biology

130

173

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SUMMARY In high-altitude vertebrates, adaptive changes in blood–O2 affinity may be mediated by modifications of hemoglobin (Hb) structure that affect intrinsic O2 affinity and/or responsiveness to allosteric effectors that modulate Hb–O2 affinity. This mode of genotypic specialization is considered typical of mammalian species that are high-altitude natives. Here we investigated genetically based differences in Hb–O2 affinity between highland and lowland populations of the deer mouse (Peromyscus maniculatus), a generalist species that has the broadest altitudinal distribution of any North American mammal. The results of a combined genetic and proteomic analysis revealed that deer mice harbor a high level of Hb isoform diversity that is attributable to allelic polymorphism at two tandemly duplicated α-globin genes and two tandemly duplicated β-globin genes. This high level of isoHb diversity translates into a correspondingly high level of interindividual variation in Hb functional properties. O2 equilibrium experiments revealed that the Hbs of highland mice exhibit slightly higher intrinsic O2 affinities and significantly lower Cl– sensitivities relative to the Hbs of lowland mice. The experiments also revealed distinct biochemical properties of deer mouse Hb related to the anion-dependent allosteric regulation of O2 affinity. In conjunction with previous findings, our results demonstrate that modifications of Hb structure that alter allosteric anion sensitivity play an important role in the adaptive fine-tuning of blood–O2 affinity.

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Survival at Extreme Altitude: Protective Effect of Increased Hemoglobin-Oxygen Affinity

Cited by 122 publications

References 8 publications

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

The in-vivo oxyhaemoglobin dissociation curve at sea level and high altitude

Genetic differences in hemoglobin function between highland and lowland deer mice

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