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Review
. 2022 Aug 8:13:885295.
doi: 10.3389/fphys.2022.885295. eCollection 2022.

Time Domains of Hypoxia Responses and -Omics Insights

James J Yu  1 , Amy L Non  2 , Erica C Heinrich  3 , Wanjun Gu  1   4 , Joe Alcock  5 , Esteban A Moya  1 , Elijah S Lawrence  1 , Michael S Tift  6 , Katie A O'Brien  1   7 , Jay F Storz  8 , Anthony V Signore  8 , Jane I Khudyakov  9 , William K Milsom  10 , Sean M Wilson  11 , Cynthia M Beall  12 , Francisco C Villafuerte  13 , Tsering Stobdan  14 , Colleen G Julian  15 , Lorna G Moore  16 , Mark M Fuster  1 , Jennifer A Stokes  17 , Richard Milner  18 , John B West  1 , Jiao Zhang  19 , John Y Shyy  19 , Ainash Childebayeva  20 , José Pablo Vázquez-Medina  21 , Luu V Pham  22 , Omar A Mesarwi  1 , James E Hall  1 , Zachary A Cheviron  23 , Jeremy Sieker  1 , Arlin B Blood  24 , Jason X Yuan  1 , Graham R Scott  24 , Brinda K Rana  25   26 , Paul J Ponganis  27 , Atul Malhotra  1 , Frank L Powell  1 , Tatum S Simonson  1
Affiliations
Review

Time Domains of Hypoxia Responses and -Omics Insights

James J Yu et al. Front Physiol. .

Abstract

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

Keywords: adaptation; high altitude; hypoxia; integrative physiology; oxygen.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Different strategies that animals utilize to overcome hypoxia. Bar-headed geese fly above the tallest mountains in the world and exhibit increased ventilation, higher blood oxygen affinity, and denser capillary networks relative to lowland species among other adaptive traits. Deer mice have adapted to high altitude through elevated Hb-O2 affinities, increased breathing, increased pulmonary oxygen uptake while attenuating sympathoadrenal activation, and other adaptive strategies. Naked mole rats are extremely hypoxia-tolerant, but knowledge of their main strategies for overcoming hypoxia is still limite. Elephant seals can dive for longer than an hour and undergo bradycardia and redistribution of peripheral blood flow to overcome hypoxia. However, unlike humans, they do not have reperfusion-related inflammation (mechanism still unknown).
FIGURE 2
FIGURE 2
Word clouds of genes under positive selection. Genes reported as top targets of positive selection in high-altitude human populations illustrated in word clouds. A total of 31 publications were used to establish word clouds based on four, fifteen, and twelve original studies from Ethiopian (A), Tibetan (B), and Andean (C) populations, respectively. All genes included are mentioned by name in the main text of at least one study and/or mentioned more than once in the supplementary materials section of the publication. Text size is indicative of the number of times a top selection candidate gene is mentioned. Gene symbols are validated using the Ensembl genome database. Major statistical methods considered in this analysis are FST, PBS, iHS and XP-EHH. Gene lists of this analysis can be found in the Supplementary Table.
FIGURE 3
FIGURE 3
Pathological conditions associated with different patterns of hypoxia. Acute or chronic exposure to high-altitude hypoxia (upper panel) can lead to several diseases including chronic mountain sickness (CMS), pulmonary hypertension, high-altitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE), and acute mountain sickness (AMS). Mechanisms underlying this variation include genetic factors, plasticity and/or lack of plasticity in ventilatory responses to hypoxia, excessive erythrocytosis, hypoxia-inducible factor (HIF) dysregulation, epigenetics, and inflammation. Additionally, clinical diseases such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) lead to chronic (sustained) hypoxia and chronic intermittent hypoxia, respectively (lower panel) and can trigger subsequent inflammation, oxidative stress, changes in gene expression, autonomic dysfunction, and hypercapnia that further contribute to various comorbidities.
FIGURE 4
FIGURE 4
Omics Adaptation to Altitude in Ethiopians, Tibetans, Andeans, and lowlanders who visit high-altitude environments (>3600 m). Genes with hypo- (green) and hyper- (red) methylated regions, differential transcriptomic regulation and/or up- (green) and down- (red) regulated families of proteins are listed by highland population. Metabolites and metabolic factors with increased levels and those that are activated in the corresponding population at high altitude are shown in green (red indicates downregulation).
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