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Tibetan sheep are indigenous to the Qinghai-Xizang Plateau. Owing to the harsh hypoxic environment in this plateau, the hemoglobin (Hb) protein in Tibetan sheep has undergone adaptive changes over time. Hb is primarily responsible for transporting O2 and CO2 between the lungs and other tissues of the body. The α subunit of Hb, encoded by the HBA gene, is a crucial component of the protein. However, whether variations in the HBA gene sequence affect the adaptation of Tibetan sheep to high-altitude hypoxia remains unclear. In this study, we sequenced the HBA gene and identified three single nucleotide polymorphisms (SNPs). These SNPs were genotyped in Tibetan and Hu sheep using Kompetitive Allele-Specific PCR (KASP). The results showed that the frequencies of the AT genotype and H1H2 haplotype were higher in Tibetan sheep than in Hu sheep. Individuals with the AT genotype exhibited higher P50 levels, whereas those with the H1H2 haplotype exhibited lower PO2 and SaO2 levels. The higher P50 levels indicated that O2 was more readily released from oxygenated Hb into the tissues, with the lower PO2 and SaO2 levels facilitating this process. These findings indicate that variations in the HBA gene sequence contribute to enhancing O2 transfer efficiency in Tibetan sheep. [ABSTRACT FROM AUTHOR]

Abstract Tibetan sheep are indigenous to the Qinghai-Xizang Plateau. Owing to the harsh hypoxic environment in this plateau, the hemoglobin (Hb) protein in Tibetan sheep has undergone adaptive changes over time. Hb is primarily responsible for transporting O2 and CO2 between the lungs and other tissues of the body. The α subunit of Hb, encoded by the HBA gene, is a crucial component of the protein. However, whether variations in the HBA gene sequence affect the adaptation of Tibetan sheep to high-altitude hypoxia remains unclear. In this study, we sequenced the HBA gene and identified three single nucleotide polymorphisms (SNPs). These SNPs were genotyped in Tibetan and Hu sheep using Kompetitive Allele-Specific PCR (KASP). The results showed that the frequencies of the AT genotype and H1H2 haplotype were higher in Tibetan sheep than in Hu sheep. Individuals with the AT genotype exhibited higher P50 levels, whereas those with the H1H2 haplotype exhibited lower PO2 and SaO2 levels. The higher P50 levels indicated that O2 was more readily released from oxygenated Hb into the tissues, with the lower PO2 and SaO2 levels facilitating this process. These findings indicate that variations in the HBA gene sequence contribute to enhancing O2 transfer efficiency in Tibetan sheep.

Introduction: The CapG gene, which is an actin-binding protein, is prevalent in eukaryotic cells and is abundantly present in various pathways associated with plateau hypoxia adaptation. Tibetan pigs, which have inhabited high altitudes for extended periods, provide an excellent research population for investigating plateau hypoxia adaptation. Results: This study focused on Tibetan pigs and Yorkshire pigs residing in Nyingchi, Tibet. The blood physiological data of Tibetan pigs were found to be significantly higher than those of Yorkshire pigs, including RBC, HGB, HCT, MCH, and MCHC. The SNP analysis of the CapG gene identified six sites with mutations only present in Tibetan pigs. Notably, the transcription factors at sites C-489T, C-274T, and A-212G were found to be altered, and these sites are known to be associated with hypoxia adaptation and blood oxygen transportation. The mRNA expression of the CapG gene exhibited highly significant differences in several tissues, with the target proteins predominantly higher in the Yorkshire pig compared to the Tibetan pig. Specifically, a notable difference was observed in the lung tissues. Immunohistochemistry analysis revealed high expression levels of CapG proteins in the lung tissues of both Tibetan and Yorkshire pigs, primarily localized in the cytoplasm and cell membrane. Conclusion: The CapG gene plays a significant role in regulating hypoxia adaptation in Tibetan pigs. This study provides a theoretical basis for the conservation and utilization of Tibetan pig resources, the breeding of highland breeds, epidemic prevention and control, and holds great importance for the development of the highland livestock economy. [ABSTRACT FROM AUTHOR]

To investigate the differences in gene expression in Himalayan marmot (Marmota himalayana) at three different altitudinal gradients and screen the candidate genes related to the adaptation of this species to the plateau low-oxygen and ultraviolet radiation environments, the non-referential transcriptomic analysis of liver tissues of M. himalayana were conducted by using the Illumina HiSeq-2500 high-throughput sequencing platform. By comparative analysis of the sequencing data after quality control and the reference genome, we screened the differentially expressed genes and then performed GO functional annotation and KEGG enrichment analysis. The results showed that the differentially expressed genes in the liver tissues of M. himalayana in the Ledu sample group (low altitude area, LD) and Yushu sample group (high altitude area, YS) differed greatly, while the difference of differentially expressed genes of this species in the Gangcha sample group(medium altitude area, GC) was small compared with the other two groups (high altitude and low altitude areas). The up-regulated genes were significantly enriched in 19 GO Terms and six KEGG pathways, and the oxidative phosphorylation-related genes (HiF-1α, MPKA3), mineral uptake and lipid metabolism-related genes (PPARs) were upregulated in the YS group. These genes may directly or indirectly play a role in the adaptation of M. himalayana to the extreme environment such as high altitude with low oxygen by adjusting the cellular metabolism, improving the redox capacity and enhancing the immune response to maintain their physiological functions and survival ability. The results of this study provide more genomic data for further research on genetic diversity of highland wildlife on hypoxic adaptation of M. himalayana. [ABSTRACT FROM AUTHOR]

Intrauterine restriction of fetal growth is one of the most interestings and nowadays intensively studied problems of modern obstetrics. Fetal growth restriction can lead to significant obstetric complications, as well as consequences after delivery. For the obstetricians the fetal growth means iatrogenic prematurity, fetal distress, perinatal morbidity but also long term consequences as metabolic disease, cardiovascular pathology and Alzhaimer disease. There was considerable controversy as to how fetal growth restriction should be defined and diagnosed. Biometric and biophysical tests have been proposed to diagnose growth restriction, but until recently there were no unanimously accepted standards for the diagnosis of this pathology. This definition was reached in 2021 by the FIGO publication. Under the condition of intrauterine hypoxia adaptation mechanisms are activated. Understanding the ongoing pathophysiological process of adaptation in a hypoxic media helps to better understand proposed diagnosis criteria and the classification.

Objective Tibetan chickens, which have unique adaptations to extreme high-altitude environments, exhibit phenotypic and physiological characteristics that are distinct from those of lowland chickens. However, the mechanisms underlying hypoxic adaptation in the liver of chickens remain unknown. Methods RNA-sequencing (RNA-Seq) technology was used to assess the differentially expressed genes (DEGs) involved in hypoxia adaptation in highland chickens (native Tibetan chicken [HT]) and lowland chickens (Langshan chicken [LS], Beijing You chicken [BJ], Qingyuan Partridge chicken [QY], and Chahua chicken [CH]). Results A total of 352 co-DEGs were specifically screened between HT and four native lowland chicken breeds. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses indicated that these co-DEGs were widely involved in lipid metabolism processes, such as the peroxisome proliferator-activated receptors (PPAR) signaling pathway, fatty acid degradation, fatty acid metabolism and fatty acid biosynthesis. To further determine the relationship from the 352 co-DEGs, protein-protein interaction network was carried out and identified eight genes (ACSL1, CPT1A, ACOX1, PPARC1A, SCD, ACSBG2, ACACA, and FASN) as the potential regulating genes that are responsible for the altitude difference between the HT and other four lowland chicken breeds. Conclusion This study provides novel insights into the molecular mechanisms regulating hypoxia adaptation via lipid metabolism in Tibetan chickens and other highland animals.

As one of the most important livestock breeds on the Qinghai-Tibet Plateau, Tibetan sheep are of great importance to the local economy, agriculture and culture. Its adaptive mechanism in low temperature and low oxygen at highland altitudes has not been reported. In this study, transcriptome sequencing was used to analyze the heart, liver, spleen, lung, kidney, and muscle tissue of sheep at low and highland altitudes. LOC101112291, SELENOW, COL3A1, GPX1, TMSB4X and HSF4 were selected as candidate genes for adapting to plateau characteristics in Tibet Sheep. Besides, glutathione metabolism, arachidonic acid metabolism, nucleotide excision repair, regulation of actin cytoskeleton, protein digestion and absorption, thyroid hormone synthesis, relaxation signaling pathways may play important roles in the adaptation to plateau hypoxia, and cold tolerance. Structural analysis also showed that sequencing genes related to the adaptation mechanism of Tibet sheep to highland altitude. This study will lay a certain foundation for Tibet sheep research. Tibet sheep are an ancient species in the Qinghai Tibet Plateau. After a long period of domestication. Tibet sheep adapt to the hypoxic environment of the plateau in terms of physiology and morphology. At the same time, Tibet sheep is also one of the major sources of material for herdsmen in tibetan. In this study, six different tissue samples (heart, liver, spleen, lung, kidney, and muscle) of Tibet sheep were analyzed to reveal the underlying mechanisms of different tissues respond to hypothermia condition. The results showed that six key genes and eight important signaling pathways involved in regulating the adaptation of Tibet sheep to the plateau. In addition, there were more alternative splicing (AS) events and single nucleotide polymorphism (SNP) sites in highland altitude Tibet sheep than in lowland altitude sheep, which was also a concern in the highland altitude adaptability of Tibet sheep. [ABSTRACT FROM AUTHOR]

The experiment was to assess hybrid Jersey cows hypoxic acclimatization blood physiological and lactation performance improvement effect. A total of 60 pure Jersey cows (about 3 800 m above sea level), 58 hybrid Jersey cows (about 3 860 m above sea level) and 56 Tibetan yellow cattle (about 3 871 m above sea level) were selected to measure DHI index, blood physiology and hemorheology indexes. The results showed that MCH, MCHC, whole blood low shear relative index, red blood cell aggregation index and coefficient, low shear flow resistance and yield stress index of hybrid Jersey cows were significantly higher than those of pure Jersey cows (P<0.05). The number of RBC, HGB, HCT, coefficient of variation of RDW, fibrinogen, plasma viscosity and red blood cell viscosity were significantly lower than those of pure Jersey cows (P<0.05). Compared with Tibetan yellow cattle, the RBC and RDW indexes of hybrid Jersey cows were significantly decreased (P<0.05). Hybrid Jersey cows milk protein rate and solid than cream was significantly higher than pure Jersey cows (P<0.05), butterfat rate was significantly lower than Tibetan yellow cattle (P<0.05), mammary volume was higher than pure Jersey cows and Tibetan yellow cattle. The experiment indicates that hybrid Jersey cows are also more able to adapt to the low oxygen environment than pure Jersey cows. [ABSTRACT FROM AUTHOR]

Tibetan chickens (Gallus gallus; TBCs) are a good model for studying hypoxia-related challenges. However, lipid composition in TBC embryonic brains has not been elucidated. In this study, we characterized brain lipid profiles of embryonic day 18 TBCs and dwarf laying chickens (DLCs) during hypoxia (13% O 2 , HTBC18, and HDLC18) and normoxia (21% O 2 , NTBC18, and NDLC18) by using lipidomics. A total of 50 lipid classes, including 3540 lipid molecular species, were identified and grouped into glycerophospholipids, sphingolipids, glycerolipids, sterols, prenols, and fatty acyls. Of these lipids, 67 and 97 were expressed at different levels in the NTBC18 and NDLC18, and HTBC18 and HDLC18 samples, respectively. Several lipid species, including phosphatidylethanolamines (PEs), hexosylceramides, phosphatidylcholines (PCs), and phospha-tidylserines (PSs), were highly expressed in HTBC18. These results suggest that TBCs adapt bet-ter to hypoxia than DLCs and may have distinct cell membrane composition and nervous system development, at least partly owing to differential expression of several lipid species. One tri-glyceride, one PC, one PS, and three PE lipids were identified as potential markers that discrim-inated between lipid profiles of the HTBC18 and HDLC18 samples. The present study provides valuable information about the dynamic composition of lipids in TBCs that may explain the adaptation of this species to hypoxia. • Lipid profile characterization of TBCs embryonic brain has been little examined. • Hypoxia leads to an altered lipid profile between TBCs and lowland chicken. • TBCs have better nervous system development regulated by different lipids. • We provides basic data for exploring hypoxia-induced problems associated with lipid. [ABSTRACT FROM AUTHOR]

The increase in atmospheric oxygen levels imposed significant environmental pressure on primitive organisms concerning intracellular oxygen concentration management. Evidence suggests the rise of cholesterol, a key molecule for cellular membrane organization, as a cellular strategy to restrain free oxygen diffusion under the new environmental conditions. During evolution and the increase in organismal complexity, cholesterol played a pivotal role in the establishment of novel and more complex functions associated with lipid membranes. Of these, caveolae, cholesterol-rich membrane domains, are signaling hubs that regulate important in situ functions. Evolution resulted in complex respiratory systems and molecular response mechanisms that ensure responses to critical events such as hypoxia facilitated oxygen diffusion and transport in complex organisms. Caveolae have been structurally and functionally associated with respiratory systems and oxygen diffusion control through their relationship with molecular response systems like hypoxia-inducible factors (HIF), and particularly as a membrane-localized oxygen sensor, controlling oxygen diffusion balanced with cellular physiological requirements. This review will focus on membrane adaptations that contribute to regulating oxygen in living systems.

ABSTRACT Tibetan pigs are characterized by significant phenotypic differences relative to lowland pigs. Our previous study demonstrated that the genes CRYAB and CTGF were differentially expressed in heart tissues between Tibetan (highland breed) and Yorkshire (lowland breed) pigs, indicating that they might participate in hypoxia adaptation. CRYAB (ɑB-crystallin) and CTGF (connective tissue growth factor) have also been reported to be associated with lung development. However, the expression patterns of CRYAB and CTGF in lung tissues at different altitudes and their genetic characterization are not well understood. In this study, qRT-PCR and western blot of lung tissue revealed higher CRYAB expression levels in highland and middle-highland Tibetan and Yorkshire pigs than in their lowland counterparts. With an increase in altitude, the expression level of CTGF increased in Tibetan pigs, whereas it decreased in Yorkshire pigs. Furthermore, two novel single-nucleotide polymorphism were identified in the 5′ flanking region of CRYAB (g.39644482C>T and g.39644132T>C) and CTGF (g.31671748A>G and g.31671773T>G). The polymorphism may partially contribute to the differences in expression levels between groups at the same altitude. These findings provide novel insights into the high-altitude hypoxia adaptations of Tibetan pigs.

Abstract Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract

Abstract The cornea is an avascular, transparent tissue that is essential for visual function. Any disturbance to the corneal transparency will result in a severe vision loss. Due to the avascular nature, the cornea acquires most of the oxygen supply directly or indirectly from the atmosphere. Corneal tissue hypoxia has been noticed to influence the structure and function of the cornea for decades. The etiology of hypoxia of the cornea is distinct from the rest of the body, mainly due to the separation of cornea from the atmosphere, such as prolonged contact lens wearing or closed eyes. Corneal hypoxia can also be found in corneal inflammation and injury when a higher oxygen requirement exceeds the oxygen supply. Systemic hypoxic state during lung diseases or high altitude also leads to corneal hypoxia when a second oxygen consumption route from aqueous humor gets blocked. Hypoxia affects the cornea in multiple aspects, including disturbance of the epithelium barrier function, corneal edema due to endothelial dysfunction and metabolism changes in the stroma, and thinning of corneal stroma. Cornea has also evolved mechanisms to adapt to the hypoxic state initiated by the activation of hypoxia inducible factor (HIF). The aim of this review is to introduce the pathology of cornea under hypoxia and the mechanism of hypoxia adaptation, to discuss the current animal models used in this field, and future research directions.

Abstract Oxygen is one of the important substances for the survival of most life systems on the earth, and plateau and underground burrow systems are two typical hypoxic environments. Small mammals living in hypoxic environments have evolved different adaptation strategies, which include increased oxygen delivery, metabolic regulation of physiological responses and other physiological responses that change tissue oxygen utilization. Multi‐omics predictions have also shown that these animals have evolved different adaptations to extreme environments. In particular, vascular endothelial growth factor (VEGF) and erythropoietin (EPO), which have specific functions in the control of O2 delivery, have evolved adaptively in small mammals in hypoxic environments. Naked mole‐rats and blind mole‐rats are typical hypoxic model animals as they have some resistance to cancer. This review primarily summarizes the main living environment of hypoxia tolerant small mammals, as well as the changes of phenotype, physiochemical characteristics and gene expression mode of their long‐term living in hypoxia environment.

Subterranean rodents could maintain their normal activities in hypoxic environments underground. Eospalax fontanierii, as one kind of subterranean rodent found in China can survive very low oxygen concentration in labs. It has been demonstrated that long non-coding RNAs (lncRNAs) have important roles in gene expression regulations at different levels and some lncRNAs were found as hypoxia-regulated lncRNAs in cancers. We predicted thousands of lncRNAs in the liver and heart tissues by analyzing RNA-Seq data in Eospalax fontanierii. Those lncRNAs often have shorter lengths, lower expression levels, and lower GC contents than mRNAs. Majors of lncRNAs have expression peaks in hypoxia conditions. We found 1128 DE-lncRNAs (differential expressed lncRNAs) responding to hypoxia. To search the miRNA regulation network for lncRNAs, we predicted 471 and 92 DE-lncRNAs acting as potential miRNA target and target mimics, respectively. We also predicted the functions of DE-lncRNAs based on the co-expression networks of lncRNA-mRNA. The DE-lncRNAs participated in the functions of biological regulation, signaling, development, oxoacid metabolic process, lipid metabolic/biosynthetic process, and catalytic activity. As the first study of lncRNAs in Eospalax fontanierii, our results show that lncRNAs are popular in transcriptome widely and can participate in multiple biological processes in hypoxia responses.

There are studies on the hypoxia adaptation in yak, but there are few studies on the regulation of ferroptosis by hypoxia. This study was the first time to explore ferroptosis-related genes about hypoxia in yak. In this study, the oviduct epithelial cells between yak and bovine are performed by integrative analysis for functions, regulating network and hub genes. The results showed 29 up-regulated ferroptosis genes and 67 down-regulated ferroptosis genes, and GO-KEGG analysis showed that up-regulated differentially expressed genes (DEGs) were significantly enriched in ribosome pathway and oxidative phosphorylation pathway. Down-regulated DEGs were significantly enriched in longevity regulating pathway-mammal pathway. Mitophagy-Animal Pathway was a significant enrichment pathway for the up-regulated differentially expressed ferroptosis genes (DE-FRGs). HIF-1 signaling pathway is a significant pathway for the down-regulated DE-FRGs. By constructing DE-FRGs protein-protein interaction (PPI) network, 10 hub DE-FRGs (Jun, STAT3, SP1, HIF1A, Mapk1, Mapk3, Rela, Ulk1, CDKN1A, EPAS1) were obtained. The bta-mir-21-5p, bta-mir-10a and bta-mir-17-5p related to STAT3 were predicted. The results of this study indicated the important genes and pathways of the hypoxia in yak, and it was the first time to study ferroptosis genes and pathways related to the hypoxia adaptation by bulk-seq in yak. This study provided sufficient transcriptome datas for hypoxia adaptation.

Ecological performance of animals depends on physiological and biochemical processes that are adjusted to the environment. The responses to hypoxia or anoxia have been frequently studied in subterranean aquatic organisms in order to find potential adaptations to restrict oxygen conditions occurring in the underground habitats. However, some previous studies have compared phylogenetic distant epigean and hypogean species or the epigean and hypogean populations of the same species due to little chance to compare closely related epigean and hypogean species. Therefore, in this study, we compared the effects of exposure to hypoxia, followed by reoxygenation, and increased temperature on oxygen consumption, potential metabolic activity, and antioxidant activities in closely related epigean and hypogean species: Niphargus zagrebensis and N. stygius. Oxygen consumption of N. stygius increased similarly during post-hypoxic recovery at 10 and 20°C (approx. 5-times), while N. zagrebensis increased its oxygen consumption for 9.7 and 4.4-times at 10 and 20°C, respectively. We observed higher exploitation of metabolic potential for current oxygen consumption during reoxygenation in N. zagrebensis than N. stygius. Exposure to hypoxia and subsequent reoxygenation at 20°C increased catalase (CAT) activity in N. stygius, but not in N. zagrebensis. We observed increased glutathione reductase activity in both Niphargus species. We concluded that respiratory and antioxidant responses to severe hypoxia and increased temperature differed between closely related epigean and hypogean Niphargus species. Hypogean Niphargus species possess physiological and biochemical characteristics that are advantageous in temperature stable subterranean environments which support inhabiting of species that have low energetic demands, while epigean Niphargus species can successfully inhabit specific surface habitats.

The Asian house rat (AHR), Rattus tanezumi, has recently invaded the northern half of China. The AHR is a highly adaptive rat species that has also successfully conquered the Qinghai‐Tibet Plateau (QTP) and replaced the brown rat (BR), R. norvegicus, at the edge of the QTP. Here, we assembled a draft genome of the AHR and explored the mechanisms of its northward invasion and the genetic basis underlying plateau adaptation in this species. Population genomic analyses revealed that the northwardly invasive AHRs consisted of two independent and genetically distinct populations which might result from multiple independent primary invasion events. One invasive population exhibited reduced genetic diversity and distinct population structure compared with its source population, while the other displayed preserved genetic polymorphisms and little genetic differentiation from its source population. Genes involved in G‐protein coupled receptors and carbohydrate metabolism may contribute to the local adaptation of northern AHRs. In particular, RTN4 was identified as a key gene for AHRs in the QTP that favours adaptation to high‐altitude hypoxia. Coincidently, the physiological performance and transcriptome profiles of hypoxia‐exposed rats both showed better hypoxia adaptation in AHRs than in BRs that failed to colonize the heart of the QTP, which may have facilitated the replacement of the BR population by the invading AHRs at the edge of the QTP. This study provides profound insights into the multiple origins of the northwardly invasive AHR and the great tolerance to hypoxia in this species. [ABSTRACT FROM AUTHOR]

Hypoxia occurs not only in natural environments including high altitude, underground burrows and deep sea, but also in human pathological conditions, such as hypoxic solid tumors. It has been well documented that hypoxia related signaling pathway is associated with a poor clinical outcome. Our group has recently identified multiple novel genes critical for solid tumor growth comparing the genome-wide convergent/parallel sequence evolution of highland mammals. Among them, a single mutation on the retinol saturase gene (RETSAT) containing amino acid switch from glutamine (Q) to arginine (R) at the position 247 was identified. Here, we demonstrate that RETSAT is mostly downregulated in multiple types of human cancers, whose lower expression correlates with worse clinical outcome. We show that higher expression of RETSAT is positively associated with immune infiltration in different human cancers. Furthermore, we identify that the promoter region of RETSAT is highly methylated, which leads to its decreased expressions in tumor tissues comparing to normal tissues. Furthermore, we show that RETSAT knockdown promotes, while its overexpression inhibits, the cell proliferation ability of mouse embryonic fibroblasts (MEFs) and B16 in vitro. In addition, the mice carrying homozygous Q247R mutation (RETSATR/R) is more resistant to xenograft tumor formation, as well as DMBA/TPA induced cutaneous keratinocyte carcinoma formation, compared to littermate wild-type (RETSATQ/Q) mice. Mechanistic study uncovers that the oncogenic factor, the prolyl isomerase (PPIase) Pin1 and its related downstream signaling pathway, were both markedly repressed in the mutant mice compared to the wild-type mice. In summary, these results suggest that interdisciplinary study between evolution and tumor biology can facilitate identification of novel molecular events essential for hypoxic solid tumor growth in the future.

Objective As an iconic symbol of Qinghai-Tibetan Plateau and of high altitude, yak are subjected to hypoxic conditions that challenge aerobic metabolism. Matrix metalloproteinases-3 (MMP3) is assumed to be a key target gene of hypoxia-inducible factor-1α that function as a master regulator of the cellular response to hypoxia. Therefore, the aim of this investigation was to identify the DNA polymorphism of MMP3 gene in domestic yak and to explore its possible association with high-altitude adaptation. Methods The single-nucleotide polymorphisms (SNPs) genotyping and mutations scanning at the MMP3 locus were conducted in total of 344 individuals from four domestic Chinese yak breeds resident at different altitudes on the Qinghai-Tibetan Plateau, using high-resolution melting analysis and DNA sequencing techniques. Results The novel of SNPs rs2381 A→G and rs4331 C→G were identified in intron V and intron VII of MMP3, respectively. Frequencies of the GG genotype and the G allele of SNP rs2381 A→G observed in high-altitude Pali yak were significantly higher than that of the other yak breeds resident at middle or low altitude (p0.05). Haplotype GC was the dominant among the 4 yak breeds, and Pearson correlation analysis showed that the frequencies of GC was significantly lower in Ganan (GN), Datong (DT), and Tianzhu white yaks (TZ) compared with Pali (PL) yak. The two SNPs were in moderate linkage disequilibrium in high-altitude yaks (PL) but not in middle-altitude (GN, DT) and low-altitude (TZ) yaks. Conclusion These results indicate that MMP3 may have been subjected to positive selection in yak, especially that the SNP rs2381 A→G mutation and GC haplotypes might contribute to adaptation for yak in high-altitude environments.

Tibetan pigs are native mammalian species on the Tibetan Plateau that have evolved distinct physiological traits that allow them to tolerate high-altitude hypoxic environments. However, the genetic mechanism underlying this adaptation remains elusive. Here, based on multitissue transcriptional data from high-altitude Tibetan pigs and low-altitude Rongchang pigs, we performed a weighted correlation network analysis (WGCNA) and identified key modules related to these tissues. Complex network analysis and bioinformatics analysis were integrated to identify key genes and three-node network motifs. We found that among the six tissues (muscle, liver, heart, spleen, kidneys, and lungs), lung tissue may be the key organs for Tibetan pigs to adapt to hypoxic environment. In the lung tissue of Tibetan pigs, we identified KLF4, BCL6B, EGR1, EPAS1, SMAD6, SMAD7, KDR, ATOH8, and CCN1 genes as potential regulators of hypoxia adaption. We found that KLF4 and EGR1 genes might simultaneously regulate the BCL6B gene, forming a KLF4–EGR1–BCL6B complex. This complex, dominated by KLF4, may enhance the hypoxia tolerance of Tibetan pigs by mediating the TGF-β signaling pathway. The complex may also affect the PI3K-Akt signaling pathway, which plays an important role in angiogenesis caused by hypoxia. Therefore, we postulate that the KLF4–EGR1–BCL6B complex may be beneficial for Tibetan pigs to survive better in the hypoxia environments. Although further molecular experiments and independent large-scale studies are needed to verify our findings, these findings may provide new details of the regulatory architecture of hypoxia-adaptive genes and are valuable for understanding the genetic mechanism of hypoxic adaptation in mammals.

Hypoxia can induce cell damage, inflammation, carcinogenesis, and inhibit liver regeneration in non-adapted species. Because of their excellent hypoxia adaptation features, subterranean rodents have been widely studied to clarify the mechanism of hypoxia adaptation. Eospalax fontanierii, which is a subterranean rodent found in China, can survive for more than 10 h under 4% O2 without observable injury, while Sprague-Dawley rats can survive for less than 6 h under the same conditions. To explore the potential mechanism of hypoxia responses in E. fontanierii, we performed RNA-seq analysis of the liver in E. fontanierii exposed to different oxygen levels (6.5% 6h, 10.5% 44h, and 21%). Based on the bioinformatics analysis, 39,439 unigenes were assembled, and 56.78% unigenes were annotated using public databases (Nr, GO, Swiss-Prot, KEGG, and Pfam). In total, 725 differentially expressed genes (DEGs) were identified in the response to hypoxia; six with important functions were validated by qPCR. Those DEGs were mainly involved in processes related to lipid metabolism, steroid catabolism, glycolysis/gluconeogenesis, and the AMPK and PPAR signaling pathway. By analyzing the expression patterns of important genes related to energy associated metabolism under hypoxia, we found that fatty acid oxidation and gluconeogenesis were increased, while protein synthesis and fatty acid synthesis were decreased. Furthermore, the upregulated expression of specific genes with anti-apoptosis or anti-oxidation functions under hypoxia may contribute to the mechanism by which E. fontanierii tolerates hypoxia. Our results provide an understanding of the response to hypoxia in E. fontanierii, and have potential value for biomedical studies.

Ecological performance of animals depends on physiological and biochemical processes that are adjusted to the environment. The responses to hypoxia or anoxia have been frequently studied in subterranean aquatic organisms in order to find potential adaptations to restrict oxygen conditions occurring in the underground habitats. However, some previous studies have compared phylogenetic distant epigean and hypogean species or the epigean and hypogean populations of the same species due to little chance to compare closely related epigean and hypogean species. Therefore, in this study, we compared the effects of exposure to hypoxia, followed by reoxygenation, and increased temperature on oxygen consumption, potential metabolic activity, and antioxidant activities in closely related epigean and hypogean species: Niphargus zagrebensis and N. stygius. Oxygen consumption of N. stygius increased similarly during post-hypoxic recovery at 10 and 20°C (approx. 5-times), while N. zagrebensis increased its oxygen consumption for 9.7 and 4.4-times at 10 and 20°C, respectively. We observed higher exploitation of metabolic potential for current oxygen consumption during reoxygenation in N. zagrebensis than N. stygius. Exposure to hypoxia and subsequent reoxygenation at 20°C increased catalase (CAT) activity in N. stygius, but not in N. zagrebensis. We observed increased glutathione reductase activity in both Niphargus species. We concluded that respiratory and antioxidant responses to severe hypoxia and increased temperature differed between closely related epigean and hypogean Niphargus species. Hypogean Niphargus species possess physiological and biochemical characteristics that are advantageous in temperature stable subterranean environments which support inhabiting of species that have low energetic demands, while epigean Niphargus species can successfully inhabit specific surface habitats. [ABSTRACT FROM AUTHOR]

Tibetan pigs are native mammalian species on the Tibetan Plateau that have evolved distinct physiological traits that allow them to tolerate high-altitude hypoxic environments. However, the genetic mechanism underlying this adaptation remains elusive. Here, based on multitissue transcriptional data from high-altitude Tibetan pigs and low-altitude Rongchang pigs, we performed a weighted correlation network analysis (WGCNA) and identified key modules related to these tissues. Complex network analysis and bioinformatics analysis were integrated to identify key genes and three-node network motifs. We found that among the six tissues (muscle, liver, heart, spleen, kidneys, and lungs), lung tissue may be the key organs for Tibetan pigs to adapt to hypoxic environment. In the lung tissue of Tibetan pigs, we identified KLF4 , BCL6B , EGR1 , EPAS1 , SMAD6 , SMAD7 , KDR , ATOH8 , and CCN1 genes as potential regulators of hypoxia adaption. We found that KLF4 and EGR1 genes might simultaneously regulate the BCL6B gene, forming a KLF4–EGR1–BCL6B complex. This complex, dominated by KLF4 , may enhance the hypoxia tolerance of Tibetan pigs by mediating the TGF-β signaling pathway. The complex may also affect the PI3K-Akt signaling pathway, which plays an important role in angiogenesis caused by hypoxia. Therefore, we postulate that the KLF4–EGR1–BCL6B complex may be beneficial for Tibetan pigs to survive better in the hypoxia environments. Although further molecular experiments and independent large-scale studies are needed to verify our findings, these findings may provide new details of the regulatory architecture of hypoxia-adaptive genes and are valuable for understanding the genetic mechanism of hypoxic adaptation in mammals. [ABSTRACT FROM AUTHOR]

The Tibetan chickens (Gallus gallus; TBCs) are an indigenous breed found in the Qinghai-Tibet Plateau that are well-adapted to a hypoxic environment. As of now, energy metabolism of the TBCs embryonic brain has been little examined. This study investigated changes in energy metabolism in TBCs during hypoxia, and compared energy metabolism in TBCs and Dwarf Laying Chickens (DLCs), a lowland chicken breed, to explore underlying mechanisms of hypoxia adaptation. We found TBCs exhibited decreased oxygen consumption rates (OCR) and ATP levels as well as an increased extracellular acidification rate (ECAR) during hypoxia. Nevertheless, OCR/ECAR ratios indicated aerobic metabolism still dominated under hypoxia. Most important, our results revealed significant differences in TBCs brain cellular metabolism compared to DLCs under hypoxia. Compared to DLCs, TBCs had higher OCR and TCA cycle activities during hypoxia. Also, TBCs had more mitochondrial content, increased mitochondrial aspect ratio and MFN1, MFN2, and OPA1 proteins which have previously been reported to control mitochondrial fusion were expressed at higher levels in TBCs compared to DLCs, suggesting that TBCs may regulate energy metabolism by increasing the level of mitochondrial fusion. In summary, TBCs can reduce aerobic metabolism and increase glycolysis to enable adaptation to hypoxia. Regulation of mitochondrial fusion via MFN1, MFN2, and OPA1 potentially enhances the ability of TBCs to survive on the Qinghai-Tibet Plateau.

Introduction: The CapG gene, which is an actin-binding protein, is prevalent in eukaryotic cells and is abundantly present in various pathways associated with plateau hypoxia adaptation. Tibetan pigs, which have inhabited high altitudes for extended periods, provide an excellent research population for investigating plateau hypoxia adaptation. Results: This study focused on Tibetan pigs and Yorkshire pigs residing in Nyingchi, Tibet. The blood physiological data of Tibetan pigs were found to be significantly higher than those of Yorkshire pigs, including RBC, HGB, HCT, MCH, and MCHC. The SNP analysis of the CapG gene identified six sites with mutations only present in Tibetan pigs. Notably, the transcription factors at sites C-489T, C-274T, and A-212G were found to be altered, and these sites are known to be associated with hypoxia adaptation and blood oxygen transportation. The mRNA expression of the CapG gene exhibited highly significant differences in several tissues, with the target proteins predominantly higher in the Yorkshire pig compared to the Tibetan pig. Specifically, a notable difference was observed in the lung tissues. Immunohistochemistry analysis revealed high expression levels of CapG proteins in the lung tissues of both Tibetan and Yorkshire pigs, primarily localized in the cytoplasm and cell membrane. Conclusion: The CapG gene plays a significant role in regulating hypoxia adaptation in Tibetan pigs. This study provides a theoretical basis for the conservation and utilization of Tibetan pig resources, the breeding of highland breeds, epidemic prevention and control, and holds great importance for the development of the highland livestock economy., Competing Interests: 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., (Copyright © 2024 Yan, Wang, Wei, Zhang, Ye, Duan, Chamba and Shang.)

Hypoxic environments occur normally at high altitude, or in underground burrows and in deep sea habitats. They also occur pathologically in human ischemia and in hypoxic solid tumors. Hypoxia in various cancer types and its related molecular mechanisms are associated with a poor clinical outcome. This review will discuss how hypoxia can influence two aspects of tumorigenesis, namely the direct, cell-intrinsic oncogenic effects, as well as the indirect effects on tumor progression mediated by an altered tumor microenvironment. We will also discuss recent progress in identifying the functional roles of hypoxia-related factors (HIFs), along with their regulators and downstream target genes, in cancer stem cells and therapy. Importantly, we propose, using convergent evolution schemes to identify novel biomarkers for both hypoxia adaptation and hypoxic solid tumors as an important strategy in the future. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factors (HIFs) are master transcription factor regulating hypoxic responses in vertebrates. Species of Schizothoracine, a sub-family of cyprinidae, are highly endemic to the hypoxic Qinghai-Tibetan Plateau (QTP). What roles the HIFs play in hypoxic adaptation in the Schizothoracine fish is little known. In this study, the HIF-1α/B gene from Gymnocypris dobula (Gd) was characterized. The predicted protein for Gd-HIF-1α/B contains the main domains (bHLH, PAS, PAC, ODD, N-TAD, and C-TAD). Moreover, a specific mutation that the proline hydroxylation motif (LXXLAP) mutated into PxxLAP was observed in Gd-HIF-1α/B CODD domain, which may lead to changes in the function. To clarify whether HIF-1α/B of G. dobula possesses hypoxic adaptive features, Gd-HIF1α/B and Schizothorax prenanti-HIF1α/B (Sp-HIF1α/B) were cloned into an expression vector and transfected into 293T cells. Cell viability was found to be significantly higher in cells transfected with Gd-HIF-1α/B than those transfected with Sp-HIF-1α/B under hypoxic conditions. In addition, G. dobula HIF-1α/B showed stronger activity in transactivating the expression of nitric oxide (NO)–synthesizing enzyme, NOS2B under hypoxia stresses than the orthologous gene from S. prenanti, which were accompanied with upregulated expressions of NOS2B in heart of G. dobula, which may attribute to elevated NO levels detected in G. dobula than the lower land species. These results indicated that the HIF-1α plays an important role in mediating the iNOS signaling system in the process of evolutionary adaptation of the Schizothoracine to the highland environment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Changes of red blood cell in peripheral blood and bone marrow erythropoietic system in plateau pikas are of great significance for hypoxic adaptation. OBJECTIVE: To explore the hypoxic adaptation of erythropoietic system in plateau pikas by comparing the morphological changes of peripheral blood and bone marrow between plateau pikas and rats exposed to hypoxia. METHODS: There were 12 healthy wild plateau pikas and 12 clean Sprague-Dawley rats and were randomly divided into experimental and control groups, 6 in each group. The experimental group animals were fed in a simulated 5 000 m altitude hypobaric hypoxia chamber for 28 consecutive days, and the control group animals were fed in the laboratory at 2 260 m altitude. RESULTS AND CONCLUSION: (1) The diameter of the erythrocytes was smaller and red blood cell count was higher in plateau pikas than those in the rats of control group. After 28 days of hypoxia, red blood cell count, hemoglobin and hematocrit were increased in both experimental groups (P < 0.001), but the increased rate of plateau pikas were less than that of the rats. The mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration showed no significant changes in plateau pikas. (2) Results of bone marrow smear showed that the proportion of polychromatic and orthochromatic erythroblasts had no significant changes in plateau pikas after hypoxia, but increased significantly in the rats (P < 0.05). (3) Hematoxylin-eosin staining results of the sternum indicated that the immature erythroblasts islands did not change significantly in plateau pikas, but increased significantly in rats. (4) So the erythroid changes in peripheral blood and bone marrow of plateau pikas before and after hypoxia are significantly lower than those of the Sprague-Dawley rats, and they may be related to the hypoxia adaptation mechanism. [ABSTRACT FROM AUTHOR]

The increase in atmospheric oxygen levels imposed significant environmental pressure on primitive organisms concerning intracellular oxygen concentration management. Evidence suggests the rise of cholesterol, a key molecule for cellular membrane organization, as a cellular strategy to restrain free oxygen diffusion under the new environmental conditions. During evolution and the increase in organismal complexity, cholesterol played a pivotal role in the establishment of novel and more complex functions associated with lipid membranes. Of these, caveolae, cholesterol-rich membrane domains, are signaling hubs that regulate important in situ functions. Evolution resulted in complex respiratory systems and molecular response mechanisms that ensure responses to critical events such as hypoxia facilitated oxygen diffusion and transport in complex organisms. Caveolae have been structurally and functionally associated with respiratory systems and oxygen diffusion control through their relationship with molecular response systems like hypoxia-inducible factors (HIF), and particularly as a membrane-localized oxygen sensor, controlling oxygen diffusion balanced with cellular physiological requirements. This review will focus on membrane adaptations that contribute to regulating oxygen in living systems.

The first ascent of Mount Everest by Tenzing Norgay and Sir Edmund Hillary in 1953 brought global attention to the Sherpa people and human performance at altitude. The Sherpa inhabit the Khumbu Valley of Nepal, and are descendants of a population that has resided continuously on the Tibetan plateau for the past ∼25,000 to 40,000 years. The long exposure of the Sherpa to an inhospitable environment has driven genetic selection and produced distinct adaptive phenotypes. This review summarizes the population history of the Sherpa and their physiological and genetic adaptation to hypoxia. Genomic studies have identified robust signals of positive selection across EPAS1, EGLN1, and PPARA, that are associated with hemoglobin levels, which likely protect the Sherpa from altitude sickness. However, the biological underpinnings of other adaptive phenotypes such as birth weight and the increased reproductive success of Sherpa women are unknown. Further studies are required to identify additional signatures of selection and refine existing Sherpa-specific adaptive phenotypes to understand how genetic factors have underpinned adaptation in this population. By correlating known and emerging signals of genetic selection with adaptive phenotypes, we can further reveal hypoxia-related biological mechanisms of adaptation. Ultimately this work could provide valuable information regarding treatments of hypoxia-related illnesses including stroke, heart failure, lung disease and cancer.

Objective: Tibetan chickens, which have unique adaptations to extreme high-altitude environments, exhibit phenotypic and physiological characteristics that are distinct from those of lowland chickens. However, the mechanisms underlying hypoxic adaptation in the liver of chickens remain unknown., Methods: RNA-sequencing (RNA-Seq) technology was used to assess the differentially expressed genes (DEGs) involved in hypoxia adaptation in highland chickens (native Tibetan chicken [HT]) and lowland chickens (Langshan chicken [LS], Beijing You chicken [BJ], Qingyuan Partridge chicken [QY], and Chahua chicken [CH])., Results: A total of 352 co-DEGs were specifically screened between HT and four native lowland chicken breeds. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses indicated that these co-DEGs were widely involved in lipid metabolism processes, such as the peroxisome proliferator-activated receptors (PPAR) signaling pathway, fatty acid degradation, fatty acid metabolism and fatty acid biosynthesis. To further determine the relationship from the 352 co-DEGs, protein-protein interaction network was carried out and identified eight genes (ACSL1, CPT1A, ACOX1, PPARC1A, SCD, ACSBG2, ACACA, and FASN) as the potential regulating genes that are responsible for the altitude difference between the HT and other four lowland chicken breeds., Conclusion: This study provides novel insights into the molecular mechanisms regulating hypoxia adaptation via lipid metabolism in Tibetan chickens and other highland animals.

High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole altitudinal range across China to uncover the genetic basis for adaptation to high-altitude hypoxia. Our genome data set includes 65 lowland animals across ten Chinese native breeds, 61 horses living at least 3,300 m above sea level across seven locations along Qinghai-Tibetan Plateau, as well as 7 Thoroughbred and 5 Przewalski's horses added for comparison. We find that Tibetan horses do not descend from Przewalski's horses but were most likely introduced from a distinct horse lineage, following the emergence of pastoral nomadism in Northwestern China ∼3,700 years ago. We identify that the endothelial PAS domain protein 1 gene (EPAS1 , also HIF2A) shows the strongest signature for positive selection in the Tibetan horse genome. Two missense mutations at this locus appear strongly associated with blood physiological parameters facilitating blood circulation as well as oxygen transportation and consumption in hypoxic conditions. Functional validation through protein mutagenesis shows that these mutations increase EPAS1 stability and its hetero dimerization affinity to ARNT (HIF1B). Our study demonstrates that missense mutations in the EPAS1 gene provided key evolutionary molecular adaptation to Tibetan horses living in high-altitude hypoxic environments. It reveals possible targets for genomic selection programs aimed at increasing hypoxia tolerance in livestock and provides a textbook example of evolutionary convergence across independent mammal lineages. [ABSTRACT FROM AUTHOR]

The first ascent of Mount Everest by Tenzing Norgay and Sir Edmund Hillary in 1953 brought global attention to the Sherpa people and human performance at altitude. The Sherpa inhabit the Khumbu Valley of Nepal, and are descendants of a population that has resided continuously on the Tibetan plateau for the past ∼25,000 to 40,000 years. The long exposure of the Sherpa to an inhospitable environment has driven genetic selection and produced distinct adaptive phenotypes. This review summarizes the population history of the Sherpa and their physiological and genetic adaptation to hypoxia. Genomic studies have identified robust signals of positive selection across EPAS1 , EGLN1 , and PPARA , that are associated with hemoglobin levels, which likely protect the Sherpa from altitude sickness. However, the biological underpinnings of other adaptive phenotypes such as birth weight and the increased reproductive success of Sherpa women are unknown. Further studies are required to identify additional signatures of selection and refine existing Sherpa-specific adaptive phenotypes to understand how genetic factors have underpinned adaptation in this population. By correlating known and emerging signals of genetic selection with adaptive phenotypes, we can further reveal hypoxia-related biological mechanisms of adaptation. Ultimately this work could provide valuable information regarding treatments of hypoxia-related illnesses including stroke, heart failure, lung disease and cancer. [ABSTRACT FROM AUTHOR]

Endothelial PAS domain protein 1 gene (EPAS1) is a key transcription factor that activates the expression of oxygen-regulated genes. In this study, in order to better understand the effects of EPAS1 gene on hematologic parameters in yak, we firstly quantified the tissue expression patterns for EPAS1 mRNA of yak, identified polymorphism in this gene and evaluated its association with hematologic parameters. Expression of EPAS1 mRNA was detected in all eight tissues (heart, liver, lung, spleen, pancreas, kidney, muscles and ovary). The expressions of EPAS1 in lung and pancreas were extremely higher than other tissues examined. Three novel single nucleotide polymorphisms (SNPs) (g.83052 C>T, g.83065 G>A and g.83067 C>A) within the EPAS1 were identified and genotyped in Pali (PL), Gannan (GN) and Tianzhu White (TZW) yak breeds. Significant higher frequencies of the AA and GA genotypes and A allele of the g.83065 G>A were observed in the PL and GN breeds than that in the TZW breed (PA polymorphism was significantly associated with hemoglobin (HGB) concentration in yaks (P

Background--Hypoxia is often associated with cardiopulmonary diseases, which represent some of the leading causes of mortality worldwide. Long-term hypoxia exposures, whether from disease or environmental condition, can cause cardiomyopathy and lead to heart failure. Indeed, hypoxia-induced heart failure is a hallmark feature of chronic mountain sickness in maladapted populations living at high altitude. In a previously established Drosophila heart model for long-term hypoxia exposure, we found that hypoxia caused heart dysfunction. Calcineurin is known to be critical in cardiac hypertrophy under normoxia, but its role in the heart under hypoxia is poorly understood. Methods and Results--In the present study, we explore the function of calcineurin, a gene candidate we found downregulated in the Drosophila heart after lifetime and multigenerational hypoxia exposure. We examined the roles of 2 homologs of Calcineurin A, CanA14F, and Pp2B in the Drosophila cardiac response to long-term hypoxia. We found that knockdown of these calcineurin catalytic subunits caused cardiac restriction under normoxia that are further aggravated under hypoxia. Conversely, cardiac overexpression of Pp2B under hypoxia was lethal, suggesting that a hypertrophic signal in the presence of insufficient oxygen supply is deleterious. Conclusions--Our results suggest a key role for calcineurin in cardiac remodeling during long-term hypoxia with implications for diseases of chronic hypoxia, and it likely contributes to mechanisms underlying these disease states. [ABSTRACT FROM AUTHOR]

Erythrocytes are vital to human adaptation under hypoxic conditions because of their abundance in number and irreplaceable function of delivering oxygen (O2). However, although multiple large-scale altitude studies investigating the overall coordination of the human body for hypoxia adaptation have been conducted, detailed research with a focus on erythrocytes was missing due to lack of proper techniques. The recently maturing metabolomics profiling technology appears to be the answer to this limitation. Metabolomics profiling provides unbiased high-throughput screening data that reveal the overall metabolic status of erythrocytes. Recent studies have exploited this new technology and provided novel insight into erythrocyte physiology and pathology. In particular, a series of studies focusing on erythrocyte purinergic signaling have reported that adenosine signaling, coupled with 5′ AMP-activated protein kinase (AMPK) and the production of erythrocyte-enriched bioactive signaling lipid sphingosine 1-phosphate, regulate erythrocyte glucose metabolism for more O2 delivery. Moreover, an adenosine-dependent “erythrocyte hypoxic memory” was discovered that provides an explanation for fast acclimation upon re-ascent. These findings not only shed new light on our understanding of erythrocyte function and hypoxia adaptation, but also offer a myriad of novel therapeutic possibilities to counteract various hypoxic conditions. [ABSTRACT FROM AUTHOR]

To determine specific metabolic alterations in the myocardium of plateau pikas (Ochotona curzoniae) and potential metabolic biomarkers involved in their adaptation to the high-altitude environment of the Qinghai-Tibet Plateau. Ten pikas were captured by traps in the Kekexili Reserve (4630m a.s.l; n = 5) and at the foot of the Laji Mountain (2600m a.s.l; n = 5) on the Qinghai-Tibet Plateau, Qinghai Province, China. Metabolite levels were determined by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) metabolomics, and multivariate statistical analysis was performed. Several metabolites involved in carbohydrate, fat, energy, and redox homeostasis pathways were significantly altered in pikas living at 4630 m. In addition, those pikas showed increased levels of lactic acid, sarcosine, 4-hydroxybutyrate, methionine, tartaric acid, ribose, tyrosine, pentadecanoic acid, 2-monoolein, 3,5-dihydroxyphenylglycine, trehalose-6-phosphate, succinic acid, myoinositol, fumaric acid, taurine, 2-hydroxybutanoic acid, gluconic acid, citrulline, and glutathione, but decreased levels of oleic acid and 2'-deoxyadenosine 5'-monophosphate. Metabolic activity is significantly altered in the myocardium of pikas in the high-altitude areas of the Qinghai-Tibet Plateau. This study provides important insights into metabolic biomarkers related to the adaptation of pikas to high-altitude hypoxia. [ABSTRACT FROM AUTHOR]

Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing Vmax and Km. Pharmacological activation of AMP-activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF-1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF-1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia. [ABSTRACT FROM AUTHOR]

Hypoxia tolerance is a plastic trait, and can vary between species. We compared hypoxia tolerance (hypoxic loss of equilibrium, LOE, and critical O 2 tension, P crit ) and traits that dictate O 2 transport and metabolism in pumpkinseed ( Lepomis gibbosus ), bluegill ( L. macrochirus ), and the naturally occurring hybrid in different acclimation environments (wild versus lab-acclimated fish) and at different temperatures. Wild fish generally had lower P crit and lower PO 2 at LOE in progressive hypoxia than lab-acclimated fish, but time to LOE in sustained hypoxia (PO 2 of 2 kPa) did not vary between environments. Wild fish also had greater gill surface area and higher haematocrit, suggesting that increased O 2 transport capacity underlies the environmental variation in P crit . Metabolic (lactate dehydrogenase, LDH; pyruvate kinase, PK; citrate synthase; cytochrome c oxidase) and antioxidant (catalase and superoxide dismutase) enzyme activities varied appreciably between environments. Wild fish had higher protein contents across tissues and higher activities of LDH in heart, PK in brain, and catalase in brain, liver, and skeletal muscle. Otherwise, wild fish had lower activities for most enzymes. Warming temperature from 15 to 25 °C increased O 2 consumption rate, P crit , PO 2 at LOE, and haemoglobin-O 2 affinity, and decreased time to LOE, but pumpkinseed had ≥ 2-fold longer time to LOE than bluegill and hybrids across this temperature range. This was associated with higher LDH activities in the heart and muscle, and lower or similar antioxidant enzyme activities in several tissues. However, the greater hypoxia tolerance of pumpkinseed collapsed at 28 °C, demonstrating that the interactive effects of hypoxia and warming temperature can differ between species. Overall, distinct mechanisms appear to underpin interspecific and environment-induced variation in hypoxia tolerance in sunfish. [ABSTRACT FROM AUTHOR]

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DNA sequence variation has been widely reported as the genetic basis for adaptation, in both humans and other animals, to the hypoxic environment experienced at high altitudes. However, little is known about the patterns of gene expression underlying such hypoxic adaptations. In this study, we examined the differences in the transcriptomes of four organs (heart, kidney, liver and lung) between yak and cattle, a pair of closely related species distributed at high and low altitudes respectively. Of the four organs examined, heart shows the greatest differentiation between the two species in terms of gene expression profiles. Detailed analyses demonstrated that some genes associated with the oxygen supply system and the defense systems that respond to threats of hypoxia are differentially expressed. In addition, genes with significantly differentiated patterns of expression in all organs exhibited an unexpected uniformity of regulation along with an elevated frequency of nonsynonymous substitutions. This co-evolution of protein sequences and gene expression patterns is likely to be correlated with the optimization of the yak metabolic system to resist hypoxia. [ABSTRACT FROM AUTHOR]