title: AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.
abstract: Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260 m) for 1, 7, and 16 days, and following reascent after 7 days at 1525 m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000 m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide, and sulfur/H2S metabolism. Metabolic adaptations were preserved 1 week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Angelo
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Travis
authors.initials: T
authors.lastname: Nemkov
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston , Houston, Texas, United States.
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston , Houston, Texas, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston , Houston, Texas, United States.
authors.forename: Anren
authors.initials: A
authors.lastname: Song
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado , Anschutz Medical Campus, Aurora, Colorado, United States.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Monte
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado , Anschutz Medical Campus, Aurora, Colorado, United States.|Department of Biology, University of Colorado Colorado Springs , Colorado Springs, Colorado, United States.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Subudhi
authors.affiliation: Department of Human Physiology, University of Oregon , Eugene, Oregon, United States.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lovering
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado , Anschutz Medical Campus, Aurora, Colorado, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dvorkin
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado , Anschutz Medical Campus, Aurora, Colorado, United States.
authors.forename: Colleen G
authors.initials: CG
authors.lastname: Julian
authors.affiliation: Department of Pathology, Centre for Cardiovascular Diseases and Sciences, LSU Health , Shreveport, Louisiana, United States.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Kevil
authors.affiliation: Department of Pathology, Centre for Cardiovascular Diseases and Sciences, LSU Health , Shreveport, Louisiana, United States.
authors.forename: Gopi K
authors.initials: GK
authors.lastname: Kolluru
authors.affiliation: Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania, United States.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Department of Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston , Houston, Texas, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver , Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Hansen
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado , Anschutz Medical Campus, Aurora, Colorado, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Roach
mesh_terms: D000064:Acclimatization / Q000502:physiology; D000222:Adaptation, Physiological; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000378:metabolism* / Q000503:physiopathology; D001120:Arginine / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis; D064368:Healthy Volunteers; D006801:Humans; D010427:Pentose Phosphate Pathway; D011687:Purines / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
chemical_list: D011687:Purines; D013455:Sulfur; D001120:Arginine; D005978:Glutathione
keywords: hydrogen sulfide; mass spectrometry; metabolic linkage; metabolomics; nitric oxide; red blood cell