title: Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest.
abstract: Ascent to high altitude is associated with a fall in the partial pressure of inspired oxygen (hypobaric hypoxia). For oxidative tissues such as skeletal muscle, resultant cellular hypoxia necessitates acclimatization to optimize energy metabolism and restrict oxidative stress, with changes in gene and protein expression that alter mitochondrial function. It is known that lowlanders returning from high altitude have decreased muscle mitochondrial densities, yet the underlying transcriptional mechanisms and time course are poorly understood. To explore these, we measured gene and protein expression plus ultrastructure in muscle biopsies of lowlanders at sea level and following exposure to hypobaric hypoxia. Subacute exposure (19 d after initiating ascent to Everest base camp, 5300 m) was not associated with mitochondrial loss. After 66 d at altitude and ascent beyond 6400 m, mitochondrial densities fell by 21%, with loss of 73% of subsarcolemmal mitochondria. Correspondingly, levels of the transcriptional coactivator PGC-1α fell by 35%, suggesting down-regulation of mitochondrial biogenesis. Sustained hypoxia also decreased expression of electron transport chain complexes I and IV and UCP3 levels. We suggest that during subacute hypoxia, mitochondria might be protected from oxidative stress. However, following sustained exposure, mitochondrial biogenesis is deactivated and uncoupling down-regulated, perhaps to improve the efficiency of ATP production.
authors.affiliation: Centre for Altitude, Space, and Extreme Environment Medicine, University College London (UCL) Institute of Child Health, University College London, London, UK.
authors.forename: Denny Z
authors.initials: DZ
authors.lastname: Levett
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Radford
authors.forename: David A
authors.initials: DA
authors.lastname: Menassa
authors.forename: E Franziska
authors.initials: EF
authors.lastname: Graber
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Morash
authors.forename: Hans
authors.initials: H
authors.lastname: Hoppeler
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Martin
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.forename: Hugh E
authors.initials: HE
authors.lastname: Montgomery
authors.forename: Michael P W
authors.initials: MP
authors.lastname: Grocott
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murray
mesh_terms: D000064:Acclimatization / Q000502:physiology*; D000328:Adult; D000531:Altitude; D001706:Biopsy; D004734:Energy Metabolism / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000648:ultrastructure; D009051:Mountaineering / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology* / Q000648:ultrastructure; D012313:RNA / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D009124:Muscle Proteins; D012313:RNA