Abstract
At high altitude oxygen delivery to the tissues is impaired leading to oxygen insufficiency (hypoxia). Acclimatisation requires adjustment to tissue metabolism, the details of which remain incompletely understood. Here, metabolic responses to progressive environmental hypoxia were assessed through metabolomic and lipidomic profiling of human plasma taken from 198 human participants before and during an ascent to Everest Base Camp (5,300 m). Aqueous and lipid fractions of plasma were separated and analysed using proton (1H)-nuclear magnetic resonance spectroscopy and direct infusion mass spectrometry, respectively. Bayesian robust hierarchical regression revealed decreasing isoleucine with ascent alongside increasing lactate and decreasing glucose, which may point towards increased glycolytic rate. Changes in the lipid profile with ascent included a decrease in triglycerides (48–50 carbons) associated with de novo lipogenesis, alongside increases in circulating levels of the most abundant free fatty acids (palmitic, linoleic and oleic acids). Together, this may be indicative of fat store mobilisation. This study provides the first broad metabolomic account of progressive exposure to environmental hypobaric hypoxia in healthy humans. Decreased isoleucine is of particular interest as a potential contributor to muscle catabolism observed with exposure to hypoxia at altitude. Substantial changes in lipid metabolism may represent important metabolic responses to sub-acute exposure to environmental hypoxia.
Highlights
Reduced cellular oxygen availability is a feature of many disease states
Ascent to high altitude resulting in exposure to environmental hypobaric hypoxia may reduce tissue oxygen availability: the associated fall in barometric pressure is in turn associated with a decrease in the inspired partial pressure of oxygen (PO2)
Enhanced glycolytic capacity has been suggested by increased intramuscular levels of glycolytic intermediates[8] and hypoxic inducible factor 1-α (HIF-1α) mediated upregulation of glucose transporters and glycolytic enzymes[9,10]
Summary
Reduced cellular oxygen availability (hypoxia) is a feature of many disease states. Oxygen delivery may be globally impaired by diseases of the heart or lung, or by anaemia (in which the concentration of oxygen-carrying haemoglobin is reduced); or regionally or locally impaired by macrovascular and microvascular disease respectively[1,2]. Studies examining metabolic acclimatisation in healthy human lowlanders have predominantly focused upon tissue specific responses, those of skeletal muscle These suggest a shift away from oxidative processes including β-oxidation, TCA cycle activity and oxidative phosphorylation (reviewed in5) and towards increased reliance upon carbohydrate metabolism. Hypoxia-induced alterations to lipid storage and mobilisation include a fall in circulating high density lipoproteins alongside increased triglyceride (TG) concentrations[11], inhibition of lipoprotein lipase activity[12] and suppression of de novo lipogenesis[13,14] These responses are likely to be mediated at the transcriptional level through HIF-1/2α15–17 and may be affected by changes in circulating catecholamines[6,11], which are known to stimulate lipolysis via hormone sensitive lipase[18]. A transcriptional regulator of fatty acid oxidation in the liver, heart and muscle, peroxisome proliferator activated receptor α (PPARα), has been identified as a key regulator of hypoxic metabolic remodeling processes, with the metabolic adaptations of native high altitude Sherpa populations being linked to a putatively advantageous allele for the PPARα gene[8,19,20]
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