Investigation into metabolic profile changes in environmental hypoxia and the potential for dietary nitrate to alleviate hypoxic stress.

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Oxygen (O2) insufficiency (hypoxia), either in response to environmental exposure or pathological states is a driver of metabolic remodelling, the details of which are ill- defined. This work aimed to further understanding of metabolic responses to environmental hypoxia. In the first study, plasma metabolite changes were measured in 198 human subjects upon ascent to Everest Base Camp (5300m) using metabolomic and lipidomic techniques. Results were indicative of a shift towards anaerobic glycolysis, a mobilisation of fat stores and alterations to fat lipoprotein transport with ascent. In the second study, a pilot study, subjects (n=5) were examined pre and post an attempted winter crossing of Antarctica, including a 24 week stay above 2,500m. Metabolomics analysis of serum samples alongside whole body physiological and exercise measurements were indicative of a shift in metabolic signature, including an increased reliance upon carbohydrate metabolism during exercise.
Developing a means of attenuating the metabolic stress of hypoxia would be highly beneficial for aiding human adaptation and ameliorating the effects of disease states where hypoxia is a comorbidity. An additional aim was to explore the potential of dietary nitrate for this purpose. In the third study, the potential for nitrate supplementation to aid hypoxic acclimatisation of skeletal muscle mitochondria and the role of PPARα (a master regulator of fat oxidation) were assessed using a mouse model of wild type (n=42) and PPARα-/- strains (n=42). Nitrate supplementation (0.7mM) recovered hypoxic induced decreases in fatty acid and carbohydrate oxidation in response to prolonged, severe hypoxic exposure (10% O2, 28 days) and did so independently of PPARα. In the fourth study, the effects of acute dietary nitrate supplementation (12mM nitrate vs. placebo ingested 3 hours pre-exercise) upon exercise endurance and related metabolite changes were investigated in chronic obstructive pulmonary disease (COPD) patients (n=21, age 68+7 years). Whilst neither median endurance time nor targeted plasma metabolites differed between treatments, O2 consumption was significantly lower following nitrate treatment vs. placebo. The absence of plasma lactate changes between treatments indicates this effect was not mediated through increased reliance upon anaerobic metabolism.
In conclusion, this work highlighted several potential biomarkers of interest in healthy humans exposed to environmental hypoxia, including alterations to carbohydrate and lipid metabolism. Dietary nitrate demonstrated potential for recovering metabolic function in vitro, yet failed to illicit beneficial effects in a clinical population in vivo.
Date of Award2017
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorStephen Harridge (Supervisor) & Lindsay Edwards (Supervisor)

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