Metabolite Modulation in Human Plasma in the Early Phase of Acclimatization to Hypobaric Hypoxia

Abstract

The exposure of healthy subjects to high altitude represents a model to explore the pathophysiology of diseases related to tissue hypoxia. We explored a plasma metabolomics approach to detect alterations induced by the exposure of subjects to high altitude. Plasma samples were collected from 60 subjects both on plain and at high altitude (5300 m). Metabolite profiling was performed by gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS) in conjunction with univariate and multivariate statistical analyses. ELISA assays were further employed to measure the levels of several relevant enzymes together with perturbed metabolic pathways. The results showed that hypobaric hypoxia caused significant and comprehensive metabolic changes, as represented by significant changes of 44 metabolites and 4 relevant enzymes. Using MetaboAnalyst 3.0, it was found that several key metabolic pathways were acutely perturbed. In addition, 5 differentially expressed metabolites in pre-exposure samples from the acute mountain sickness-susceptible (AMS-S) group compared with those from the AMS-resistant (AMS-R) group are identified, which warrant further validation as potential predictive biomarkers for AMS-S individuals. These results provide new insights for further understanding the pathophysiological mechanism of early acclimatization to hypobaric hypoxia and other diseases correlated to tissue hypoxia.

Characterizing the plasma metabolome during 14 days of live‐high, train‐low simulated altitude: A metabolomic approach

“…() reported increased concentrations of blood lactate, succinate and citrate in 60 healthy male volunteers exposed to an altitude of 5300 m. It is likely that differences between our findings and those of Liao et al. () are methodological in nature, because varying effects on metabolic pathways have been observed between moderate (2000–3000 m) and high (3000–5500 m) altitudes (Lou et al., ). The use of moderate altitude exposure in the present study would probably have promoted different physiological responses when compared with studies completed at higher altitudes, albeit that athletes favour the use of moderate altitude so that they can continue to train effectively (Chapman, Stickford, & Levine, ).…”

“…For example, Liao et al. () reported increased concentrations of blood lactate, succinate and citrate in 60 healthy male volunteers exposed to an altitude of 5300 m. It is likely that differences between our findings and those of Liao et al. () are methodological in nature, because varying effects on metabolic pathways have been observed between moderate (2000–3000 m) and high (3000–5500 m) altitudes (Lou et al., ).…”

“…Although several haematological and non-haematological changes are well defined after hypoxic exposure (Gore et al, 2007;Reynafarje, Ramos, Faura, & Villavicencio, 1964), to our knowledge the pre- (Holden et al, 1995;Liao et al, 2016). Horscroft and Murray (2014) recently suggested that promotion of amino acids as energy substrates might be favoured during high-altitude exposure.…”

“…Changes in plasma amino acids were observed to decrease and might reflect metabolic remodelling in order to meet energy requirements. Decreased concentrations of several plasma amino acids, such as proline and tyrosine, during altitude exposure might reflect utilization of glucogenic substrates (Holden et al., ; Liao et al., ). Horscroft and Murray () recently suggested that promotion of amino acids as energy substrates might be favoured during high‐altitude exposure.…”

Hypoxia and Inactivity Related Physiological Changes (Constipation, Inflammation) Are Not Reflected at the Level of Gut Metabolites and Butyrate Producing Microbial Community: The PlanHab Study

“…From a physiological perspective, inactivity was shown to result in tissue hypoxia through reduced capillary oxyhemoglobin saturation, changes in muscle composition, modified expression of genes, and cellular metabolism and release of pro-inflammatory cytokines (Bermon et al, 2015; Ringseis et al, 2015; Liao et al, 2016). On the other hand, adaptation to hypoxia results in coordinated cascade-like down-regulation of metabolic demands and supply to prevent a mismatch in ATP utilization and production in cell tissues (Wheaton and Chandel, 2011).…”