Author(s): MARTIN, D., STAUFFER E., CHAMPIGNEULLE B., PICHON A., ROBACH P., BRUGNIAUX J., NADER E., CONNES P., TARDIVEL, C., CAZADE, M., VERGÈS S., MARTIN J. C., Institution: UNIVERSITY OF RENNES, Country: FRANCE, Abstract-ID: 2146

INTRODUCTION:
Chronic hypoxia associated with high-altitude residence represents a major environmental constraint requiring profound biological adaptation. While adaptive mechanisms allow many highlanders to maintain physiological homeostasis, prolonged or extreme exposure can lead to maladaptive conditions such as chronic mountain sickness (CMS). The metabolic determinants underlying inter-individual variability in adaptation to hypoxia remain incompletely understood. This study aimed (i) to characterize systemic metabolic and erythrocyte adaptations to chronic hypoxia and (ii) to identify biological signatures associated with CMS severity.
METHODS:
We integrated untargeted blood (plasma and erythrocytes) metabolomic and lipidomic data from two independent human cohorts within the Expedition 5300 research program, including individuals living at sea level, moderate altitude (3,800 m), and very high altitude (5,100–5,300 m). The first expedition was used to model altitude- and CMS-associated biological signatures, while the second served as an external validation cohort. Multivariate hierarchical models (HPLS-DA), redundancy analyses, and machine-learning approaches were applied to jointly analyse metabolic, lipidomic, clinical, and hemorheological parameters.
RESULTS:
The plasma metabolome robustly discriminates the living altitude and reveals a marked remodelling of energy metabolism. Reduced availability of metabolites related to fatty acid β-oxidation, including L-carnitine and its precursor, is strongly associated with decreased oxygen availability (Spearman’s r = 0.53, p < 0.001). Concomitantly, increased circulating Nicotinamide and Lactate levels indicate a coordinated shift toward anaerobic glycolytic metabolism at the whole-organism level. CMS severity is specifically associated with reduced Nicotinamide levels among individuals living at very high altitudes, revealing a potential target to limit hypoxia-induced maladaptation. At the erythrocyte level, chronic hypoxia induces substantial remodelling of their membrane lipidome. Distinct lipid clusters are associated with blood viscosity, erythrocyte deformability and aggregation, and haemoglobin concentration. Notably, a specific phosphatidylserine species -PS(16:0/18:1)- is associated with increased haemoglobin concentration (Spearman’s r = 0.45, p < 0.01), suggesting altered erythrocyte turnover and potentially impaired eryptosis.
CONCLUSION:
Our results reveal systemic adaptations to chronic hypoxia involving coordinated modulation of energy metabolism and erythrocyte membrane composition. Nicotinamide availability and specific erythrocyte lipid signatures emerge as key determinants of successful adaptation or maladaptation to high altitude. These findings provide a mechanistic framework linking metabolic flexibility, red blood cell properties, and CMS severity, and suggest potential nutritional or therapeutic strategies to mitigate hypoxia-related pathologies.