Abstract
Ultra-endurance exercise places extreme physiological demands on oxygen transport, yet its impact on red blood cells (RBCs) remains underexplored. We conducted a multi-omics analysis of plasma and RBCs from endurance athletes before and after a 40-km trail race (MCC) and a 171-km ultramarathon (UTMB (®) ). Ultra-running led to oxidative stress, metabolic shifts, and inflammation-driven RBC damage, including increased acylcarnitines, kynurenine accumulation, oxidative lipid and protein modifications, reduced RBC deformability, enhanced microparticle release, and increased senescence markers such as externalized phosphatidylserine (PS). Post-race interleukin-6 strongly correlated with kynurenine elevation, mirroring inflammatory responses in severe infections. These findings challenge the assumption that RBC damage in endurance exercise is primarily mechanical, revealing systemic inflammation and metabolic remodeling as key drivers. This study underscores RBCs as both mediators and casualties of extreme exercise stress, with implications for optimizing athlete recovery, endurance training, and understanding inflammation-linked RBC dysfunction in clinical settings. TEASER: Marathon running imparts molecular damage to red blood cells, the effects of which are exacerbated by increased distances of ultramarathons.