The metabolic signature of excessive endurance exercise—A prospective study in Tour de France cyclists

Despite well-established health benefits of regular exercise, molecular mechanisms driving performance adaptations and potential adverse health effects of excessive endurance exercise warrant further investigation. We leveraged the Tour de France (TdF) as an ecological model to characterize the systemic metabolic response to excessive endurance exercise in elite cyclists using targeted and untargeted metabolomics on fasted blood samples. Our analyses revealed significant alterations in 43% of measured metabolites, with pronounced changes during the initial 10 days, followed by further deterioration throughout the race. In contrast to acute exercise responses, the TdF predominantly decreased circulating metabolite availability across multiple pathways, including depletion of amino acids, specific saturated fatty acids, and medium/long-chain acylcarnitines. These findings provide mechanistic insights into the impact of excessive endurance exercise on systemic metabolism and identify potential targets for intervention strategies to maximize performance while minimizing adverse health consequences.