Metabolomic Signatures of Habitual Physical Activity in Childhood

Physical activity (PA) supports health across the life course, yet the biological pathways linking habitual PA to long-term health remain incompletely understood. Metabolomics provides a powerful tool to study PA-related metabolic adaptations, but how habitual PA shapes the metabolome in childhood remains poorly characterized. Addressing this gap, we examined cross-sectional associations between accelerometer-measured habitual PA and the plasma metabolome in 515 children aged 5.5 to 11 years from the European Childhood Obesity Project (CHOP) and additionally determined whether associations differed between sexes and across the body mass index (BMI) range. Using targeted metabolomics, we quantified 315 metabolites and derived 91 metabolite sums and ratios. Associations with PA were assessed using linear mixed-effects models. Replication was performed in an independent pediatric cohort. Among the 406 metabolite variables, 73 were associated (p < 0.05) with at least one PA variable, of which 12 replicated, including lysophosphatidylcholine (LPC) a C14:0 and LPCs/phosphatidylcholines (PCs) with higher levels in more active children, and PC aa C40:6, monounsaturated PCs/saturated PCs, and valine/LPC a C18:1 with lower levels in more active children. At the metabolite-class level, intensity-dependent association patterns emerged. Amino acids and acylcarnitines were lower in more active children predominantly for time spent in higher-intensity PA, whereas LPCs were higher mainly with more total PA (80% light PA) and less sedentary time. Associations were more pronounced at older ages and differed (p < 0.05) by BMI for 42 metabolite variables and by sex for 45 variables in the interaction analyses. These findings provide insights into PA-related metabolic adaptations early in life and may help elucidate biological pathways linking childhood PA to long-term health.