Kurgan, N.; Kjaergaard, J.; Jespersen, N. Z.; Diez-Obrero, V.; Moreno-Justicia, R.; Heywood, S. E.; Lindqvist, C. B.; Ottander, L.; Samodova-Sommer, D.; Nielsen, N. S.; Durrer, C. G.; Ried-Larsen, M.; Rasmussen, S.; Loos, R. J. F.; Smit, R. A. J.; Pedersen, B. K.; Deshmukh, A. S.

Physical activity improves health, yet the molecular mechanisms remain partially understood. This study presents a high-resolution, time-resolved atlas profiling 10,127 proteins across plasma, saliva, and urine from healthy adults post-acute exercise. Exercise regulated over 3,000 proteins, revealing distinct, fluid-specific temporal dynamics. By integrating fluid-specific exercise signatures with tissue and disease atlases, we delineated the contribution of tissues and associations to various diseases. Network analysis across body fluids elucidated coordinated remodeling in the extracellular matrix and immune activation orchestrating exercise-induced networks. Many exercise-responsive plasma proteins were robust across age, sex, and exercise modalities, indicating a conserved systemic signature. Integration with genetic data established exercise-regulated proteins as modulators of metabolic traits and identified over 200 targeted by approved drugs, highlighting their impact on disease-relevant pathways. This comprehensive atlas, available as an open-access resource cbmr.ku.dk/research/research-groups/deshmukh-group/shiny-apps/, advances our molecular insight into exercise adaptations and enables exerkine discovery, biomarker development, and pharmacological exercise-mimetic strategies.