Organism-wide secretome mapping of tissue crosstalk in exercise

Physical activity is a powerful physiologic stimulus that provides benefits to multiple organ systems and confers protection against disease. These physiologic effects are in part mediated by blood-borne factors that mediate tissue crosstalk and function as molecular effectors of physical activity. To globally understand how physical activity reshapes cellular secretomes, here we applied a proximity biotinylation approach to profile cell type-specific secretomes from blood plasma following treadmill running in mice. This organism-wide, 21-cell type, 10-tissue in-vivo secretome atlas reveals complex cell type-specific and bidirectional modulation of secreted proteins across all cell types following exercise training. We identify a gradient of secretome responses across cell types, with secretomes from Pdgfra+ being one of the most exercise-responsive in the entire dataset. Peptide-level correlation analysis revealed widespread and cell type-specific exercise regulation of secreted proteoforms. Finally, we show that exercise-inducible secretion of soluble CES2 proteins from the liver suppresses obesity in high fat diet-fed mouse models. Together, these data identify specific exercise-regulated cell types and secreted proteins and illuminate the dynamic remodeling of cell and tissue crosstalk by physical activity.