An organism‐wide atlas of tissue crosstalk in physical activity

Abstract

Physical activity is a powerful physiologic stimulus that evokes tissue crosstalk and provides benefits for multiple organ systems. However, our understanding of how exercise remodels endocrine communication pathways remains largely incomplete due to a lack of tools. We have previously developed a chemical biology technology to label the collection of secreted proteins (e.g., secretome) from blood plasma in a cell type‐selective manner in mice1. Here we apply our approach to generating a 10‐organ, 21‐cell type plasma proteome atlas of secreted proteins in response to treadmill running in mice. 3% of detected protein‐cell type pairs exhibit selective bidirectional changes in response to exercise. Our secretome atlas validates known exercise‐regulated cell type–protein pairs, identifies new cellular sources for exercise‐regulated plasma proteins and discovers undescribed protein hormones that recapitulate the potent anti‐obesity effect of physical activity. We further show that the change in protein secretion from multiple cell types is induced in part by the elevation of extracellular lactate. On the cell type level, surprisingly, PDGFRa+ cells exhibit the most dynamic exercise‐regulated secretome, exceeding that of other classically exercise‐responsive cell types including myocytes, adipocytes, and hepatocytes. Further functional analysis reveals dramatic downregulation of several complement proteins from PDGFRa+ cells and may explain the anti‐fibrotic effect of physical activity across multiple organs. Taken together, these data provide a molecular and cell type‐specific map and uncover fundamental regulation of the dynamic changes to secreted polypeptides that mediate tissue crosstalk in physical activity.1. Wei, W*., Riley, NM* et al. Cell type‐selective secretome profiling in vivo. Nat Chem Biol (2021).