Multi-omics atlas of chronic exercise.

Eight weeks of voluntary wheel running in mice induced widespread, tissue-specific multi-omic remodeling across 22 tissues and plasma, with the largest transcriptomic changes in skeletal muscle and canonical fiber-type switching. Most tissues changed more during the active phase, except hypothalamus, kidney, and lung, and females showed broader transcriptional responses. Pairing single-nucleus methylomes with transcriptomes resolved the cell types driving epigenetic remodeling, including coordinated gene-body demethylation tracking fiber-type switching in specific myonuclei, and machine learning identified conserved exercise signatures across mammalian species.