Intrinsic and Extrinsic Contributors to the Cardiac Benefits of Exercise

•This review discusses systemic and cardiac adaptations contributing to the benefits of exercise, including changes in cardiomyocyte function, growth and proliferation, coronary microvasculature and lymphatics, cardiac fibrosis, systemic and cardiac metabolism and inflammation, and effects related to the gut microbiome.•Insights from mechanistic and preclinical studies of exercise adaptation highlight the value of exercise as a platform for discovering potential therapeutic targets.