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Regular exercise and a physically active lifestyle have favorable effects on health. Several issues related to this theme are addressed in this report. A comment on the requirements of personalized exercise medicine and in-depth biological profiling along with the opportunities that they offer is presented. This is followed by a brief overview of the evidence for the contributions of genetic differences to the ability to benefit from regular exercise. Subsequently, studies showing that mutations in TP53 influence exercise capacity in mice and humans are succinctly described. The evidence for effects of exercise on endothelial function in health and disease also is covered. Finally, changes in cardiac and skeletal muscle in response to exercise and their implications for patients with cardiac disease are summarized. Innovative research strategies are needed to define the molecular mechanisms involved in adaptation to …