Reboul C. Moderate exercise prevents impaired Ca 2ϩ handling in heart of CO-exposed rat: implication for sensitivity to ischemia-reperfusion.Sustained urban carbon monoxide (CO) exposure exacerbates heart vulnerability to isch-emia-reperfusion via deleterious effects on the antioxidant status and Ca 2ϩ homeostasis of cardiomyocytes. The aim of this work was to evaluate whether moderate exercise training prevents these effects. Wistar rats were randomly assigned to a control group and to CO groups, living during 4 wk in simulated urban CO pollution (30-100 parts/million, 12 h/day) with (CO-Ex) or sedentary without exercise (CO-Sed). The exercise procedure began 4 wk before CO exposure and was maintained twice a week in standard filtered air during CO exposure. On one set of rats, myocardial ischemia (30 min) and reperfusion (120 min) were performed on isolated perfused rat hearts. On another set of rats, myocardial antioxidant status and Ca 2ϩ handling were evaluated following environmental exposure. As a result, exercise training prevented CO-induced myocardial phenotyp-ical changes. Indeed, exercise induced myocardial antioxidant status recovery in CO-exposed rats, which is accompanied by a normaliza-tion of sarco(endo)plasmic reticulum Ca 2ϩ-ATPase 2a expression and then of Ca 2ϩ handling. Importantly, in CO-exposed rats, the normal-ization of cardiomyocyte phenotype with moderate exercise was associated with a restored sensitivity of the myocardium to ischemia-reperfusion. Indeed, CO-Ex rats presented a lower infarct size and a significant decrease of reperfusion arrhythmias compared with their sedentary counterparts. To conclude, moderate exercise, by preventing CO-induced Ca 2ϩ handling and myocardial antioxidant status alterations, reduces heart vulnerability to ischemia-reperfusion.