Differential Cardiac Adaptation to Free‐Wheel Running in Old and Young Mice: Impact of the Cardiac Circadian Clock

Abstract

Critical cardiovascular processes are under control of the central circadian clock. Disruption of this clock (i.e. during aging) results in increased risk for development of chronic disease such as cardiovascular disease. Exercise is a protective intervention implicit in both age and circadian related pathologies, yet its role in regulating circadian gene expression in the heart remains untested. We hypothesized that circadian rhythm would be disrupted in aged mice and rescued by free‐wheel running. We analyzed wheel running patterns in male and female C57BL/6J mice at young (3–6 months) and old (18–20 months) ages exposed to standard 12h light/dark cycle. As expected, young female mice ran further than male mice, and old mice ran significantly less than young mice. Older mice of both sexes had a delayed start time in activity and early cessation of free‐wheel running, which likely contributes to shorter total diurnal running distances. Free‐wheel running resulted in an expected left ventricular (LV) hypertrophy in young animals, however older animals demonstrated a regression of LV mass. Old mice demonstrated dysregulated cardiac circadian clock expression (BMAL, Per2) compared to young animals, an effect which was not rescued by free‐wheel running. Together our data suggest that the aged heart undergoes a unique adaptation to running compared to the young heart. While voluntary running was not sufficient to rescue age‐related changes in circadian rhythm, ongoing studies will determine if forced exercise and/or chronotimed exercise can improve age‐related cardiac and circadian dysfunction.