Effects of time-of-day dependent exercise training on social jetlag induced susceptibility to cardiometabolic disease

Project Summary This proposal will test the hypothesis that chronic social jetlag attenuates adaptations to exercise training and increases susceptibility to cardiometabolic stress. Social jetlag (SJL) is a novel and pervasive form of circadian rhythm disruption caused by desynchrony between scholastic/professional clocks (i.e. - work or school schedules) and the endogenously driven circadian rhythm (weekend/free day schedules). Recent studies suggest that almost 80% of the population undergoes some degree of SJL (i.e. – ≥1:00 shift between weekday/weekend), with nearly 30% experiencing >2 hours of shifting. Social jetlag has been associated with cardiovascular risk factors and metabolic diseases including obesity, diabetes, and low cardiometabolic fitness (VO2max). However, it is currently unknown how SJL impacts the exercise training response. As exercise is a frontline intervention for the prevention and reversal of cardiovascular and metabolic diseases, it is essential to determine if, and when, exercise can be most effectively prescribed and most protective of the heart. We have previously shown that acute exercise differentially activates myocardial gene expression and signaling depending on the time of day it is performed in mice with intact circadian rhythms. However, it is unclear how exercise, and exercise timing, may be impacted during circadian rhythm disruption via SJL. As such, our overarching hypothesis is that SJL increases the susceptibility to cardiometabolic disease, and the time-of-day that exercise is performed will modulate its efficacy to elicit training adaptations and prevent cardiometabolic disease. To address this hypothesis, we will pursue the following three specific aims. 1) Determine the impact of social jetlag on molecular and physiologic exercise training-induced adaptations in mice, 2) Determine the effects of temporally prescribed exercise during chronic social jetlag on behavioral circadian rhythms, and 3) Determine the impact of chronic social jetlag on cardiometabolic health in mice, and potential reversal with TOD-dependent exercise prescription. Preliminary data presented in this application reveal temporal preference during time- restricted exercise training (i.e. – mice run further during the first half of the active phase compared to the second half), with little difference cardiorespiratory fitness, suggesting exercise training in the late active period may elicit comparable training adaptations with lower volume. How time-restricted voluntary exercise impacts metabolic perturbations during high fat feeding, as well as during SJL, is not currently known. Successful completion of these aims will expand upon these findings to include SJL-induced circadian rhythm disruption, and will increase our understanding on how exercise timing plays a critical role in cardiovascular disease prevention.