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

项目摘要 这项建议将检验这一假设，即慢性社交时差会减弱对运动训练和 增加心脏代谢应激的敏感性。社会时差(SJL)是一种新的普遍存在的昼夜节律 由于学术/专业时钟(例如，工作或学校)之间的不同步而引起的节奏中断 日程表)和内生驱动的昼夜节律(周末/空闲日日程表)。最新研究 表明几乎80%的人经历了不同程度的SJL(即-≥1：00在 工作日/周末)，近30%的人需要轮班2个小时。社交时差被认为与 心血管危险因素和代谢性疾病，包括肥胖、糖尿病和心脏新陈代谢能力低下 (VO2max)。然而，目前尚不清楚SJL如何影响运动训练反应。因为锻炼是一种 对于预防和逆转心血管和代谢性疾病的前线干预，至关重要的是 确定是否以及何时进行锻炼是最有效的处方，也是对心脏保护最好的。我们有 先前表明，急性运动不同地激活心肌基因表达和信号转导 根据一天中的不同时间，它是在昼夜节律完整的小鼠身上进行的。然而，目前还不清楚是如何 在昼夜节律紊乱期间，运动和运动时间可能会通过SJL受到影响。因此，我们的 最重要的假设是SJL增加了心脏代谢性疾病的易感性，一天中的时间 所进行的运动将调节其功效，以诱导训练适应并防止心脏代谢 疾病。为了解决这一假设，我们将追求以下三个具体目标。1)确定以下方面的影响 社会时差对分子和生理运动训练诱导的小鼠适应的影响，2)确定影响 在慢性社交时差期间临时规定的运动对行为昼夜节律的影响，以及3)确定 慢性社会时差对小鼠心脏代谢健康的影响及TOD依赖的潜在逆转作用 运动处方。本申请中提供的初步数据显示了在时间- 限制性运动训练(即，与第二阶段相比，小鼠在活动阶段的前半部分跑得更远 一半)，心肺适能差异不大，这表明在活动期后期的运动训练可能会引起 具有可比性的培训适应，但数量较少。有时间限制的自愿锻炼对代谢的影响 目前还不知道在高脂肪喂养期间以及在SJL期间的扰动。成功完成 这些目标将在这些发现的基础上扩展到包括SJL诱导的昼夜节律紊乱，并将增加 我们对运动时机如何在心血管疾病预防中发挥关键作用的理解。

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.