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

项目摘要 这项提议将检验慢性社会时差会减弱对运动训练的适应性的假设， 增加对心脏代谢应激的敏感性。社交时差（SJL）是一种新颖而普遍的昼夜节律形式， 由于学习/专业时钟（即工作或学习）之间的不同步而导致的节奏中断 时间表）和内源性驱动的昼夜节律（周末/空闲时间表）。最近的研究 表明几乎80%的人群经历了某种程度的SJL（即， 工作日/周末），近30%的人经历了>2小时的轮班。社会时差与 心血管危险因素和代谢疾病，包括肥胖、糖尿病和低心血管代谢适应性 （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 作为预防和逆转心血管和代谢疾病的一线干预措施， 确定运动是否以及何时可以最有效地规定和最保护心脏。我们有 先前的研究表明，急性运动可以不同程度地激活心肌基因表达和信号传导， 根据一天中的时间，在具有完整昼夜节律的小鼠中进行。然而，目前还不清楚如何 运动和运动时间可能在昼夜节律中断期间受到SJL的影响。所以我们的 总体假设是SJL增加了对心脏代谢疾病的易感性， 进行运动将调节其功效，以引起训练适应性并防止心脏代谢性疾病。 疾病为了解决这一假设，我们将追求以下三个具体目标。1)确定影响 社会时差对小鼠分子和生理运动训练诱导的适应性的影响，2）确定影响 在慢性社会时差对行为昼夜节律的影响中， 慢性社会时差对小鼠心脏代谢健康的影响，以及依赖于TOD的潜在逆转 运动处方。本申请中提供的初步数据揭示了时间偏好- 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 半），心肺适应性差异不大，这表明在活动后期进行运动训练可能会引起 可比较的训练适应性和较低的音量。时间限制的自愿运动如何影响代谢 目前尚不知道高脂肪喂养期间以及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诱导的昼夜节律破坏，并将增加 我们对运动时间在预防心血管疾病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.