Department of Molecular Medicine, Scripps Research, La Jolla, CA 92037, USA.
Department of Bioengineering, University of California, La Jolla, San Diego, CA 92093, USA; Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Mol Metab. 2022 Jul;61:101504. doi: 10.1016/j.molmet.2022.101504. Epub 2022 Apr 22.
Exercise is a critical component of a healthy lifestyle and a key strategy for the prevention and management of metabolic disease. Identifying molecular mechanisms underlying adaptation in response to chronic physical activity is of critical interest in metabolic physiology. Circadian rhythms broadly modulate metabolism, including muscle substrate utilization and exercise capacity. Here, we define the molecular and physiological changes induced across the daily cycle by voluntary low intensity daily exercise.
Wildtype C57BL6/J male and female mice were housed with or without access to a running wheel for six weeks. Maximum running speed was measured at four different zeitgeber times (ZTs, hours after lights on) using either electrical or manual stimulation to motivate continued running on a motorized treadmill. RNA isolated from plantaris muscles at six ZTs was sequenced to establish the impact of daily activity on genome-wide transcription. Patterns of gene expression were analyzed using Gene Set Enrichment Analysis (GSEA) and Detection of Differential Rhythmicity (DODR). Blood glucose, lactate, and ketones, and muscle and liver glycogen were measured before and after exercise.
We demonstrate that the use of mild electrical shocks to motivate running negatively impacts maximum running speed in mice, and describe a manual method to motivate running in rodent exercise studies. Using this method, we show that time of day influences the increase in exercise capacity afforded by six weeks of voluntary wheel running: when maximum running speed is measured at the beginning of the nighttime active period in mice, there is no measurable benefit from a history of daily voluntary running, while maximum increase in performance occurs at the end of the night. We show that daily voluntary exercise dramatically remodels the murine muscle circadian transcriptome. Finally, we describe daily rhythms in carbohydrate metabolism associated with the time-dependent response to moderate daily exercise in mice.
Collectively, these data indicate that chronic nighttime physical activity dramatically remodels daily rhythms of murine muscle gene expression, which in turn support daily fluctuations in exercise performance.
运动是健康生活方式的重要组成部分，也是预防和治疗代谢疾病的关键策略。了解慢性体力活动适应的分子机制在代谢生理学中至关重要。昼夜节律广泛调节代谢，包括肌肉底物利用和运动能力。在这里，我们定义了自愿低强度日常运动在整个日常周期中引起的分子和生理变化。
将野生型 C57BL6/J 雄性和雌性小鼠饲养在有或没有跑步轮的环境中，为期六周。使用电动跑步机上的电动或手动刺激，在四个不同的 Zeitgeber 时间（ZT，光照后小时）测量最大跑步速度。从跖肌中分离出 RNA，在六个 ZT 进行测序，以确定日常活动对全基因组转录的影响。使用基因集富集分析（GSEA）和差异节律检测（DODR）分析基因表达模式。在运动前后测量血糖、乳酸和酮体以及肌肉和肝脏糖原。
我们证明，使用轻度电击来激励跑步会降低小鼠的最大跑步速度，并描述了一种手动方法来激励啮齿动物运动研究中的跑步。使用这种方法，我们表明，一天中的时间会影响六周自愿轮跑带来的运动能力的提高：当在夜间活动期开始时测量最大跑步速度时，从日常自愿跑步的历史中没有可衡量的益处，而最大的性能提高发生在夜间结束时。我们表明，日常自愿运动极大地重塑了鼠类肌肉的昼夜转录组。最后，我们描述了与中度日常运动的时间依赖性反应相关的碳水化合物代谢的日常节律。
总的来说，这些数据表明，慢性夜间体力活动极大地重塑了小鼠肌肉基因表达的日常节律，这反过来又支持了运动性能的日常波动。
