Abstract
Mammalian circadian rhythms are governed by an endogenous circadian clock system, including the molecular clock works in each cell and tissue. Adaptation of the circadian clock to different environmental stimuli such as light, food, and stress is essential for homeostasis maintenance. However, the influence of oxidative stress on the circadian clock phase is not fully understood in vitro and in vivo. Here, we examined the effects of hydrogen peroxide (H2O2)-induced oxidative stress on the PERIOD2::LUCIFERASE bioluminescence rhythm in mouse embryonic fibroblasts in vitro and in mouse peripheral tissues in vivo. The circadian clock phase changed with the dose of H2O2 and time of day in vitro; similar phase changes were observed in vivo in the circadian clocks of the peripheral tissues. In addition, mice treated with hemin-induced oxidative stress also showed phase changes of peripheral clocks, similarly as H2O2 treatment. Thus, oxidative stress can entrain circadian clock systems.
Highlights
The circadian clock system in mammals plays important roles in maintaining physiology with day-night fluctuations
H2O2 – induced circadian clock phase shift in PER2::LUC mouse embryonic fibroblasts (MEF) cells The bioluminescence rhythms of the cells were monitored for 5 days, and the vehicle or H2O2 were added to the medium for 30 min at Circadian Time (CT; CT0 indicates the trough of bioluminescence and CT12 indicates the peak) 18 or CT4 after the first peak of the PER2::LUC rhythm (Fig. 1)
We identified that H2O2 treatment at the time point when the slope of bioluminescence rhythm decreases caused phase delay of the third peak of the PER2::LUC rhythm in a dose-dependent manner, when compared to the vehicle-treated group
Summary
The circadian clock system in mammals plays important roles in maintaining physiology with day-night fluctuations. The central clock, located in the hypothalamus, organizes peripheral clocks in the other peripheral tissues through endocrine and nervous pathways [1]. Environmental stimuli such as light or food are essential for maintaining the clock phase to an appropriate time, because the potential period of internal clock oscillation is not 24 h (it is about 24 h) [2, 3]. In addition to light and food, we recently found that physiological stress (e.g., restraint stress) has strong ability to synchronize the p eripheral clock system in vivo; stress-induced sympathetic activation and glucocorticoid release are included in this stress-induced entrainment [4]. Restraint stress increases oxidative stress in the peripheral tissues [5, 6]; the ability of oxidative stress to entrain the circadian clock system has not yet been elucidated in vivo.
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