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It has been well established in mammals that circadian behavior as well as the molecular clockwork can be synchronized to the light-dark cycle via the suprachiasmatic nucleus of the hypothalamus (SCN). In addition to light, it has been demonstrated that nonphotic time cues, such as restricting the time of food availability, can alter circadian behavior and clock gene expression in selected peripheral tissues such as the liver. Studies have also suggested that scheduled physical activity (exercise) can alter circadian rhythms in behavior and clock gene expression; however, currently, the effects of exercise alone are largely unknown and have not been explored in skeletal muscle. Period2::Luciferase (Per2::Luc) mice were maintained under 12 h of light followed by 12 h of darkness then exposed to 2 h of voluntary or involuntary exercise during the light phase for 4 wk. Control mice were left in home cages or moved to the exercise environment (sham). A second group of mice had restricted access to food (4 h · d(-1) for 2 wk) to compare the effects of two nonphotic cues on PER2::LUC bioluminescence. Skeletal muscle, lung, and SCN tissue explants were cultured for 5-6 d to study molecular rhythms. In the exercised mice, the phase of peak PER2::LUC bioluminescence was shifted in the skeletal muscle and lung explants but not in the SCN suggesting a specific synchronizing effect of exercise on the molecular clockwork in peripheral tissues. These data provide evidence that the molecular circadian clock in peripheral tissues can respond to the time of exercise suggesting that physical activity contributes important timing information for synchronization of circadian clocks throughout the body.
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... The same study showed that scheduled exercise, implemented by limiting access to a wheel to either early or late night (active) phase delayed liver PER2::LUC oscillation, whereas the adrenal PER2::LUC was delayed only by the early night access. In contrast, forced exercise in the inactive (light) phase significantly advanced PER2::LUC rhythm and per2 and bmal1 mRNA expression in lung, liver and adrenal gland, and also advanced CORT secretion (Wolff and Esser, 2012;Sasaki et al., 2016). Regular voluntary exercise over weeks steadily increased the average level of CORT (Otawa et al., 2007). ...
... In mice held in an LD cycle, limiting access to a running wheel in the early night led to reduced PER2::LUC amplitude in the SCN (Schroeder et al., 2012). In contrast, limiting access to a running wheel during the light phase did not affect PER2::LUC oscillation in the SCN (Wolff and Esser, 2012). Manipulating access to wheel running also entrains locomotor rhythms in VIP and/or VIP receptor knockout mice. ...
... Forced exercise however, produced by confining subjects to a treadmill, did not affect the SCN (Wolff and Esser, 2012;Sasaki et al., 2016). The reason of the differential effects of voluntary and forced exercise on the SCN may be that forced exercise is a psychological stressor, pointing to different mechanisms underlying the entraining potential of the two types of exercise. ...
Article
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Background Steroids are lipid hormones that reach bodily tissues through the systemic circulation, and play a major role in reproduction, metabolism, and homeostasis. All of these functions and steroids themselves are under the regulation of the circadian timing system (CTS) and its cellular/molecular underpinnings. In health, cells throughout the body coordinate their daily activities to optimize responses to signals from the CTS and steroids. Misalignment of responses to these signals produces dysfunction and underlies many pathologies. Questions Addressed To explore relationships between the CTS and circulating steroids, we examine the brain clock located in the suprachiasmatic nucleus (SCN), the daily fluctuations in plasma steroids, the mechanisms producing regularly recurring fluctuations, and the actions of steroids on their receptors within the SCN. The goal is to understand the relationship between temporal control of steroid secretion and how rhythmic changes in steroids impact the SCN, which in turn modulate behavior and physiology. Evidence Surveyed The CTS is a multi-level organization producing recurrent feedback loops that operate on several time scales. We review the evidence showing that the CTS modulates the timing of secretions from the level of the hypothalamus to the steroidogenic gonadal and adrenal glands, and at specific sites within steroidogenic pathways. The SCN determines the timing of steroid hormones that then act on their cognate receptors within the brain clock. In addition, some compartments of the body-wide CTS are impacted by signals derived from food, stress, exercise etc. These in turn act on steroidogenesis to either align or misalign CTS oscillators. Finally this review provides a comprehensive exploration of the broad contribution of steroid receptors in the SCN and how these receptors in turn impact peripheral responses. Conclusion The hypothesis emerging from the recognition of steroid receptors in the SCN is that mutual shaping of responses occurs between the brain clock and fluctuating plasma steroid levels.
... As mentioned previously, disturbed circadian rhythms in organs or the whole body are associated with abnormal metabolic states, such as high-fat diet, obesity, and T2DM. Scheduled bouts of exercise result in a significant shift in clock gene expression in the peripheral tissues [7]. The liver is the main regulatory organ that participates in the synthesis and decomposition of cholesterol; therefore, serum cholesterol levels also reflect liver lipid metabolism. ...
... Scheduled bouts of exercise result in a significant shift in clock gene expression in the peripheral tissues [7]. In our study, night exercise not only improved impaired CLOCK expression caused by diabetes (p < 0.05) but also decreased CLOCK expression (p < 0.05) compared with morning exercise ( Figure 3A,B), indicating that night exercise is better than morning exercise in alleviating impaired CLOCK expression induced by T2DM, which is speculated that night exercise is more consistent with the biorhythm of mice. ...
Article
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Although the benefits of aerobic exercise on obesity and type 2 diabetes are well-documented, the pathogenesis of type 2 diabetes and the intervention mechanism of exercise remain ambiguous. The correlation between mitochondrial quality and metabolic diseases has been identified. Disruption of the central or peripheral molecular clock can also induce chronic metabolic diseases. In addition, the interactive effects of the molecular clock and mitochondrial quality have attracted extensive attention in recent years. Exercise and a high-fat diet have been considered external factors that may change the molecular clock and metabolic state. Therefore, we utilized a DB/DB (BSK.Cg-Dock7m +/+ Leprdb/JNju) mouse model to explore the effect of chrono-aerobic exercise on the metabolic state of type 2 diabetic mice and the effect of timing exercise as an external rhythm cue on liver molecular clock-mitochondrial quality. We found that two differently timed exercises reduced the blood glucose and serum cholesterol levels in DB/DB mice, and compared with night exercise (8:00 p.m., the active period of mice), morning exercise (8:00 a.m., the sleeping period of mice) significantly improved the insulin sensitivity in DB/DB mice. In contrast, type 2 diabetes mellitus (T2DM) increased the expression of CLOCK and impaired the mitochondrial quality (mitochondrial networks, OPA1, Fis1, and mitophagy), as well as induced apoptosis. Both morning and night exercise ameliorated impaired mitochondrial quality and apoptosis induced by diabetes. However, compared with morning exercise, night exercise not only decreased the protein expression of CLOCK but also decreased excessive apoptosis. In addition, the expression of CLOCK was negatively correlated with the expression of OPA1 and Fis1. In summary, our research suggests that morning exercise is more beneficial for increasing insulin sensitivity and promoting glucose transport in T2DM, whereas night exercise may improve lipid infiltration and mitochondrial abnormalities through CLOCK–mitophagy–apoptosis in the liver, thereby downregulating glucose and lipid disorders. In addition, CLOCK-OPA1/Fis1–mitophagy might be novel targets for T2DM treatment.
... Further, physical activity may influence peripheral clock rhythms in skeletal muscle. In one such study, mice performed 2 h of daily exercise conducted at the same time each day for 4 weeks [18]. After one month, the circadian rhythm of PER2 in skeletal muscle was shifted by 2-3 h compared to baseline; however, there were no changes in the central circadian rhythm, further demonstrating that non-photic cues impact the rhythm of peripheral tissue clocks [18]. ...
... In one such study, mice performed 2 h of daily exercise conducted at the same time each day for 4 weeks [18]. After one month, the circadian rhythm of PER2 in skeletal muscle was shifted by 2-3 h compared to baseline; however, there were no changes in the central circadian rhythm, further demonstrating that non-photic cues impact the rhythm of peripheral tissue clocks [18]. Initial reports in humans also suggest an impact of exercise on the expression of skeletal muscle clock genes in response to acute [19] and chronic exercise [20]. ...
Article
STUDY OBJECTIVES Repeated bouts of circadian misalignment impair glucose tolerance. However, whether circadian misalignment associated with travel and jet lag impair glucose homeostasis in a free-living population is not known. The goal of the present study was to examine glycemic control during one week of Eastbound transatlantic travel in healthy men and women. METHODS Seven healthy participants (5 women; age: 35.6 ± 2.5 years, BMI: 23.9 ± 2.4 m/kg 2) traveled from Colorado, USA (GMT-7) to Europe (GMT and GMT+1) and wore a continuous glucose monitor (Freestyle Libre Pro) for 8-14 days before, during, and after travel. Indices of glycemic control were summarized over 24-hour periods and by day and night. RESULTS Mean glucose, peak glucose, and time spent in hyperglycemia increased linearly throughout the travel period relative to baseline levels. Mean glucose concentrations rose 1.03 mg/dL (95% CI: 0.34, 1.74) and duration of hyperglycemia increased by 17 minutes (95% CI: 5.5, 28.6) each 24-hour period. Increases in 24-hour glucose were primarily driven by increases in daytime parameters with rising mean glucose (0.72 mg/dL per day, [95% CI: -0.1, 1.5]) and duration of hyperglycemia (13.2 minutes per day [95% CI: 4.3, 22.1]). Mean glucose, but not peak glucose or time spent in hyperglycemia, increased each night (0.7 mg/dL per night [95% CI: 0.2, 1.2]). CONCLUSIONS Eastbound transatlantic travel induced a progressive worsening of glucose metrics during 24-hour, day, and night periods. Future research on managing glycemic control during jet lag in people with metabolic disorders is warranted.
... The evidence in support of this has been accumulating since the late 1980s and early 1990s when novel wheel access at different times of day was found to be sufficient to shift the phase of circadian behavioral rhythms in mice and hamsters . In follow-up work to these original studies, forced treadmill exercise training in rodents (Wolff and Esser 2012;Schroeder et al. 2012) and humans (Youngstedt et al. 2019) further confirmed exercise serves as a zeitgeber. Specifically, depending on the time of exercise, the muscle clock, and its output, will shift in phase in a predictable manner. ...
... Exercise has also been demonstrated as a potent time cue and able to modulate clock genes in skeletal muscle (136,141). These genes are associated with skeletal muscle metabolism mainly via 5 ′ -adenosine mono phosphate-activated protein kinase (AMPK) (67). ...
Chapter
Physiological function fluctuates across 24 h due to ongoing daily patterns of behaviors and environmental changes, including the sleep/wake, rest/activity, light/dark, and daily temperature cycles. The internal circadian system prepares the body for these anticipated behavioral and environmental changes, helping to orchestrate optimal cardiovascular and metabolic responses to these daily changes. In addition, circadian disruption, caused principally by exposure to artificial light at night (e.g., as occurs with night-shift work), increases the risk for both cardiovascular and metabolic morbidity and mortality. Regular exercise is a countermeasure against cardiovascular and metabolic risk, and recent findings suggest that the cardiovascular benefits on blood pressure and autonomic control are greater with evening exercise compared to morning exercise. Moreover, exercise can also reset the timing of the circadian system, which raises the possibility that appropriate timing of exercise could be used to counteract circadian disruption. This article introduces the overall functional relevance of the human circadian system and presents the evidence surrounding the concepts that the time of day that exercise is performed can modulate the cardiovascular and metabolic benefits. Further work is needed to establish exercise as a tool to appropriately reset the circadian system following circadian misalignment to preserve cardiovascular and metabolic health. © 2022 American Physiological Society. Compr Physiol 12:3621-3639, 2022.
... These signals are in the form of biomechanical stresses, temperature cycles, hormonal variations (e.g., cortisol, melatonin), or nutrient exposure (Ballesta et al., 2017) for instance. Rhythmic behaviors such as feeding patterns (Greenwell et al., 2019), or physical exercise (Wolff and Esser, 2012) also impact the peripheral clocks in an SCN-independent fashion (dashed black arrow in Fig. 2.7). ...
Thesis
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Mathematical modeling of biological processes aims at providing formal repre-sentations of complex systems to enable their study, both in a qualitative and quan-titative fashion. The need for explainability suggests the recourse to mechanisticmodels, which explicitly describe molecular interactions. Nevertheless, such mod-els currently rely on the existence of prior knowledge on the underlying reactionnetwork structure. Moreover, their conception remains an art which necessitatescreativity combined to multiple interactions with analysis and data fitting tools.This rules out numerous applications conceivable in personalized medicine, andcalls for methodological advances towards machine learning of patient-tailoredmodels. This thesis intends to devise algorithms to learn models of dynamicalinteractions from temporal data, with an emphasis on explainability for the humanmodeler. Its applications are in the context of personalized chronotherapies, thatconsist in optimizing drug administration with respect to the patient’s biologicalrhythms over the 24-hour span. Three main themes are explored: mechanisticmodeling, network inference and treatment personalization. The first chapter de-scribes the development of the first quantitative mechanistic model of the cellularcircadian clock integrating transcriptomic, proteomic and sub-cellular localizationdata. This model has been successfully connected to a model of cellular pharmacol-ogy of an anticancerous drug, irinotecan, achieving personalization of its optimaladministration timing. The second chapter introduces a novel protocol for inferringwhole-body systemic controls enforced on peripheral clocks. On the long run, thisapproach will make it possible to integrate individual data collected from wearablesfor personalized chronotherapies. The third chapter presents a general algorithmto infer reactions with chemical kinetics from time series data.
... For example, BMAL1, PER2, and CRY1 expression modulates exercise capacity via regulation of mitochondrial function and fuel-optimization through modulation of lipid and glucose metabolism (Gutierrez-Monreal et al., 2020). Exercise, in turn, affects the molecular clock and induces expression of clock proteins (Rovina et al., 2021), leading to phase-shifts in the expression and oscillation patterns of clock factors in skeletal muscle (Wolff and Esser, 2012;Kemler et al., 2020), in line with altered expression of CRY1, PER2, and BMAL1 in trained human muscle biopsies promoting phase shifts in circadian rhythmicity (Zambon et al., 2003). Most circadian muscle genes show peak expression in the middle of the active phase, attributed to higher metabolic demands and increased contractile activity (McCarthy et al., 2007). ...
Article
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Circadian rhythms regulate a host of physiological processes in a time-dependent manner to maintain homeostasis in response to various environmental stimuli like day and night cycles, food intake, and physical activity. Disruptions in circadian rhythms due to genetic mutations, shift work, exposure to artificial light sources, aberrant eating habits, and abnormal sleep cycles can have dire consequences for health. Importantly, exercise training efficiently ameliorates many of these adverse effects and the role of skeletal muscle in mediating the benefits of exercise is a topic of great interest. However, the molecular and physiological interactions between the clock, skeletal muscle function and exercise are poorly understood, and are most likely a combination of molecular clock components directly acting in muscle as well as in concordance with other peripheral metabolic organ systems like the liver. This review aims to consolidate existing experimental evidence on the involvement of molecular clock factors in exercise adaptation of skeletal muscle and to highlight the existing gaps in knowledge that need to be investigated to develop therapeutic avenues for diseases that are associated with these systems.
... Both, animal (Yamanaka et al., 2008;Wolff and Esser, 2012) and human studies (Yamanaka et al., 2006;Okamoto et al., 2013;Basti et al., 2021) have also found that exercise can alter circadian rhythms in behaviour and gene expression. In addition, the circadian clock seems to also have an influence on the benefits of exercise interventions pertaining to cognitive and physical performance (Atkinson and Reilly, 1996;Drust et al., 2005;Waterhouse et al., 2005;Facer-Childs and Brandstaetter, 2015b;a;Facer-Childs et al., 2018). ...
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A variety of organisms including mammals have evolved a 24h, self-sustained timekeeping machinery known as the circadian clock (biological clock), which enables to anticipate, respond, and adapt to environmental influences such as the daily light and dark cycles. Proper functioning of the clock plays a pivotal role in the temporal regulation of a wide range of cellular, physiological, and behavioural processes. The disruption of circadian rhythms was found to be associated with the onset and progression of several pathologies including sleep and mental disorders, cancer, and neurodegeneration. Thus, the role of the circadian clock in health and disease, and its clinical applications, have gained increasing attention, but the exact mechanisms underlying temporal regulation require further work and the integration of evidence from different research fields. In this review, we address the current knowledge regarding the functioning of molecular circuits as generators of circadian rhythms and the essential role of circadian synchrony in a healthy organism. In particular, we discuss the role of circadian regulation in the context of behaviour and cognitive functioning, delineating how the loss of this tight interplay is linked to pathological development with a focus on mental disorders and neurodegeneration. We further describe emerging new aspects on the link between the circadian clock and physical exercise-induced cognitive functioning, and its current usage as circadian activator with a positive impact in delaying the progression of certain pathologies including neurodegeneration and brain-related disorders. Finally, we discuss recent epidemiological evidence pointing to an important role of the circadian clock in mental health.
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The interplay of environmental, social, and behavioral factors influencing human circadian phase in ecological conditions remains elusive. The Uruguayan national dance school END-SODRE operating in two shifts (morning: 8:30-12:30 and night: 20:00-24:00) allowed us to evaluate how social demands, chronotype, environmental light, physical activity, and sleep patterns affected individual circadian phase measured by the onset of the nocturnal increase of melatonin (DLMO) in a single study. The DLMO was 1.5h earlier in morning-shift dancers (n=7) compared to night-shift dancers (n=11). Sleep time and chronotype (only in night-shift dancers) were associated with the circadian phase. In training days, during each participant’s phase-advance and phase-delay time windows, light exposure was similar between morning and night-shift dancers and did not correlate with DLMO. In contrast, the time spent in moderate-vigorous physical activity during each participant’s phase-lag time window was higher in night-shift dancers than in morning-shift dancers and positively correlated with DLMO.
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Voluntary training and food modulate the fecal microbiota in humans and mice. Although there are some reports of the timing effects of voluntary training and feeding on metabolism, the timing effects of these factors on microbiota have not been investigated. Therefore, we investigated the effects of the timing of voluntary training and feeding on the gut microbiota. The ICR mice were housed under conditions with an early (in the morning) or late (evening) active phase of increased physical activity. Furthermore, to investigate why voluntary training affects the gut microbiota, mice were housed in a cold environment and received propranolol administration with increased physical activity. After that, we collected cecal contents and feces and measured cecal pH. Short-chain fatty acids (SCFA) were measured from cecal contents. Microbiota was determined using sequencing of the V3-V4 region of the 16S rDNA gene. This study found that increased evening physical activity rather than morning activity decreases cecal pH, increases SCFA, and changes the microbiota. It is especially important that increased evening physical activity is induced under the post-prandial voluntary training condition. Also, we found that cold room housing, sympathetic blockade, or both suppressed the increased physical activity-induced changes in cecal pH, SCFA, and microbiota. Allobaculum responded to increased physical activity through body temperature increases and sympathetic activation. Post-prandial increased physical activity, rather than pre-prandial increased physical activity by evening voluntary wheel training, altered the microbiota composition, which may be related to the increase in body temperature and sympathetic nervous system activation.
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Exposing male C57BL/6J mice repeatedly, in an unpredictable and uncontrollable fashion to rats, alters their cognitive performance and the neuroendocrine stress response, weeks to months after the rat stress. Continuous observation of the behavioural activity of male C57BL/6J mice in their home cage before (baseline) and after rat exposure could reveal if repeated rat exposure leads to changes in circadian activity patterns, which is a key feature of chronic stress and stress-related disorders in humans. Rat stress (1) decreased exploratory and foraging activity as characterized by increased time spent in the shelter and less time in the open area; (2) reduced sucrose consumption and inhibited the development of sucrose preference, suggesting changes in the reward system and (3) the exploration pattern in a novel environment included more behavioural perseverations, but no change in general locomotor activity. Comparison to baseline activity pattern, i.e., before any intervention, revealed that already the control procedure to rat exposure (spending the same amount of time in another cage) disrupted the organization of behavioural activity patterns, albeit to a different and lesser degree than observed in rat stressed mice. While only the longitudinal design of the study allowed detecting these dynamic patterns of circadian activities, the distinct behavioural changes in foraging and explorative activities support our notion that repeated rat exposure might serve as mouse model of chronic stress.
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Circadian rhythm entrainment has long been thought to depend exclusively on periodic cues in the external environment. However, evidence now suggests that appropriately timed vigorous activity may also phase shift the circadian clock. Previously it was not known whether levels of exercise/activity associated with spontaneous behavior provided sufficient feedback to phase shift or synchronize circadian rhythms. The present study investigated this issue by monitoring the sleep-wake, drinking, and wheel-running circadian rhythms of mice (Mus musculus) during unrestricted access to running wheels and when free wheel rotation was limited to either 12- or 6-h intervals with a fixed period of 24 h. Wheel rotation was controlled remotely. Mice spontaneously ran in wheels during scheduled access, and free-running sleep-wake and drinking circadian rhythms became entrained to scheduled exercise in 11 of 15 animals. However, steady-state entrainment was achieved only when exercise commenced several hours into the subjective night. The temporal placement of running during entrainment was related (r = 0.7003, P less than 0.02) to free-running period before entrainment. Mice with a free-running period less than 23.0 h did not entrain but exhibited relative coordination between free-running variables and the wheel availability schedule. Thus the circadian timekeeping system responds to temporal feedback arising from the timing of volitional exercise/activity, suggesting that the biological clock not only is responsive to periodic geophysical events in the external environment but also derives physiological feedback from the spontaneous activity behaviors of the organism.
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The suprachiasmatic nuclei receive photic input information directly through a retinohypothalamic tract (RHT) and indirectly through a projection from the intergeniculate leaflet of the lateral geniculate complex, the geniculohypothalamic tract (GHT). Prior work has established that the RHT is sufficient for entrainment, but has not shown whether it is necessary because it has not been possible to transect that pathway. The present study addresses this problem by employing knife cuts to sever the RHT in male hamsters. Three knife cut procedures were used and one of these succeeded in separating the SCN from the optic chiasm in 8 animals with limited damage to the chiasm and the SCN. The effectiveness of the RHT lesion was confirmed by cholera toxin-HRP histochemistry which demonstrated that the knife cuts eliminate the normal retinal innervation of the SCN while sparing projections to thalamic and tectal visual centers. In a light-dark cycle, the lesioned animals exhibit free-running rhythms indicating that the RHT is necessary for entrainment. A surprising observation is the presence of extensive axonal sprouting of retinal fibers in brains of animals with RHT lesions. The newly-formed axons grow extensively into the SCN, anterior hypothalamus and basal forebrain, but form anomalous axonal plexuses which have no evident function.