Circadian rhythm and exercise

J Phys Fitness Sports Med, 3(1): 65-72 (2014)DOI: 10.7600/jpfsm.3.65

JPFSM: Review Article

Circadian rhythm and exerciseShigenobu Shibata* and Yu Tahara

Received: January 6, 2014 / Accepted: February 10, 2014

Abstract In mammals, the circadian clock organizes physiological processes, including sleep/wake patterns, hormonal secretion, and metabolism, and regulates athletic performance. The circadian system is responsive to environmental changes such as light/dark cycles, food intake, and exercise. In this review, we will focus on the central and peripheral circadian mo-lecular clock system, discussing how circadian rhythm affects athletic performance and muscle metabolism, and how exercise entrains the circadian rhythm. Importance of exercise training in rescuing circadian deficit–induced metabolic disorder is also discussed. The interaction of the circadian clock and exercise, called “chrono-exercise,” is poised to become an important research field of chronobiology.Keywords : circadian rhythm, exercise, performance, nutrition, obesity, metabolism

Molecular mechanism underlying the functions of circa-dian and system clocks

The circadian clock system is present in organisms from prokaryotes to mammals. In Latin, “circadian” means “approximately day.” Therefore, “circadian rhythm” re-fers to approximate 24-h cycles. The earth completes one full rotation in 24 h. It appears that our circadian system was evolved to adjust to this 24-h cycle - in plants and cyanobacteria to be able to efficiently utilize sunlight for photosynthesis, and in mammals, to obtain food. One of the most important features of our circadian system is that the time is kept even under constant darkness, and in the absence of external feedback information. This suggests that our body has its own internal clock. In 1972, Moore and Eichler1) found that the destruction of the suprachi-asmatic nucleus (SCN) in a rat hypothalamus led to the loss of sleep/wake cycles and corticosterone rhythms. Since then, the SCN has been considered as the location of the mammalian master clock system. The SCN directly receives information about light and darkness through the retinal-hypothalamic tract, and organizes the local clock in the peripheral tissues through a number of pathways in-volving neural and hormonal functions2,3). The molecular mechanisms that maintain the mammalian circadian clock system have been extensively studied over the past 2 decades. Thus, the transcriptional–translational feedback loop involving major clock genes (Bmal1, Clock, Per1/2, Cry1/2) is an important component of the circadian sys-tem2). BMAL1 and CLOCK, which are transcriptional activators, play a positive role in activating Per and Cry

genes through the “E-box” promoter sequence. Per and Cry are translated into proteins in the cytoplasm and are transported back into the nucleus following interaction with each other in order to stop their own transcription by BMAL1 and CLOCK. Thus, Per and Cry are rhythmically expressed over a 24-h period. This transcriptional regula-tion leads to rhythmic expression of approximately 10% of all genes in each peripheral cell4-6). In addition to such transcriptional regulation of the circadian clock, in recent years, post-transcriptional and translational regulations have been found to play important roles in maintaining circadian rhythms. Genome-wide RNA-seq and ChIP-seq analyses found that only 22% of the rhythmically oscillat-ing messenger RNAs are driven by de novo transcription, with RNA polymerase II recruitment and chromatin re-modeling also involved in such rhythms7). Furthermore, it was reported that the non-transcriptional redox cycle has a 24-h rhythm in human red blood cells, which are devoid of DNA and nuclei. This redox rhythm of peroxiredoxins was shown to exist not only in human blood cells but also in prokaryotic cells8,9). In the SCN, the redox state regu-lates the output of rhythmic neuronal firing10). These ob-servations suggest that our understanding of the circadian clock system is expanding, and that this system employs an elaborate network of interdependent processes to gen-erate and maintain accurate clock rhythms. One feature of the circadian system is its entrainment to a 24-h oscillation by external or internal signals, because the oscillation period of the circadian clock is not exactly 24 h, but approximately 24 h. Information in the form of light received from retinal input is the typical external, entrainable factor in mammals. Other entrainable factors include food, temperature, exercise, and drugs. Among *Correspondence: [email protected]

Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan

66 JPFSM : Shibata S and Tahara Y

these factors, food is the best known synchronizer (com-parable to light)11-14).

Chrono-pharmacology, chrono-nutrition, and chrono-exercise

Chrono-pharmacology deals with the timing of drug administration as determined by circadian changes in the expression and activity of the targeted protein, quanti-ties of drugs needed to enhance the potency, and/or the absorption and excretion of drugs. Chrono-pharmacology also allows us to predict the optimal timing for food in-take from an understanding of circadian changes in the digestive system or metabolic activity. Recently, the term “chrono-nutrition” has also been used to refer to the study of the relationship between food and the circadian clock system. Altering the timing of food intake can change the

timing of our internal clock. The new field of chrono-exercise deals with the relationship between exercise and the circadian clock system. Fig. 1 shows the interac-tion between the circadian clock and exercise. Two key concepts in chrono-exercise are (i) the timing of exercise contributes to the maintenance of health and athletic per-formance; and (ii) the timing of exercise contributes to rapid changes in or resetting of our internal clock system (Fig. 1).

Contribution of the timing of exercise to athletic perfor-mance

Fig. 2 shows the dependence of athletic performance on circadian rhythm. The influence of circadian rhythms on human physical performance has been extensively researched15-17). Many physiological processes associated with athletic performance have been shown to follow a specific circadian rhythm18). Generally, peak performance in strength, anaerobic power output, and joint flexibility, occur in the late afternoon, approximately corresponding to the peak in body temperature17,19-21). In contrast, perfor-mances are relatively poor in the morning16). As there is a clear relationship between the circadian fluctuations in the core body temperature and physical performance, ac-tive warm-up sessions are proposed to improve exercise performance in the morning. Interestingly, when a test of physical fitness, measured by heart rate and prolonged submaximal exercise, was carried out in hot conditions, peak performance was found to occur in the morning22). Best sprints and rapidity performances occurred between 0830 and 1030 hours23), and several complex skills that required a great deal of coordination tended to peak ear-lier in the day than did gross motor skills. An increase in core body temperature has been shown

Fig. 1 Interactions between the circadian clock and exercise. Timing of exercise affects the phase of the circadian

clock, and the circadian clock affects exercise-related athletic performance and energy metabolism.

Fig. 2 The circadian clock controls exercise performance. General athletic performance is good during the late afternoon, when the body temperature peaks. Better sprints and rapidity

performance occur in the morning up to noon.

Fig.1 Shibata & Tahara

Exercise

input

Circadian Clock

output

Athletic performanceEnergy metabolism


Circadian Clock

SprintsRapidity performance

General athletic performanceMuscle contraction

Body temperature

67JPFSM : Chrono-exercise

to increase energy metabolism and improve appetite com-pliance17). Recent evidence has challenged the traditional view of the relationship between body temperature and exercise performance. When the role of circadian rhythm on neural activation and the contractile properties of hu-man adductor pollicis muscle were investigated24), the force produced during maximal voluntary contraction was found to be higher in the evening than in the morning. Therefore, it was suggested that the modulation of periph-eral contractile functions was responsible for circadian fluctuation in force. Furthermore, these authors proposed that higher force production in the afternoon was likely due to increased calcium release from the sarcoplasmic reticulum, enhanced calcium ion sensitivity of contractile proteins such as actin and myosin, and altered myosin ATPase activity. More recently, Guette et al.25) reported similar findings, supporting the idea that changes at the muscular level might be responsible for diurnal fluctua-tions in force. These authors suggested that the actin–myosin cross bridge cycling was affected by circadian fluctuations in the concentration of inorganic phosphate. It appears that a variety of mechanisms might be involved in the circadian control of physical performance. Howev-er, elucidation of these mechanisms will be a challenging task.

Contribution of the timing of exercise to the mainte-nance of health

Fig. 3 shows how the order in which exercise and feed-ing are conducted could affect metabolic parameters and appetite. Aerobic exercise training improves body compo-sition and aerobic fitness, decreases leptinemia, prevents intramuscular lipid accumulation, and increases insulin sensitivity in obese individuals26,27). Chronic exercise training is associated with reduced body weight gain and lower adiposity in humans28,29) and rodents30-32).

The timing of exercise relative to that of the consump-tion of a meal is one of the factors controlling metabolism and appetite. Studies comparing the effects of the tim-ing of exercise, before or after a single meal, have found greater total fat oxidation when the exercise was per-formed in the fasting state33,34). Exercise performed imme-diately before the consumption of a meal was also shown to reduce postprandial triglyceride concentration35-37). These studies have demonstrated that exercise in the fast-ing state was more effective for weight loss. Compared to exercise training in the fasting state, post-prandial exercise may promote metabolic changes that are more beneficial for weight loss. Thus, compared with exercise performed immediately before a meal, 36 min of treadmill exercise performed 40 min after a Mediter-ranean breakfast stimulated a greater increase in resting energy expenditure in the first 24 h after the exercise38). Moreover, postprandial exercise also resulted in a higher fat metabolism in the 24 h period after exercise, indicat-ing fat loss39). While some studies demonstrated that postprandial exercise lowered postprandial triglyceride content35,40-42), others found no such changes36,43). These differences likely reflect the different experimental pa-rameters used, including diet, physical attributes, and physiological conditions of the individuals, such as en-ergy intake, exercise duration, and intensity of exercise. Thus, long-term follow-up trials under free-living condi-tions are warranted to verify and validate these findings. Well-controlled animal experiments are also necessary to understand how the interaction between the timing of the meal and exercise controls energy metabolism. Aerobic exercise and associated muscle adaptations are important not only for weight loss, but also for prevent-ing weight regain. The 2009 American College of Sports Medicine position44) recommended 250 to 300 min of exercise per week (mostly aerobic). In a longitudinal study, Jakicic et al.45) observed that obese women who performed less than 150 min of aerobic exercise per week for 6 months lost 50% less weight than other women who exercised more than 250 min/week. After six additional months of physical training, the former group gained weight while the latter group continued to lose weight. In these individuals, regular and lengthier exercise likely reduces hunger pangs and desire to eat after calorie-restricted weight loss due to profound effects on energy balance, fuel utilization, lipid accretion, and peripheral homeostatic signals46). Thus, the importance of exercise for protection from weight regain has been demonstrated in humans47) and animals46). However, how the timing of exercise affects weight is not well understood. A common strategy to facilitate weight and fat loss is to perform aerobic ex-ercise after overnight fasting. Exercise in the fasted state enhances fat oxidation due to decreased glycogen availability, and causes lipolysis by reducing plasma insulin while elevating plasma epinephrine and norepi-


Exercise + Breakfastβ-oxidation increase

Serum TG reduction

Exercise+BreakfastAppetite decrease

Serum TG reduction or stableFig. 3 Exercise timing relative to that of breakfast affects meta-

bolic syndrome and appetite. Exercise before breakfast increases beta-oxidation and

reduces serum TG levels, while exercise after breakfast decreases appetite and reduces serum TG.


nephrine48-50). However, some studies have shown that postprandial exercise may be more beneficial for weight control, than fasted exercise, because of more favorable effects on appetite regulation and resting metabolism51,52). Although exercise is known to increase fat oxidation, it also influences food intake and the metabolism of food consumed53-55). Thus, the interactions between exercise and food intake need to be carefully examined to fully understand the overall effects of exercise on fat balance.

Effect of exercise on circadian rhythm

As described earlier, the circadian rhythm is entrained by the light/dark cycle, as well as non-photic signals such as exercise. A single pulse of wheel-running or forced treadmill running, when applied during daytime or sub-jective daytime, can produce a phase-advance56,57). The mechanism behind this entrainment is thought to be a feedback signal from the behavioral activation to SCN58). The serotonergic system has been found to be involved in non-photic entrainment59). Light augments the gene ex-pression of Per1 and Per2 in the SCN12,60), whereas non-photic stimulation represses their expression59,61,62). It has been reported that a scheduled exercise regimen phase-shifts the circadian clock in the skeletal muscle and lungs of mice, but not in the SCN63). Furthermore, scheduled exercise accelerates re-entrainment to new light/dark cycles in mouse skeletal muscle and lungs, but not in the liver and SCN64). Under light/dark conditions, the SCN controls the wheel-running rhythm. However, the phase of the peripheral clock is not affected by wheel-running itself because it was found to be identical in mice housed in locked or unlocked wheel-running apparatuses. Effects of timed physical exercise on human circadian rhythms have been examined65-70). A single trial of physi-cal exercise was demonstrated to cause a phase-dependent phase shift. Exercise performed at midnight produced phase-delay shifts66,69), whereas that performed during early evening or late day induced phase-advance shifts67). Timed physical exercise was shown to accelerate the phase-advance shift of plasma melatonin rhythm when the sleep/wake schedule was phase-advanced in a step-wise manner68). In contrast, physical exercise accelerated re-entrainment of the human sleep/wake cycle but not that of the plasma melatonin rhythm to an 8-h phase-advance sleep schedule71). These data, derived from humans and animals, have strongly suggested that physical exercise performed at unusual phases - daytime for nocturnal mice and nighttime for diurnal humans - phase-shifts the SCN and/or some peripheral clocks.

Metabolism and energy expenditure

The circadian system in mammals tightly controls en-ergy metabolism. Thus, mutations or deletions of clock genes lead to dysfunctional energy metabolism3). Thus,

CLOCK mutant mice exhibit attenuated feeding rhythm and develop obesity when fed a regular or high-fat diet72). Owing to disrupted glucocorticoid rhythms, PER2-null mice show disrupted feeding patterns and develop obesity when fed a high-fat diet73). PER2-null mice also experi-ence disruptions in the circadian rhythm of α-melanocyte-stimulating hormone, which regulates hypothalamic processes related to feeding behavior. It has been reported that Rev-erbα and Rev-erbβ, which play important roles in the functioning of nuclear receptors and core clock genes, regulate lipid metabolism74,75). Antagonists of Rev-erbs have been shown to prevent high-fat diet–induced obesity and disruption of circadian rhythm in mice76). It has also been reported that BMAL1-knockout mice show obesity and lower insulin secretion compared to their wild-type counterparts77). Interestingly, adipocyte-specific deletion of BMAL1 led to obesity and a shift in the timing of food intake from nocturnal to diurnal78). This shift was caused by changes in circulating polyunsaturated fatty acids and nonesterified polyunsaturated fatty acids in the hypotha-lamic neurons78). Thus, disruption of the circadian clock causes metabolic dysfunction, clearly suggesting that the circadian system controls various metabolic processes. Activities of important regulators of metabolism, in-cluding Ampk, Sirt1, Pparα, and Pgc1α, oscillate with circadian rhythms and act as key mediators of core cir-cadian mechanisms. AMPK senses nutrients in the pe-ripheral tissues and acts to destabilize the CRY protein at the core of the circadian system79). Sirt1, an anti-aging gene, is regulated by nicotinamide adenine dinucleotide (NAD+) and regulates histone acetyltransferase activity of the CLOCK protein80,81). Furthermore, SIRT1 promotes the deacetylation and degradation of PER282). PPARα is a nuclear receptor that regulates lipid metabolism in the liver. PPARα binds PER283) and promotes Bmal1 expres-sion84). PGC1α, a transcriptional coactivator involved in the regulation of energy metabolism, is also involved in circadian regulation and promotes the expression of Bmal1 and Rev-erbα85). Thus, core metabolic genes and their activities cooperate closely with the clock system to regulate, orchestrate, fine-tune, and coordinate diverse physiological processes.

Effect of exercise on circadian disturbance

In Fig. 4, we show how scheduled exercise can contrib-ute to the recovery of the circadian rhythm from deficits caused by various factors. Genetic disruption of clock genes in mice disturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circa-dian dyssynchrony, a characteristic feature of shift work and sleep disruption in humans, also leads to metabolic pathologies2,86,87). Scheduled food access was found to be helpful in preventing the night shift work-induced obesity in rats and mice. Extensive epidemiological stud-ies of rotating night-shift work revealed that nurses who


worked for longer periods during their shift had a higher risk for type 2 diabetes than nurses who worked shorter shifts88). Karatsoreos et al.89) reported that in mice, a 20-h light/dark cycle induced obesity, an irregular release of metabolic hormones, and a loss of dendritic length in the prelimbic prefrontal cortex. Scheduled feeding during the dark phase with restricted arousal for 8 h during the light period prevented obesity induction90). Furthermore, sched-uled feeding of night-shift work mice during the normal dark phase prevented the dyssynchrony of rhythmically expressed hepatic genes91). Therefore, meal timings are important in preventing obesity induced by disordered circadian rhythm. As discussed earlier, physical exercise is known to strengthen and entrain the circadian system and prevent weight gain. Therefore, exercise may help to prevent metabolic syndrome caused by circadian deficits. Mice housed under artificial dim light at night show elevated body mass and reduced glucose tolerance92), and exercise attenuates this metabolic disorder93). Scheduled exercise accelerates re-entrainment of the peripheral clock to shifts in the light/dark cycle64,94). Timed physical exercise was shown to accelerate the phase-shift against the shift of sleep schedule68,71). Physi-cal activity is thought to be beneficial to the shift worker and generally improve sleep quality95-97). Although con-ducted without appropriate controls for light exposure and exercise intensity, field studies have shown that physical exercise accelerates re-entrainment following transmerid-ian travel98). It is also reported that night workers have problems maintaining physical fitness compared to day workers99). Chrono-exercise is poised to become a very important research field. Understanding the precise nature of the interactions between circadian rhythm, food intake, and exercise will significantly improve human health and productivity.


Circadian deficit

Scheduled exercise

Clock gene mutationMetabolic syndrome

Shift workNight workJet lag

Recovery of circadian rhythm

Fig. 4 Scheduled exercise recovers the circadian deficits caused by various factors.

Acknowledgments

This work was supported by funding to S.S. in the form of Grants-in-Aid for Scientific Research from JSPS (23300278, 23659126), the Fuji Foundation for Protein Research (2010, 2012), the Iijima Memorial Foundation for the Promotion of Food

Science and Technology (2011), and KIBANKEISEI (2012) from matching fund subsidy, MEXT, Japan.

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