Mammalian circadian clocks are regulated by the transcription-translational negative feedback loop (TTFL), circadian locomotor output cycle kaput (CLOCK), and brain and muscle Arnt-like protein-1 (BMAL1), which are transcription factors that regulate the expression of many circadian clock genes, including period (Per) and cryptochrome (Cry). CLOCK and BMAL1 form heterodimers via their PAS domains and transcribe period (Per) and cryptochrome (Cry) [16]. CRY binds to PERIOD in the cytoplasm via the CRY-binding domain at the C-terminus of PERIOD. PERIOD and CRY heterodimers, which are phosphorylated by casein kinase1 (CK1), translocate to the nucleus and inhibit Per and Cry transcription by removing BMAL1 and CLOCK [17]. Additionally, hyperphosphorylated PERIOD by CK1, is ubiquitinated and degraded via the ubiquitin-proteasome pathway [18]. The entire TTFL cycle lasted approximately 24 h. The sleep-wake cycle is one of the most prominent physiological processes regulated by the circadian clock. Early in the night, CLOCK and BMAL1 are activated, transcribe Per. Consequently, PERIOD synthesis began during the day and continued to increase. Over time, the PERIOD-CRY complex inhibits the CLOCK-BMAL1 complex. The following day, Cry and Per levels declined because of degradation [19]. Recent publications have extended our understanding of the mechanisms of the mammalian circadian clock at the genome-wide level [20]. The circadian clock also governs daily chromatin remodeling and histone modifications [21]. The basal transcription machinery, transcription regulatory components, and RNA polymerase II exhibit daily oscillations in target genes [22]. Therefore, the circadian clock influences the timing of transcription factor recruitment and the transcriptional activity of target genes.

Circadian clocks are adaptive mechanisms that have evolved to help organisms optimize biological and physiological processes within a 24-hour living environment [23,24]. Entrainment is the main part of the circadian clock that ensures that its timing remains synchronized with external cues such as stress, light, exercise, and food. This process allows organisms to adjust and align their internal rhythms with the natural environmental cycles, promoting optimal functioning and adaptation to the surrounding conditions. The most distinct environmental cue is the 24 h period of the Earth’s rotation, which repeatedly results in a unique transition between light and dark environments. Consequently, circadian clocks are mainly synchronized by light-signal sensing in the SCN of the hypothalamus [25,26]. This master clock receives light cue inputs and transmits daily signals to downstream tissues, synchronizing the peripheral clocks in the organs and tissues [27]. Although peripheral clocks are synchronized by a master clock, each peripheral organ and tissue possesses a clock because they have distinct functions in maintaining the overall body system. In addition, the peripheral clock is synchronized with other external time signals such as stress, feeding, and physical activity including exercise [14,15,28].

Food intake timing is a powerful zeitgeber that regulates the circadian control of metabolic pathways. The pacemaker SCN governs the onset and offset of activities, ensuring that food intake occurs exclusively during waking hours. This arrangement synchronizes the physiological preparation of peripheral tissues for ingestion, digestion, absorption, distribution, and storage of nutrients. Melatonin originates from the pineal gland, which is downstream of the SCN, suggesting that melatonin secretion is regulated by light. Scheduled exercise is a nonphotic external time cue that effectively shifts the onset of melatonin secretion. The timing of exercise contributes to the readjustment of SCN circadian clocks with anticipated activity.

Humans have a 24-hour sleep-wake cycle, the most representative physiological process controlled by the circadian clock. The sleep-wake cycle is mainly regulated by two mechanisms: the circadian clock and homeostasis [29]. They are synchronized with external time cues to improve sleep quality by optimizing the sleep duration and timing. Sleep disorders are life-threatening, and more than 70 million people are diagnosed with these disorders in the U.S. Sleep deprivation interferes with physical and cognitive functions and affects personal mood [30]. For example, circadian rhythm sleep disorders (CRSDs) are caused by alterations in the internal circadian clock or a misalignment between external circumstances and endogenous circadian clocks [4]. Several distinctive CRSDs, such as irregular sleep-wake rhythms and advanced or delayed sleep-phase disorders have been diagnosed [31-34]. Individuals in the delayed-sleep phase type experience a shift in sleep and wake times later than desired. In contrast, individuals with an advanced sleep phase shift sleep and wake times earlier than normal, posing difficulties in remaining awake until the desired sleep time. The irregular sleep-wake type is characterized by an unrecognizable and disorganized pattern of sleep and wake patterns. The free-running type involves a gradual delay in bedtime of a few hours each day, resulting in insomnia and difficulty waking up in the morning. Individuals with jet lag struggle to align their sleep and wake times with their desired schedules because of recent travel to new time zones. Shift workers fall asleep during the day or remain awake at night at the time required by their work schedule [26]. Patients with CRSDs typically experience excessive daytime sleepiness, which negatively affects their quality of life by affecting work performance, personal health, and social activities. Pharmacological approaches targeting melatonin, orexin, or core clock genes are the primary treatments for patients with CRSDs. In addition, behavioral therapies, such as light adjustment, scheduled feeding, and exercise, have reported promising results.

Sleep disorders are primarily treated using behavioral and pharmacological strategies. Pharmacological approaches mainly target either neural firing or core clock regulatory pathways. Melatonin initiates sleep at night, whereas orexins are neuro-activators that alert individuals during the daytime. It is predominantly synthesized and released in the pineal gland at night and its production is regulated by norepinephrine. High levels of G-protein-coupled receptors such as melatonin receptor 1 (MT1R) and melatonin receptor 2 (MT2R) are expressed in the SCN. Melatonin binds to MT1R and MT2R in the SCN and inhibits the cyclic adenosine monophosphate-protein kinase A-cAMP-responsive element-binding protein (cAMP-PKA-CREB) phosphorylation pathway, thereby inhibiting SCN neural firing [35,36]. Melatonin administration timing is associated with a circadian clock phase shift. Melatonin administration in the late afternoon elicited a phase-advancing shift. Conversely, early morning melatonin administration delays the circadian clock. These results underscore the critical role of precisely timing melatonin intake to effectively alter circadian rhythms and sleep-wake cycles [37,38]. Administration of tasimelteon, a melatonin receptor agonist, produced significant results, demonstrating a substantial shift in the internal circadian clock, leading to improved sleep quality [39]. The SCN senses light through the retinohypothalamic tract, triggering orexinergic neurons in the lateral hypothalamus to secrete orexin A and orexin B. Orexin receptors 1 (OX1R) and orexin receptor 2 (OX2R) are found in neurons throughout the central nervous system [40,41]. Orexin signaling initiates multiple downstream cascades, including phospholipase A (PLA), phospholipase C (PLC), and phospholipase D (PLD). Consequently, the cytosolic Ca2+ levels increase, stimulating responses to neural firing [42]. Antagonists of orexin receptors have been found to potentially promote sleep onset by reducing cortical arousal and facilitating easier transitions between wakefulness and sleep [43,44]. Suvorexant, an antagonist of orexin receptors, affects sleep disorders marked by difficulty in sleep onset or maintenance [45]. By blocking OX1R and OX2R, it effectively suppresses orexin neuron activity, thereby promoting sleep [24,46].

Circadian medicine is experiencing exciting progress through direct manipulation of core oscillators. Recent studies have developed drug reagents that precisely target the fundamental components of the circadian clock. Several compounds that influence Per and Cry gene expression have the potential to modify the circadian period. The carbazole compound KL001 enhances the stability of CRY1 and CRY2 in human osteosarcoma cell lines [47]. KL001 treatment extends the circadian period and reduces its amplitude. The pharmacological targeting of CK1 is promising because it is crucial for the phosphorylation of core clock components. In mice whose rhythms are disrupted by constant light exposure, the CK1δ-specific inhibitor PF-670462 treatment can re-establish behavioral rhythms [48]. Longdaysin, a groundbreaking compound, prolongs the circadian period by preventing PER1 degradation in cell cultures and zebrafish in vivo [49]. REV-ERBs are nuclear receptors that play crucial roles in the circadian clock regulation. Rev-erbα knockout (KO) mice exhibit an advanced sleep-wake pattern. Furthermore, sleep consolidation notably decreased following sleep onset, suggesting a slower build-up of homeostatic sleep requirements throughout the day [42]. Researchers identified the ideal timing for administering the Rev-erbα agonist SR9009, demonstrating its ability to induce wakefulness during the light period [43].

An essential characteristic of circadian clocks is their capacity to adapt to external cues such as light, temperature, food, and exercise. Circadian clocks adjust, synchronize, and align internal biological rhythms, including their timing (phase) and duration (period), with external environmental cues like the 24-hour light-dark cycle. Therefore, circadian behavioral therapy prioritizes aligning lifestyles with endogenous circadian rhythms, focusing on timed activities, such as eating, exposure to light, and exercise, to enhance overall circadian health. Pervasive exposure to blue light at night in modern societies is a prevalent lifestyle habit that disrupts the neuroendocrine pathways of melatonin and affects the sleep-wake cycle [50]. Exposure to high-intensity natural daylight is associated with sleep timing, total sleep duration, and sleep quality [44]. In clinical practice, receiving several hours of bright broad-spectrum light in the morning benefits the sleep-wake cycle [50]. Advancements in time-restricted feeding (TRF) have significantly impacted metabolic disorders associated with disruptions in the sleep-wake cycle. TRF has emerged as a novel strategy for addressing irregularities in the sleep-wake cycle induced by diabetes. Administering TRF exclusively during the active phase effectively restored the sleep-wake cycle in diabetes mice [46]. Restricting food access during the active phase has demonstrated substantial preventive and therapeutic benefits on human sleep quality and duration [51].

Exercise challenges homeostasis by affecting cells, tissues, and organs. Therefore, exercise serves as a non-light external cue that can adjust the internal circadian clock and influence their timing [52]. Exercise can shift circadian clocks and is influenced by exercise type, timing, intensity, and individual chronotypes [53]. Morning exercise advances the phase for individuals with earlier chronotypes, whereas evening exercise delays this phase. In contrast, both morning and evening exercise induced phase advances in individuals with later chronotypes [53]. Forced treadmill exercise or a single bout of daytime wheel running induces a phase advance in the circadian clocks [54-56]. Patients with phase-delayed sleep problems may benefit from daytime exercise interventions as a potential treatment, which would assist in helping them revert to a more regular sleep phase. In contrast, exercising at midnight shifts circadian clocks to a delayed phase [57,58]. Exercise influences the expression of core clock genes and changes their phases in skeletal muscle [15]. By utilizing exercise intervention, the SCN of the hypothalamus which regulates the master clock was shifted. Exercise interventions selectively adjusted the amplitude of ERIOD2:LUCIFERASE in early scheduled access to running wheel mice, but not in those with late scheduled activity or unrestricted wheel access [59]. Wheel running under light exposure decreased the peak levels of clock genes Per1 and Per2 in the SCN [60]. These findings indicate that the timing of exercise is critical for regulating molecular clocks in the SCN. Exercise acts as a powerful external factor for peripheral clocks, including the skeletal muscles. Resistance training can also influence the expression levels of core circadian clock genes in skeletal muscles. Specifically, Cry1, Per2, and Bmal1 are upregulated in resistance exercise-trained legs compared with non-trained legs [61]. Male rugby players exhibited elevated average expression levels of core clock genes (Bmal1, Cry1, Per1, and Per2) in blood samples compared to sedentary males [62]. Furthermore, Cry1 and Cry2 genetic deletion altered the gene signature elicited by exercise and improved mice’s ability to exercise [63].

Light and melatonin therapies are standard treatments for CRSDs; however, exercise is beneficial for patients with CRSDs who display distinct abnormal sleep patterns. Delayed Sleep Phase Disorder (DSPD) is characterized by a significant shift in an individual’s sleep and wake times, making them much later than usual. People with DSPD usually go to bed late, which leads to difficulty in waking up in the morning and feelings of excessive sleepiness during the day. DSPD is caused by a combination of genetic, environmental, and behavioral factors. Polymorphisms in the core clock gene hPer3 are associated with DSPD from a genetic perspective [64]. Genetic mutations in the casein kinase-binding domain (CKBD) can modify the phosphorylation process of hPER3, thereby altering the circadian period length. A single nucleotide polymorphism in the 5′-untranslated region of hPer2 and a genetic variation in CKBD of hPer1 and are also associated with DSPD [65,66]. Disrupted synchronization of the circadian system due to light exposure at specific times can lead to delayed sleep. DSPD is associated with increased evening and decreased morning light exposure [67]. Exercise performed in the morning (ZT 4-6) shifts the PER2 phase by 2-3 hours in PER2 bioluminescence rhythms observed in skeletal muscles and lung explants [15]. Moreover, engaging in two hours of physical activity twice per waking period, such as cycling or rowing machines, advances the timing of melatonin secretion compared to the control group [56]. Exercise induces phase advances in Per1 and Per2 in hamsters [60].

Advanced Sleep Phase Disorder (ASPD) is associated with significantly earlier sleep and wake times than DSPD. Individuals with ASPD typically experience fewer negative consequences, because their active phase aligns with their regular social and work hours. Genetic factors, such as mutations in CKI or PER2 phosphorylation sites, contribute to ASPD [68-70]. These mutations interfere with the usual phosphorylation process or accelerate phosphorylation of phosphodegron, destabilizing hPER2 [71]. Increased sensitivity or prolonged exposure to light in the early morning contributes to the development of ASPD because light exposure plays a crucial role in regulating circadian rhythms. Subjects who engaged in three 45-minute cycling sessions at night demonstrated a substantial adjustment in melatonin oscillation, aligning with a new 9-hour delay in the sleep-wake cycle [72]. Participants were studied during nocturnal physical activity, either 3 hours of moderate-intensity exercise or 1 hour of high-intensity exercise, which led to a delay in the onset of thyrotropin and melatonin compared with the control group [57].

Irregular sleep-wake disorders are defined as the absence of a clear, consolidated sleep period, with affected individuals experiencing at least three distinct sleep episodes within a 24-hour period [73]. Irregular sleep-wake disorders are frequently linked to the dysfunction of the central circadian pacemaker SCN or to environmental conditions that restrict exposure to strong time cues [74]. Individuals with non-24 h sleep-wake disorders struggle to synchronize their sleep-wake cycles with a 24 h day. The endogenous clock is resistant to entrainment by the light-dark cycle. Most individuals with non-24 h sleep-wake disorders typically have a sleep duration slightly longer than 24 hours [75]. This leads to a gradual shift in their sleep-wake patterns, making them alert at night and sleepful during the day. Exercise intervention influences this phase shift and modifies clock gene expression in both the central and peripheral clocks of the skeletal muscles. When the TTFL generates oscillations in clock genes, reduced or flattened amplitudes can lead to an overall arrhythmicity or a singular rhythm [76-78]. Maximal strength training for eight days upregulates core clock genes in the skeletal muscles [61]. Athletes also exhibit elevated levels of core clock genes in their blood samples [62]. Acute aerobic treadmill exercise upregulated the expression of Per1 and Per2 in the tibialis anterior muscles of mice. Moreover, acute high-force eccentric contractions induced by electrical stimulation upregulate Bmal1 [79].