Circadian Clocks, Redox Homeostasis, and Exercise: Time to Connect the Dots?

Abstract

Compelling research has documented how the circadian system is essential for the maintenance of several key biological processes including homeostasis, cardiovascular control, and glucose metabolism. Circadian clock disruptions, or losses of rhythmicity, have been implicated in the development of several diseases, premature ageing, and are regarded as health risks. Redox reactions involving reactive oxygen and nitrogen species (RONS) regulate several physiological functions such as cell signalling and the immune response. However, oxidative stress is associated with the pathological effects of RONS, resulting in a loss of cell signalling and damaging modifications to important molecules such as DNA. Direct connections have been established between circadian rhythms and oxidative stress on the basis that disruptions to circadian rhythms can affect redox biology, and vice versa, in a bi-directional relationship. For instance, the expression and activity of several key antioxidant enzymes (SOD, GPx, and CAT) appear to follow circadian patterns. Consequently, the ability to unravel these interactions has opened an exciting area of redox biology. Exercise exerts numerous benefits to health and, as a potent environmental cue, has the capacity to adjust disrupted circadian systems. In fact, the response to a given exercise stimulus may also exhibit circadian variation. At the same time, the relationship between exercise, RONS, and oxidative stress has also been scrutinised, whereby it is clear that exercise-induced RONS can elicit both helpful and potentially harmful health effects that are dependent on the type, intensity, and duration of exercise. To date, it appears that the emerging interface between circadian rhythmicity and oxidative stress/redox metabolism has not been explored in relation to exercise. This review aims to summarise the evidence supporting the conceptual link between the circadian clock, oxidative stress/redox homeostasis, and exercise stimuli. We believe carefully designed investigations of this nexus are required, which could be harnessed to tackle theories concerned with, for example, the existence of an optimal time to exercise to accrue physiological benefits.

Keywords: antioxidant; circadian rhythms; exercise training; reactive oxygen and nitrogen species (RONS).

Figure 1

Circadian Rhythms in Humans. Crucial biological and physiological processes such as blood pressure control, antioxidant expression, body temperature, and immune function normally fluctuate in a circadian pattern (~24 h). These oscillations are coordinated by circadian clocks distributed in virtually every cell. The core molecular clock functions to direct a daily program of gene transcription and protein expression. The molecular clock involves a transcriptional–translational feedback loop (TTFL) of core clock genes (positive limb: BMAL-1 and CLOCK; negative limb: PERs and CRYs) that act to modulate the gene expression of clock-controlled genes (CCG) which generate tissue-specific circadian rhythms in transcription and cellular function across the day, even in the absence of external cues. The principal pacemaker of the circadian clock in humans is located within the suprachiasmatic nucleus (SCN) region of the hypothalamus. This master clock coordinates the activity of downstream peripheral tissue clocks in response to several stimuli such as the day-night cycle, food ingestion, exercise, and sleep. Figure key = SCN: suprachiasmatic nucleus; HPA: hypothalamic-pituitary-adrenal axis; CCG: clock-controlled genes; E: E-box motif.

Figure 2

Exercise-induced RONS, Oxidative Stress, and Hormesis. The fundamental basis of the hormesis theory can be applied to exercise-induced RONS formation: low or transient increases in RONS, from moderate-intensity and regular exercise, activate signalling pathways that induce adaptive and protective responses. Whereas inactivity and/or sporadic strenuous/high-intensity exercise can lead to a RONS load that overwhelms antioxidant defences leading to oxidative stress, impaired physiological function, and an increased risk for chronic disease.

Figure 3

The interplay between Circadian and Redox Biology: Oxidative Stress and Disrupted Circadian Rhythms. A proposed bidirectional relationship exists between oxidative stress and circadian dysregulation whereby external factors and behaviours that disrupt circadian rhythms (jet lag, the ageing process, and regular consumption of certain foods) may also induce oxidative stress and, likely vice versa. The result is a deterioration of normal physiological functions (DNA damage, increased blood pressure, and insulin resistance) and control that increases the risk for chronic diseases.

Figure 4

The interplay between Circadian and Redox Biology: Exercise as a zeitgeber and source of RONS. Exercise is a potent stimulus to entrain dysregulated circadian systems and positively affect the core molecular clock and subsequent expression of CCGs throughout the body. At the same time, exercise-induced RONS are integral to several recognised physiological responses and adaptations via the activation of redox-sensitive transcription factors (e.g., up-regulation of immunity, antioxidant enzymatic activity, etc.). It is possible that both circadian and redox signalling are inter-connected and operate synergistically to confer protective health effects following regular exercise.