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. 2019 Apr;597(8):2253-2268.
doi: 10.1113/JP276943. Epub 2019 Mar 18.

Human circadian phase-response curves for exercise

Shawn D Youngstedt  1   2 , Jeffrey A Elliott  3   4 , Daniel F Kripke  3
Affiliations

Human circadian phase-response curves for exercise

Shawn D Youngstedt et al. J Physiol. 2019 Apr.

Abstract

Key points: Exercise elicits circadian phase-shifting effects, but additional information is needed. The phase-response curve describing the magnitude and direction of circadian rhythm phase shifts, depending on the time of the zeigeber (time cue) stimulus, is the most fundamental chronobiological tool for alleviating circadian misalignment and related morbidity. Fifty-one older and 48 young adults followed a circadian rhythms measurement protocol for up to 5.5 days, and performed 1 h of moderate treadmill exercise for 3 consecutive days at one of eight times of the day/night. Temporal changes in the phase of 6-sulphatoxymelatonin (aMT6s) were measured from evening onset, cosine acrophase, morning offset and duration of excretion. Significant phase-response curves were established for aMT6 onset and acrophase with large phase delays from 7:00 pm to 10:00 pm and large phase advances at both 7:00 am and from 1:00 pm to 4:00 pm. Delays or advances would be desired, for example, for adjustment to westward or eastward air travel, respectively. Along with known synergism with bright light, the above PRCs with a second phase advance region (afternoon) could support both practical and clinical applications.

Abstract: Although bright light is regarded as the primary circadian zeitgeber, its limitations support exploring alternative zeitgebers. Exercise elicits significant circadian phase-shifting effects, but fundamental information regarding these effects is needed. The primary aim of the present study was to establish phase-response curves (PRCs) documenting the size and direction of phase shifts in relation to the circadian time of exercise. Aerobically fit older (n = 51; 59-75 years) and young adults (n = 48; 18-30 years) followed a 90 min laboratory ultrashort sleep-wake cycle (60 min wake/30 min sleep) for up to 5½ days. At the same clock time on three consecutive days, each participant performed 60 min of moderate treadmill exercise (65-75% of heart rate reserve) at one of eight times of day/night. To describe PRCs, phase shifts were measured for the cosine-fitted acrophase of urinary 6-sulphatoxymelatonin (aMT6s), as well as for the evening rise, morning decline and change in duration of aMT6s excretion. Significant PRCs were found for aMT6s acrophase, onset and duration, with peak phase advances corresponding to clock times of 7:00 am and from 1:00 pm to 4:00 pm, delays from 7:00 pm to 10:00 pm, and minimal shifts around 4:00 pm and 2:00 am. There were no significant age or sex differences. The amplitudes of the aMT6s onset and acrophase PRCs are comparable to expectations for bright light of equal duration. The phase advance to afternoon exercise and the exercise-induced PRC for change in aMT6s duration are novel findings. The results support further research exploring additive phase-shifting effects of bright light and exercise and health benefits.

Keywords: 6-sulphatoxymelatonin; PRC; circadian time; phase advance; phase delay; phase shift; ultra-short sleep wake schedule.

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Figures

Figure 1
Figure 1. Experimental protocols
Each line on the ordinate represents one 24 h day from midnight to midnight (abscissa). Participants arrived in the laboratory at 9:30 am on day 1. An ultrashort sleep–wake cycle, involving 60 min for wake in <50 lux light (grey shaded bars), followed by 30 min for sleep in <0.5 lux (black shaded bars), began immediately and continued for 4.7–5.6 days. Three consecutive treatments (1 h exercise) commenced after 38–54 h of the ultrashort sleep–wake cycle (baseline) at one of eight laboratory clock times (days 2–5, white bars). Circadian phase was assessed during the final 24 h of baseline preceding the first exercise treatment (ending ∼1.5 h before the beginning of the first 1 h exercise) and again for the final 24 h starting 6 h after the third exercise bout (Fig. 2).
Figure 2
Figure 2. Example aMT6s time series
Circadian rhythms of urinary aMT6s excretion (ng h–1) are shown for two female participants (177,133), aged 18 years (top row: A, D, G) and 66 years (middle row: B, E, H) and one male participant (134), age 61 years (bottom row: C, F, I). Grey shaded areas (histogram plots in A–F) represent aMT6s time series used for circadian phase and waveform assessment (baseline A–C; post‐exercise D–F). White filled vertical rectangles (A–C) depict the laboratory clock time of the first of the three daily 1 h exercise bouts (Fig. 1). Cosine curves were fit to the 24 h prior to the first exercise treatment and again to the final 24 h in the laboratory. Capped horizontal lines represent the mesor (cosine fitted mean, ng h–1) and 24 h time‐span of pre‐ and post‐treatment cosine fits. White filled circles (A) represent clock times of cosine acrophases (fitted peak times). Thin lines connect temporal midpoints (ng h–1) of successive collection intervals. Times of aMT6s onsets (E) and offsets (M) are identified by arrows pointing, respectively, to upward and downward crossings of the associated mesor line. Measured changes in circadian aMT6s rhythm parameters are illustrated under Difference in (G), (H) and (I), where durations of nocturnal aMT6s peaks are represented as horizontal filled rectangles (pre‐ above, post‐treatment below) that span between clock times of E and M in (A) to (F). The time Difference values for E, A and M, and change in peak duration, respectively, are listed (left to right), beneath the three post‐exercise bars, and in Table 2. All individual Difference values such as these were subsequently transformed to the normalized (corrected) circadian phase‐shift and peak duration changes listed in Table 3 and plotted in the PRCs (Figs 3, 4, 5, 6) by subtracting from each the associated mean Difference of the entire sample (Table 2 and Methods).
Figure 3
Figure 3. PRC for phase shifts of aMT6s rhythm acrophase (the peak time of the 24 h cosine fit to the ng h–1 curve, Figure 2
A, phase shifts induced by exercise are shown for 101 participants (closed circles, Young, n = 48; open triangles, Older, n = 53). Rectangular bars (above graph in Figs 3, 4, 5, 6) represent home‐recorded actigraphic sleep times. The ordinate displays the acrophase shift corrected for the mean phase drift (delay) across the sample. The primary abscissa represents the timing of the mid‐points of the 1 h exercise stimuli transformed (normalized) to CT by adjusting for the difference between each subject's baseline acrophase and the mean baseline acrophase of all participants (Tables 1, 2, 3). B, normalized individual phase‐shifts in aMT6s acrophase in (A) were averaged into 3 h wide bins of CT stimulus time to yield a PRC curve (mean ± 95% confidence limits) representing all subjects (Young + Older). ANOVA showed a significant time effect (F 7,93 = 2.13, P = 0.048). Phase shift means that differed significantly from each other (Tukey's post hoc test, P < 0.05) are noted with the same lowercase letters. Phase shifts that differed significantly from 0 are indicated with an asterisk. The secondary abscissa placed between (A) and (B) gives times in relation to aMT6s acrophase at baseline (where 0 is equivalent to CT 3.44).
Figure 4
Figure 4. PRC for phase shifts of aMT6s rhythm onset (the evening rise, E in Figure 2)
A, phase shifts of aMT6s rhythm onsets (ordinate) are plotted for Young (n = 48) and Older (n = 51) participants with respect to the circadian time (CT) of exercise referenced to baseline aMT6s onset (Fig. 2 and Methods). B, the above individual phase‐shifts in aMT6s onset were averaged into non‐overlapping 3 h wide bins of CT to generate a PRC representing all phase shift responses (Young and Older groups combined). ANOVA showed a significant time effect (F 7,91 = 4.92, P < 0.001). CT bin mean shifts that differed significantly from one another are designated by shared letters (Tukey's post hoc test, P < 0.05). Mean shifts differing from zero are designated by asterisks. Both here and in Figs 5 and 6, the secondary abscissa placed between (A) and (B) gives times of exercise in relation to aMT6s onset at baseline (0 being equivalent to CT 22.62). Other conventions are as in Fig. 3.
Figure 5
Figure 5. PRC for phase shifts of aMT6s rhythm offset (the morning decline, M in Figure 2)
A, phase shifts of aMT6s rhythm offsets (ordinate) are plotted for Young (n = 48) and Older (n = 49) participants with respect to the normalized CT of exercise referenced to baseline amT6s onset (Fig. 2 and Methods). B, the above individual phase‐shifts in aMT6s offset were averaged into non‐overlapping 3 h wide bins of stimulus time (CT) to generate a PRC representing all phase shift responses (Young and Older groups combined). Other conventions are as in Fig. 4.
Figure 6
Figure 6. PRC for change in aMT6s rhythm peak duration (i.e., in the width of the nocturnal peak from E to M in Figure 2)
A, change in aMT6s rhythm peak duration (ordinate) are plotted for Young (n = 48) and Older (n = 49) participants with respect to the CT of the exercise stimuli (Table 2 and Methods). B, the above individual changes in aMT6s duration were averaged into non‐overlapping 3 h wide bins of stimulus time (CT) to generate a PRC representing all responses (Young and Older groups combined). ANOVA showed a significant time effect (F 7,89 = 2.20, P = 0.042), whereas post hoc tests revealed no time points that differed from one another or from zero. Other conventions are as in Figure 4.
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