Am J Physiol Regulatory Integrative Comp Physiol
281: R197–R205, 2001.
Phase-advance shifts of human circadian pacemaker are
accelerated by daytime physical exercise
TOSHIHIKO MIYAZAKI, SATOKO HASHIMOTO, SATORU MASUBUCHI,
SATO HONMA, AND KEN-ICHI HONMA
Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060 Japan
Received 4 December 2000; accepted in final form 12 March 2001
melatonin; rectal temperature; entrainment
that a light-dark alternation is a
potent zeitgeber for the circadian pacemaker in most
mammals including humans (6, 14, 22). The light entrainment is assumed to be accomplished by daily
phase shifts of the circadian pacemaker by light given
at appropriate times of day (8, 13, 18). Other than
light, physical activity was demonstrated in nocturnal
rodents to facilitate the light entrainment of the circadian pacemaker (19), which also depended on the time
of day when physical activity was performed. Physical
activity is also known to change the circadian period of
behavioral rhythm in rodents (1, 30). However, it is a
matter of debate whether physical exercise is capable
of entraining the circadian pacemaker in humans. Van
Reeth et al. (26) reported a significant phase-delay
shift of plasma melatonin rhythm in humans by a
single pulse of physical exercise at midnight. Physical
exercise was also demonstrated to facilitate phase-
IT IS WELL ESTABLISHED
Address for reprint requests and other correspondence: K.-I. Honma,
Dept. of Physiology, Hokkaido Univ. Graduate School of Medicine,
Sapporo 060 Japan (E-mail [email protected]).
http://www.ajpregu.org
delay shifts of the core body temperature rhythm associated with simulated night shifts (9). These findings
suggest that physical exercise somehow has an impact
on the human circadian pacemaker. But it is not
known whether physical exercise contributes to entrainment of the human circadian pacemaker to the
day-night alternation, because it is a phase-advance
shift not a phase delay that is necessary for the human
circadian pacemaker, which possesses an intrinsic period longer than 24 h (7, 10, 27), to entrain to a 24-h
cycle.
On the other hand, entrainment can be accelerated
by shortening the circadian period of pacemaker,
whereby the daily phase shift necessary for entrainment becomes smaller. Beersma and Hiddinga (2) examined the effect of physical exercise during wakefulness on the circadian period of core body temperature
with a desynchrony protocol of 20-h intervals. They did
not find a statistically significant difference in the
period between the forced schedules with and without
exercise. Physical exercise under free-running conditions also failed to change the circadian period of body
temperature (29). However, in these studies, physical
exercise was designed to cover all phases of the circadian pacemaker (2) or a particular part of the circadian
phase (29), so that the possibility was not excluded that
the phase-dependent effect of physical exercise was
missed. Actually, Buxton et al. (4) predicted a phaseresponse curve for physical exercise in which a phaseadvance portion was located at noon.
In the present study, we reexamined the entraining
effect of physical exercise on the human circadian
rhythm using a forced sleep-wake schedule of a period
of 23 h and 40 min under dim light conditions (⬍10 lx).
This external periodicity requires a phase-advance
shift of ⬎1 h/day for full entrainment of the circadian
pacemaker. The rationale for using this periodicity was
to reveal the phase-advancing effect of physical exercise, if any, by a relatively short-term experiment.
Because the free running period of the human circadian pacemaker is longer than, but close to, 24 h under
dim light conditions (17), especially immediately after
release into free running (10), the expected phase shift
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
0363-6119/01 $5.00 Copyright © 2001 the American Physiological Society
R197
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
Miyazaki, Toshihiko, Satoko Hashimoto, Satoru Masubuchi, Sato Honma, and Ken-Ichi Honma. Phase-advance shifts of human circadian pacemaker are accelerated
by daytime physical exercise. Am J Physiol Regulatory Integrative Comp Physiol 281: R197–R205, 2001.—Effects of
forced sleep-wake schedules with and without physical exercise were examined on the human circadian pacemaker under dim light conditions. Subjects spent 15 days in an isolation facility separately without knowing the time of day and
followed a forced sleep-wake schedule of a 23 h 40-min period
for 12 cycles, and physical exercise was imposed twice per
waking period for 2 h each with bicycle- or rowing-type
ergometers. As a result, plasma melatonin rhythm was significantly phase advanced with physical exercise, whereas it
was not changed without exercise. The difference in phase
was already significant 6 days after the start of exercise. The
amplitude of melatonin rhythm was not affected. A single
pulse of physical exercise in the afternoon or at midnight
significantly phase delayed the melatonin rhythms when
compared with the prepulse phase, but the amount of phase
shift was not different from that observed in the sedentary
controls. These findings indicate that physical exercise accelerates phase-advance shifts of the human circadian pacemaker associated with the forced sleep-wake schedule.
R198
EXERCISE AND HUMAN CIRCADIAN RHYTHM
in the control experiment is only a few hours at most in
12 days. The phase difference to be tested at the end of
experiment should be large enough between the control
and experimental groups; otherwise the entraining effect of physical exercise would be missed. In the experimental design mentioned above, the overall displacement (phase-advance shift) of sleep time is 4 h in 12
cycles. In addition, a single pulse of physical exercise
given at different times of day was examined for its
phase-shifting effects on the plasma melatonin rhythm
to discover the mechanism of entrainment by physical
exercise.
SUBJECTS AND METHODS
Subjects and Facility
Experimental Protocols
Two different experiments were carried out: forced sleepwake schedules with and without physical exercise (experiment 1) and a single pulse of physical exercise at three
different times of day (experiment 2).
Experiment 1: forced sleep-wake schedule with and without
physical exercise. Four series of experiments were carried
out. In each series, four subjects were studied, two performing physical exercise and the other two being sedentary.
The subjects entered the isolation facility at ⬃1700 on the
1st day. A serial blood sampling was started at 1800 for 24 h
at 1-h intervals. On the 1st night, the subjects were instructed to go to bed at their habitual sleep times and allowed
to wake up at their preferred times. From the 2nd night, a
forced sleep-wake schedule with a period of 23 h and 40 min
(8-h rest and 15 h 40-min wake periods) was imposed for 12
cycles. The time of retirement at the 2nd night (1st night of
forced schedule) was scheduled at 2400 and the wake-up time
at 0800, both of which were phase advanced by 20 min every
day. On the last day of the forced schedule (day 14), the
subjects went to bed at 2000 and got up at 0400. The subjects
were notified by phone to prepare for sleep 30 min before the
Fig. 1. Experimental protocol of forced sleep-wake schedule of 23 h
and 40 min. Solid bars, rest period; hatched bars, physical exercise.
The period indicated by 2 arrows is the time of serial blood sampling.
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
Forty-six healthy subjects of both sexes (42 men, 4 women)
participated in the present study as paid volunteers. Two
persons participated twice in different experiments. They
ranged in age from 20 to 28 yr (the average, 23.2 ⫾ 2.1 yr)
and passed a routine medical examination. Subjects who had
been abroad or had a job in the early morning or at night
within 4 wk before the experiment were excluded. The study
was approved by the ethical committee of Hokkaido University Graduate School of Medicine.
The subjects were asked to try to go to bed at midnight for
7 days before the start of experiment and to keep sleep
diaries. They stayed in a temporal isolation facility either for
3 days or for 15 days without knowing the time of day. The
facility consists of four isolation units. Each two units are
connected by a common room where the subjects performed
physical exercise. The common room is also isolated from
outside. The isolation unit consists of a living room with
kitchen and a bathroom, as described elsewhere (14). The
main illumination was supplied from the ceiling, but there
were accessory lights at bed, bathroom, and desk. The light
intensity of the rooms for physical exercise as well as the
isolation units was kept at 50 lx at the head level of a
standing subject, but the actual light intensity received by
the subjects was ⬍10 lx when measured with a photosensor
(actirum) placed on the forehead. The intensity of accessory
lights was ⬍10 lx in the ordinary position.
scheduled time for retirement and again to go to bed at the
scheduled sleep time. They were required to remain in bed
lying down until the scheduled wake-up time, except when
using the bathroom. Immediately before retirement, the
room illumination and accessory lights were turned off. At
the scheduled wake-up time, the subjects were awakened by
a morning call and required to get out of bed. The room
illumination and accessory bed lights were turned on. They
performed physical exercise twice a day during the waking
period from day 3 to day 14. The morning exercise was
started 3 h after waking up, and the afternoon exercise was
2 h after the end of morning exercise (7 h after waking up).
Physical exercise and rest (siting in a chair) were carried out
in the common rooms. Except for physical exercise or rest
period, the subjects were not allowed to leave the living room.
They were called by phone for exercise 15 min before the
scheduled time. At other times, the subjects listened to music
or watched videotapes. Reading was not impossible, but
difficult, under the dim light conditions. Napping was not
allowed. Performance tests (modified Pouly test with a computer display and a 10-key board) and questionnaires asking
about physical as well as emotional state were undertaken at
every micturition and at meal times. Meals were supplied 30
min after wake up, 30 min after the morning exercise (5 h
and 30 min after wake up), and 3 h after the afternoon
exercise (12 h after wake up). The total calories per day were
⬃2,500 kcal. In addition to the regular meals, the subjects
were allowed to take snacks and softdrinks. Serial blood
samplings were performed on day 8 starting at 1600 until
2100 on the following day and on day 14 from 1400 until 2000
on the next day. Physical exercise was not performed on day
15. The experimental protocol is illustrated in Fig. 1.
Experiment 2: a single pulse of physical exercise. This
experiment consisted of four sessions performed on different
days: the control session without physical exercise, the morning session with exercise from 0900 to 1100, the afternoon
session from 1500 to 1700, and the night session from 0000 to
0200. In each session, eight subjects participated. Subjects
did not participate in different sessions. The conditions, facilities, and equipment were the same as in experiment 1. The
subjects were required to go to bed at 1100 and wake up at
0700 on the first night but decided the times of retirement
R199
EXERCISE AND HUMAN CIRCADIAN RHYTHM
and getting up on the following nights by themselves. Meals
were supplied at the regular times: 0730, 1230, and 1830.
In the control and morning sessions, the subjects entered
the isolation facility at 1700 on the 1st day, and a serial blood
sampling was started at 1800 and ended at 1800 on the 3rd
day (48 h). In the morning session, the subjects performed
physical exercise from 0900 to 1100 on the second day. In the
afternoon session, the subjects entered the facility at 1100 on
the 1st day, and a serial blood sampling was started at 1200
and continued to 1200 on the 3rd day (48 h). Subjects performed physical exercise from 1500 to 1700 on the 2nd day. In
the night session, the subjects entered in the facility at 1700
on the 1st day, and a serial blood sampling was started at
1800 and ended at 1800 on the 4th day (72 h). Subjects
performed physical exercise from 0000 to 0200 on the 3rd day
(i.e., the 2nd night).
Two subjects performed physical exercise for 2 h, and the
other two sat quietly in chairs for the same period. Every
time, the staff instructed them on how to perform the physical exercise. Physical exercise was done with bicycle- and
rowing-type ergometers. When the subjects used a bicycletype ergometer in the morning, they would use a rowing-type
ergometer in the afternoon and vice versa. They performed
physical exercise for 15 min at a heart rate of 140 beats/min,
followed by 15 min rest. This pattern was repeated four times
in 2 h. Heart rate was monitored by the heart rate monitor
(Polar PE3000), and the staff advised the subjects of the
strength of exercise. In experiment 2, only a bicycle-type
ergometer was used for physical exercise.
Measurement of Plasma Melatonin and Rectal Temperature
Blood (⬃3 ml) was sampled at 1-h intervals through an
indwelling catheter with a heparin lock placed in the forearm
vein. Immediately after sampling, plasma was separated by
centrifugation and stored at ⫺40°C until the determination
of melatonin by radioimmunoassay (11). The intra- and interassay variances of the melatonin assay were 6.7 and 7.0%,
respectively. Rectal temperature was measured continuously
by a thermistor probe with a line connected to a computer in
the operation room, to which a record was fed every 30 s.
The phase and amplitude of plasma melatonin rhythm
were analyzed by a geometric method reported previously
(11). The original rhythm was transformed by a three-point
moving average method. The difference between the maximum and minimum values of a smoothed 24-h rhythm was
defined as the amplitude of the rhythm. The ascending phase
was defined as the time when a horizontal line through the
midpoint of the maximum and minimum values (middle line)
crossed the ascending limb of the nocturnal melatonin rise,
and the descending phase was defined as the time when the
middle line crossed the descending limb of melatonin
rhythm. The peak phase was the midpoint between the
ascending and descending phases. The amount of phase shift
of the plasma melatonin rhythm was calculated for the first
half (from day 2 to day 8), the second half (from day 9 to day
15), and the whole session, using the peak phase as a reference. The amplitude of the individual melatonin rhythm was
calculated as follows. The melatonin rhythms in individuals
were standardized in such a way that each melatonin value
was expressed as a percentage of the peak value on day 1.
The amplitude was defined as the difference between the
daytime minimum value and the peak value and expressed
as percent peak value.
The rectal temperature rhythm in experiment 1 was analyzed as follows. Rectal temperature recorded every 10 min
was transformed to two states, a higher and lower temperature than the mean body temperature. The mean body temperature was calculated using data for 14 days (from day 2 to
day 15). For this calculation, temperature values during
physical exercise and shower taking were omitted. In experiment 2, differences in rectal temperature between the exercise and control days were calculated based on local time.
Statistics
A two-way ANOVA with post hoc t-tests was used for
comparison of melatonin rhythm parameters with and without exercise under the forced sleep-wake schedule in experiment 1. Repeated t-tests were used for comparison of phases
of melatonin rhythms and rectal temperature between the
control and exercise days in experiment 2.
Table 1. Phases and phase shifts of individual melatonin rhythms with and without exercise
Subject
Without exercise
Day 1
Day 8
Day 14
Day phase shift (days 1–8)
Day phase shift (days 1–14)
With exercise
Day 1
Day 8
Day 14
Day phase shift (days 1–8)
Day phase shift (days 1–14)
AB
OG
5.41
5.46
6.81
⫺0.05
⫺1.40
6.21
7.04
7.07
⫺0.83
⫺0.86
KI
TK
5.42
4.90
5.00
0.51
0.41
3.06
2.67
1.32
0.38
1.73
KK
NG
4.00
3.90
2.84
0.10
1.17
7.69
7.25
6.05
0.44
1.64
YG
NT
3.64
3.76
1.79
⫺0.11
1.85
2.32
2.75
0.88
⫺0.43
1.44
TB
ZN
TS
SK
2.18
3.61
3.01
⫺1.43
⫺0.83
4.26
5.57
8.32
⫺1.31
⫺4.05
3.56
5.16
4.82
⫺1.60
⫺1.26
6.79
12.32
19.00
⫺5.53
⫺12.21
IT
KT
AO
YS
4.88
3.85
4.87
1.02
0.01
6.57
5.57
3.54
1.00
3.03
4.94
1.15
2.21
3.79
2.73
7.26
9.96
13.60
⫺2.70
⫺6.34
Mean
(n ⫽ 7)
4.76
5.43
5.56
⫺0.67
⫺0.80
SE
0.69
0.53
0.79
0.31
0.71
Mean
(n ⫽ 7)
SE
4.40
3.52*
2.80†
0.88*
1.60†
0.56
0.56
0.63
0.53
0.42
Values are peak phase of melatonin rhythm. Results from SK and PS are not used for statistics. * P ⬍ 0.05, † P ⬍ 0.01 vs. without exercise.
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
Physical Exercise
Data Analysis
R200
EXERCISE AND HUMAN CIRCADIAN RHYTHM
RESULTS
Table 1 demonstrates the amounts of phase shift in
individual melatonin rhythm in experiment 1, and Fig.
2 illustrates the averaged melatonin rhythms with and
without physical exercise. The peak phases of individual melatonin rhythm on day 1 were located from 2.32
to 6.57 h, with an average value of 4.40 h (SE 0.56 h) in
the subjects performing exercise, and from 2.18 to
7.69 h with an average of 4.76 h (SE 0.69 h) in the
subjects being quiet. There was no statistically significant difference in the initial phase between the two
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
Fig. 2. Plasma melatonin rhythms under the forced schedule with
(F) and without (E) physical exercise. Square column in each panel
indicates the rest period. The melatonin values are expressed by the
mean and SE (n ⫽ 7).
groups (t-test). In one subject from each group (YS,
SK), the melatonin rhythm showed a large phase-delay
shift in the course of experiment, and the amounts of
phase shift were significantly different from the means
of respective groups (Smirnoff’s test). Therefore, these
values were not included in the following analyses. The
average phase shift of the melatonin peak for the entire
period was ⫹1.60 h (n ⫽ 7, SE 0.42 h) with physical
exercise and ⫺0.80 h (n ⫽ 7, SE 0.71 h) without
exercise. A positive sign indicates a phase-advance
shift and a negative sign a phase-delay shift. The
difference in phases is statistically significant (2-way
ANOVA, P ⬍ 0.01). The phase shift of the melatonin
peak was already significantly different in the first 6
days (t-test, P ⬍ 0.05). The phase shift at that time was
⫹0.88 h (SE 0.53 h) with physical exercise and ⫺0.67
(SE 0.31 h) without exercise. The rate of phase shift
seemed to be different when the ascending and descending phases of nocturnal melatonin rise were compared. The ascending phase in the group with physical
exercise was significantly phase advanced already on
day 8 from that in the group without exercise (⫺0.59 ⫾
0.56 vs. 1.21 ⫾ 0.47 h, P ⬍ 0.05), whereas the difference in the descending phase was not statistically
significant. On the other hand, differences in both the
ascending and descending phases were statistically
significant on day 14 (ascending; ⫺1.50 ⫾ 0.69 vs.
1.19 ⫾ 0.70 h, P ⬍ 0.05: descending; 7.13 ⫾ 0.77 vs.
9.93 ⫾ 1.01 h, P ⬍ 0.05).
Calculated from the phase shifts of melatonin peak,
the period of melatonin rhythm during the forced
sleep-wake schedule was 23.88 h (SE 0.04 h) with
physical exercise and 24.06 h (SE 0.06 h) without
exercise. The difference was small but statistically
significant (P ⬍ 0.01). The amplitude of melatonin
rhythm had a tendency to decrease in the course of
experiment, but statistically significant differences
were not detected either among days or between the
groups.
Figures 3 and 4 illustrate the peak phase of melatonin rhythm and the transformed rectal temperature
rhythms in all subjects in experiment 1. Except for one
subject from each group (YS and SK), the lower part of
body temperature coincided for the most part with the
scheduled sleep time or slightly deviated from it. In
subjects YS and SK, the lower temperature part and
the peak phase of melatonin rhythm were substantially phase delayed.
Figure 5 and Table 2 demonstrate the effects of
single pulses of physical exercise at different times of
day on the onset, peak, and offset phases of the plasma
melatonin rhythm (experiment 2). There was no difference in the phases of melatonin rhythm after the control and morning pulses. Statistically significant phase
delays were detected in the peak phase after the afternoon pulse and all three phases after the night pulse.
In the latter case, the three phases were compared
between days 1 and 3, because physical exercise on day
2 could shift the melatonin rhythm immediately so
that the shape of nocturnal melatonin rise would be
changed, which might blur the phases of the melatonin
EXERCISE AND HUMAN CIRCADIAN RHYTHM
R201
rhythm, and because physical exercise might change
the level of plasma melatonin per se (5) , which, however, was not the case in the present study. Plasma
melatonin levels were not changed significantly during
exercise or within 3 h after physical exercise (data not
shown). On the other hand, the amount of phase shift
in any of three exercise sessions was not significantly
different from that observed in the sedentary control
session.
Figure 6 illustrates differences in rectal temperature
between the day of exercise and of rest. Rectal temperature increased during physical exercise and decreased
afterward even below the level of the sedentary day
(postexercise hypothermia). The biphasic effects of
physical exercise on rectal temperature seem to depend
on the time of day when exercise was done. The increase in rectal temperature during exercise at midnight (1.22 ⫾ 0.17°C) was significantly larger than that
in the afternoon (0.72 ⫾ 0.08°C, P ⬍ 0.05) but not that
in the morning (0.79 ⫾ 0.15°C). On the other hand, the
postexercise hypothermia seemed to last longer in the
morning session (for ⬃8 h ) than in the afternoon (for
⬃4 h) and night sessions (postexercise hypothermia
was lacking).
DISCUSSION
In the present study, physical exercise in the daytime accelerated phase-advance shifts of the human
circadian pacemaker under the forced sleep-wake period of 23 h and 40 min. The peak phase of plasma
melatonin rhythm was significantly phase advanced by
1.60 h (SE 0.42) in 12 cycles with physical exercise,
whereas the peak phase was slightly but not significantly delayed without exercise (⫺0.80 ⫾ 0.71 h). The
phase difference between exercise and rest was statistically significant. With physical exercise, the circadian
body temperature rhythm also seemed to catch up with
the forced schedule better than without exercise. To
our knowledge, this is the first report in which physical
exercise was demonstrated to phase advance the human circadian pacemaker.
The mechanism by which physical exercise phase
advanced the pacemaker is not known. Previously,
physical exercise at midnight was demonstrated to
phase delay the circadian pacemaker in humans (4, 26)
and accelerate the adaptation of core body temperature
rhythm to a 9-h phase-delayed sleep (9). From the
partial phase-response curve for physical activity, Buxton et al. (4) predicted that the phase-advancing effect
of physical exercise could be observed at noon. In the
present study, a single pulse of moderate physical
exercise given either in the morning or afternoon hours
did not yield a significant phase-advance shift (Fig. 5).
However, the present findings do not exclude the possibility that a single pulse of physical exercise at the
right time of day might phase advance the human
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
Fig. 3. Two-state expression of rectal temperature and the peak phase of plasma melatonin in subjects under the forced schedule with
physical exercise. Shaded area, hypothermic
period; E, peak phase of melatonin rhythm.
Solid bars, rest period; open bars, period for
physical exercise.
R202
EXERCISE AND HUMAN CIRCADIAN RHYTHM
circadian pacemaker, because an expected phase shift
by a single pulse is ⬃0.12 h, which is too small to be
detected by the plasma melatonin rhythms.
Alternatively, physical exercise may shorten the endogenous period of the human circadian pacemaker,
which makes the circadian pacemaker entrain more
easily to the forced sleep schedule. Wever (29) examined the effects of physical workload on the free run
period in human subjects and failed to find statistically
significant changes in the period. Beersma and Hiddinga (2) also studied the effects of physical activity on
the human circadian period by a desynchrony protocol
of a forced sleep-wake cycle with a 20-h period. Although they could not find statistically significant effects of physical activity, the circadian period of core
body temperature showed a tendency to shorten. Core
body temperature is known to be masked by sleep and
wakefulness, which might blur the effects of exercise
(28). Rectal temperature was influenced not only during physical exercise but also for a relatively long
period after exercise (Fig. 6). On this reason, the
plasma melatonin rhythm was used in the present
study as a marker of the circadian pacemaker, which is
known to escape from many masking factors, except for
bright light (12).
Exogenous melatonin in the late afternoon phase
advanced the human circadian pacemaker (15, 16).
Moreover, daytime physical exercise was reported to
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
Fig. 4. Two-state expression of rectal temperature and the peak phase of plasma melatonin in subjects under the forced schedule
without physical exercise. Shaded area, hypothermic period; E, peak phase of melatonin
rhythm. Solid bars, rest period.
Fig. 5. Effects of a single pulse of physical exercise at different times
of day on plasma melatonin rhythm. E, Melatonin rhythm on the day
before physical exercise; F, melatonin rhythm on the day of physical
exercise (control, morning, afternoon pulse) or on the day after
physical exercise (night pulse). The melatonin values are expressed
by the mean and SE (n ⫽ 8).
EXERCISE AND HUMAN CIRCADIAN RHYTHM
Table 2. Phases and phase shifts of melatonin
rhythm after a single pulse of exercise at different
times of day
Onset
Offset
⫺0.93 ⫾ 0.79
⫺0.77 ⫾ 0.77
⫺0.16 ⫾ 0.16
3.00 ⫾ 0.65
3.11 ⫾ 0.66
⫺0.11 ⫾ 0.12
6.94 ⫾ 0.57
7.12 ⫾ 0.65
⫺0.18 ⫾ 0.18
0.39 ⫾ 0.80
0.44 ⫾ 0.90
⫺0.05 ⫾ 0.22
4.24 ⫾ 0.64
4.26 ⫾ 0.65
⫺0.02 ⫾ 0.12
8.06 ⫾ 0.72
8.21 ⫾ 0.63
⫺0.15 ⫾ 0.29
0.09 ⫾ 0.83
0.67 ⫾ 0.76
⫺0.58 ⫾ 0.25
4.12 ⫾ 0.78
4.47 ⫾ 0.81*
⫺0.35 ⫾ 0.13
7.96 ⫾ 0.91
8.07 ⫾ 0.85
⫺0.11 ⫾ 0.39
0.23 ⫾ 0.64
0.68 ⫾ 0.71*
⫺0.45 ⫾ 0.15
4.15 ⫾ 0.56
4.60 ⫾ 0.61†
⫺0.45 ⫾ 0.12
8.13 ⫾ 0.68
8.75 ⫾ 0.68†
⫺0.62 ⫾ 0.21
subjected under lights of ⬍1 lx (unpublished observation). A similar value was reported in blind subjects
whose circadian rhythms were free running under temporal isolation (27). If we take this value as an endogenous circadian period, the forced sleep-wake itself has
a potency to affect the human circadian pacemaker.
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
Control
Day 1
Day 2
Phase shift
Morning
exercise
Day 1
Day 2
Phase shift
Afternoon
exercise
Day 1
Day 2
Phase shift
Night
exercise
Day 1
Day 3
Phase shift
Peak
R203
Values are means ⫾ SE in phase of reference point each day. Day
1 is the prepulse day and day 2 is the pulse day. Day 1, day 2, and
day 3 are the prepulse, pulse, and postpulse days, respectively.
* P ⬍ 0.05, † P ⬍ 0.01 vs. 1st day.
increase plasma melatonin levels (5, 24, 25), which
might account for the phase-shifting effect of physical
exercise. However, this possibility is unlikely, because
single trials of physical exercise did not change plasma
melatonin levels (data not shown). Alternatively, physical exercise may increase the sensitivity to light and
thereby accelerate the light-induced phase-advance
shift. This possibility is not excluded completely but is
unlikely, because the light intensity actually received
by the subjects was ⬍10 lx, which seems to be under
the threshold for the phase-resetting capability of
light (3).
Daytime physical exercise might increase the
arousal state of subjects (23) and strengthen the sleepwakefulness rhythm that feeds back onto the circadian
pacemaker. In nocturnal rodents, the feedback of physical activity onto the circadian pacemaker is well established (1, 30). In this context, the phase shifts of
melatonin rhythm observed without exercise are interesting. The phase of the melatonin rhythm was not
changed at all for 12 cycles under the forced sleep-wake
schedule without exercise, which indicates the period
of circadian rhythm is very close to 24 h. This finding
could be interpreted in two different ways. The circadian pacemaker was desynchronized from the sleepwake cycle and exhibited the endogenous periodicity
close to 24 h. Czeisler et al. (7) reported the circadian
period in humans was very close to 24 h, as estimated
by a desynchrony protocol. Similar results were also
obtained by other authors (17). Alternatively, the
present finding could be interpreted to indicate that
the forced sleep-wake schedule itself had an impact on
the free run period of the human circadian pacemaker.
Recently, we observed free running melatonin rhythms
with the mean circadian period of 24.47 h in sighted
Fig. 6. Effects of a single pulse of physical exercise at different times
of day on rectal temperature. Solid bars, times of physical exercise;
open bars, sleep. Each horizontal bar at the sleep onset and end
indicates SE. Changes in rectal temperature are expressed with the
mean and SE (n ⫽ 8). Horizontal bars indicate the portion where
rectal temperature decreases significantly below the control level
(P ⬍ 0.05).
R204
EXERCISE AND HUMAN CIRCADIAN RHYTHM
of rectal temperature rhythms on which physical exercise exerts dual effects in a phase-dependent manner.
Perspectives
Light is known to be a strong regulator for the
human circadian pacemaker and is used as a therapy
for circadian rhythm disorders such as delayed sleepphase syndrome and non-24-h sleep-wake syndrome.
Physical exercise, although less effective, is also capable of facilitating the entrainment of the human circadian rhythm and may be useful in cases in which lights
are not available, e.g., blind people or people in space
where lights are very expensive. In space, the natural
24-h periodicity is lacking and one may follow an artificial (forced) sleep-wake schedule with a period that
deviates more or less from the endogenous circadian
periods in individual astronauts. Light is very expensive in space and may not be available for resetting the
astronauts’ circadian pacemakers. Timed physical exercise may be helpful for them.
The present study was supported financially in part by a grant
from the Japan Space Forum “Ground Research Announcement for
Space Utilization” (No. 139) and by a grant from The Descente and
Ishimoto Memorial Foundation for the Promotion of Sport Science.
We appreciate the generous supply of melatonin antibody from Prof.
K. Kawashima, Kyoritsu Pharmaceutical College.
REFERENCES
1. Aschoff J, Figala J, and Poppel E. Circadian rhythms of
locomotor activity in the golden hamster (Mesocricetus auratus)
measured with two different techniques. J Comp Physiol Psychol
85: 20–28, 1973.
2. Beersma DG and Hiddinga AE. No impact of physical activity
on the period of the circadian pacemaker in humans. Chronobiol
Int 15: 49–57, 1998.
3. Boivin DB, Duffy JF, Kronauer RE, and Czeisler CA. Doseresponse relationships for resetting of human circadian clock by
light. Nature 379: 540–542, 1996.
4. Buxton OM, Framl SM, L’Hermite-Baleriaux M, Leproult
R, Turk FW, and Van Cauter E. Roles of intensity and duration of nocturnal exercise in causing phase delays of human
circadian rhythms. Am J Physiol Endocrinol Metab 273: E536–
E542, 1997.
5. Carr DB, Reppert M, Bullen B, Skrinar G, Beitins I, Arnold
M, Rosenblatt M, Martin JB, and Mcarthur JW. Plasma
melatonin increases during exercise in women. J Clin Endocrinol Metab 53: 224–225, 1981.
6. Czeisler CA, Allan JS, Strogatz SH, Ronda JM, Sanchez R,
Rios CD, Freitag WO, Richardson GS, and Kronauer RE.
Bright light resets the human circadian pacemaker independent
of the timing of the sleep-wake cycle. Science 233: 667–671, 1986.
7. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell
JF, Rimmer DW, Ronda JM, Silva EJ, Allan JS, Emens JS,
Dijk DJ, and Kronauer RE. Stability, precision, and near-24hour period of the human circadian pacemaker. Science 284:
2177–2181, 1999.
8. Czeisler CA, Kronauer RE, Allan JS, Duffy JF, Jewett ME,
Brown EN, and Ronda JM. Bright light induction of strong
(type 0) resetting of the human circadian pacemaker. Science
244: 1328–1333, 1989.
9. Eastman CI, Hoese EK, Youngstedt SD, and Liu L. Phaseshifting human circadian rhythms with exercise during the
nightshift. Physiol Behav 58: 1287–1291, 1995.
10. Endo T, Honma S, Hashimoto S, and Honma K. After-effect
of entrainment on the period of human circadian system. Jpn
J Physiol 49: 425–430, 1999.
11. Hashimoto S, Nakamura K, Honma S, Tokura H, and
Honma K. Melatonin rhythm is not shifted by lights that sup-
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
Complete entrainment was not established in the
present study even with physical exercise. If the circadian pacemaker is fully entrained by the forced sleepwake schedule with physical exercise, a phase-advance
shift of 4 h would be expected in 12 cycles, which
was not the case. In the present study, physical
exercise was given intermittently at the strength of
140 beats/min in heart rate twice in the daytime. A
failure of complete entrainment might be due to the
strength of zeitgeber or to possible conflicting effects
produced by double zeitgeber pulses. The phase-delaying effect of physical exercise depended on the strength
and duration of exercise (4). The phase-shifting effects
of bright light were reported to decrease when given
intermittently (21). On the other hand, it is well established that the zeitgeber effect is dependent on the
phase of the circadian pacemaker in which the zeitgeber was given (20). Although the amount of phase shift
yielded by a pulse of exercise in the afternoon was not
significantly different from that in the sedentary control, afternoon exercises might exert conflicting effects
on the circadian pacemaker so that the overall effect
was diminished. These issues are the targets of future
studies.
Whatever the mechanism might be, physical exercise can facilitate the entrainment of human circadian
pacemaker to a forced sleep-wake schedule under dim
light conditions. The implications of this finding are
not trivial, because they suggest that physical exercise
is helpful for entrainment to the natural 24-h periodicity if one could not get enough light. Especially for
people with delayed sleep phase or non-24-h sleepwake syndromes, daytime physical exercise might
have therapeutic value.
A pulse of physical exercise at any time of day failed
to change the amount of phase shift of plasma melatonin rhythm observed in the control session (Table 2).
These results are inconsistent with previous reports in
which physical exercise at midnight significantly phase
delayed the melatonin rhythm (4, 26). In the present
study, physical exercise at midnight significantly
phase delayed the three phases of plasma melatonin
rhythm when compared with the prepulse phase,
whereas the amount of phase shift was not different
from that in the sedentary control session. The discrepancy between the previous and present results could be
explained, at least in part, by the frequency of blood
sampling for the determination of plasma melatonin.
More frequent blood sampling in the previous studies
may provide melatonin rhythms capable of being analyzed with a higher time resolution than the present
study.
On the other hand, a single pulse of physical exercise
showed dual effects on rectal temperature: increase
during exercise and decrease for several hours after
exercise (Fig. 6). The effects seem to be phase dependent. The largest increase was observed in the night
session (1.22°C), whereas the longest after-exercise
hypothermia was detected in the morning session (⬃8
h). The mechanisms for these phenomena are not
known, but the findings suggest care in interpretation
EXERCISE AND HUMAN CIRCADIAN RHYTHM
12.
13.
14.
15.
16.
18.
19.
20.
21. Rimmer DW, Boivin DB, Shanahan TL, Kronauer RE,
Duffy JF, and Czeisler CA. Dynamic resetting of the human
circadian pacemaker by intermittent bright light. Am J Physiol
Regulatory Integrative Comp Physiol 279: R1574–R1579, 2000.
22. Rusak B and Zucker I. Neural regulation of circadian
rhythms. Physiol Rev 59: 449–526, 1979.
23. Sutoo DE and Akiyama K. The mechanism by which exercise
modifies brain function. Physiol Behav 60: 177–181, 1996.
24. Strassman RJ, Appenzeller O, Lewy A, Qualls CR, and
Peake GT. Increase in plasma melatonin, ␤ endorphin, and
cortisol after a 28.5-mile mountain race: relationship to performance and lack of effect of naltrexone. J Clin Endocrinol Metab
69: 540–545, 1989.
25. Theron JJ, Oosthuizen JMC, and Rauthenbach MM. Effect
of physical exercise on plasma melatonin levels in normal volunteers. SA Med J 66: 838–841, 1984.
26. Van Reeth O, Sturis J, Byrne MM, Blackman JD, HermiteBaleriaux ML, Leproult R, Oliner C, Refetoff S, Turek FW,
and Van Cauter E. Nocturnal exercise phase delays circadian
rhythms of melatonin and thyrotoropin secretion in normal men.
Am J Physiol Endocrinol Metab 266: E964–E972, 1994.
27. Wever RA. The circadian system of man: results of experiments
under temporal isolation. New York: Springer-Verlag, 1979.
28. Wever RA. Internal interactions within the human circadian
system: the masking effect. Experientia 41: 332–342, 1985.
29. Wever RA. Influence of physical workload on freerunning circadian rhythms of man. Pflügers Arch 381: 119–126, 1979.
30. Yamada N, Shimoda K, Ohi K, Takahashi S, and Takahashi K. Free-access to a running wheel shortens the period of
free-running rhythm in blinded rats. Physiol Behav 42: 87–91,
1988.
Downloaded from http://ajpregu.physiology.org/ by 10.220.33.3 on June 17, 2017
17.
press nocturnal melatonin in humans under entrainment. Am J
Physiol Regulatory Integrative Comp Physiol 270: R1073–R1077,
1996.
Honma K, Hashimoto S, Endo T, and Honma S Light and
plasma melatonin rhythm in humans. Biol Signals 6: 307–312,
1997.
Honma K and Honma S. A human phase response curve for
bright light pulses. Jpn J Psych Neurol 42: 167–168, 1988.
Honma K, Honma S, and Wada T. Entrainment of human
circadian rhythms by artificial bright light cycles. Experientia
43: 572–574, 1987.
Krauchi K, Cajochen C, Mori D, Graw P, and Wirz-Justice
A. Early evening melatonin and S-20098 advance circadian
phase and nocturnal regulation of core body temperature. Am J
Physiol Regulatory Integrative Comp Physiol 272: R1178–R1188,
1997.
Lewy AJ, Ahmed S, Jackson JM, and Sack RL. Melatonin
shifts human circadian rhythms according to a phase-response
curve. Chronobiol Int 9: 380–392, 1992.
Middleton B, Arendt J, and Stone BM. Human circadian
rhythms in constant dim light (8 lux) with knowledge of clock
time. J Sleep Res 5: 69–76, 1996.
Minors DS, Waterhouse JM, and Wirz-Justice A. A human
phase-response curve to light. Neurosci Lett 133: 36–46, 1991.
Mrosovsky N and Salmon PA. A behavioral method for accelerating re-entrainment of rhythms to new light-dark cycles.
Nature 330: 372–373, 1987.
Pittendrigh CA and Daan S. A functional analysis of circadian
pacemakers in nocturnal rodents. IV. Entrainment: pacemaker
as clock. J Comp Physiol [A] 106: 291–331, 1976.
R205