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C i r c a d i a n r h y t h m s i n e n d o c r i n o l o g y a n d m e ta b o l i s m

Circadian rhythms and exercise —

re-setting the clock in metabolic
disease
Brendan M. Gabriel1 and Juleen R. Zierath   1,2,3*
Abstract | Perturbed diurnal rhythms are becoming increasingly evident as deleterious events
in the pathology of metabolic diseases. Exercise is well characterized as a crucial intervention in
the prevention and treatment of individuals with metabolic diseases. Little is known, however,
regarding optimizing the timing of exercise bouts in order to maximize their health benefits.
Furthermore, exercise is a potent modulator of skeletal muscle metabolism, and it is clear that
skeletal muscle has a strong circadian profile. In humans, mitochondrial function peaks in the late
afternoon, and the circadian clock might be inherently impaired in myotubes from patients with
metabolic disease. Timing exercise bouts to coordinate with an individual’s circadian rhythms
might be an efficacious strategy to optimize the health benefits of exercise. The role of exercise
as a Zeitgeber can also be used as a tool in combating metabolic disease. Shift work is known to
induce acute insulin resistance, and appropriately timed exercise might improve health markers
in shift workers who are at risk of metabolic disease. In this Review , we discuss the literature
regarding diurnal skeletal muscle metabolism and the interaction with exercise bouts at different
times of the day to combat metabolic disease.

Core clock
A set of protein-coding genes
(active in nearly all mammalian
cells) that oscillate in
expression and activity in a
circadian manner.
1
Department of Physiology
and Pharmacology,
Karolinska Institutet,
Stockholm, Sweden.
2
Department of Molecular
Medicine and Surgery,
Section of Integrative
Physiology, Karolinska
Institutet, Stockholm, Sweden.
3
The Novo Nordisk
Foundation Center for Basic
Metabolic Research, Faculty
of Health and Medical
Sciences, University of
Copenhagen, Copenhagen,
Denmark.
*e-mail: juleen.zierath@ki.se
https://doi.org/10.1038/
s41574-018-0150-x
Mammalian cells possess an internal molecular clock
that consists of transcriptional and/or translational
autoregulatory feedback loops. At a physiological level,
circadian clocks drive whole-body metabolism. At a
molecular level, cell-autonomous circadian rhythms
are produced by the activity of transcriptional activa-
tors CLOCK and BMAL1 and their target genes, which
form a repressor complex that interacts with CLOCK
and BMAL1 to inhibit transcriptional activity1,2. The
feedback loop of the cell-autonomous core clock is highly
regulated by several factors, including the activity of the
master clock located in the hypothalamic superchias-
matic nucleus (SCN)1–3. Mounting evidence suggests
that disruption of this machinery is highly detrimental
to metabolism; for example, in several animal models
disruption of the clock machinery results in obesity and
insulin resistance4,5. Additionally, indirect disruption of
the core clock machinery via poor sleeping patterns or
variable shift work can have similar deleterious effects
on metabolism in humans6,7.
Several studies demonstrate that exercise modifies
the rhythm of the clock machinery in skeletal mus-
cle8–10 (Fig. 1); however, the optimal timing of exercise
for health and the potential of exercise training to ame-
liorate the effects of disrupted circadian rhythms have
not been fully elucidated. Habitual exercise training has
myriad health benefits and can be a therapeutic tool in
both prevention and treatment of metabolic disease11.
Metabolic diseases, such as obesity and type 2 diabetes
mellitus (T2DM), are a growing, global health burden.
The prevailing modern lifestyle interacts with under­
lying biology to create an environment in which metabolic
diseases can flourish. Within this environment, expo-
sure to artificial light, altered working and/or sleeping
hours, diet, lack of physical activity and easily accessi-
ble, high-calorie foods are all contributory factors to a
global rise in metabolic disease and T2DM1. One area
of the modern lifestyle that has been scrutinized over
the past decade has been the effect of disrupted circa-
dian rhythms on health. The disruption of these diurnal
rhythms is linked to an increased risk of developing
­metabolic disease6,7,12.
Diurnal rhythms can be disrupted by shift work,
genetic mutations that give rise to divergent circa-
dian rhythms or aberrant exposure to artificial light
sources13–15. Additionally, patterns of eating and other
behaviours can strongly modulate both sleep patterns
and the internal cellular clock machinery that regulate
circadian rhythms16. In short, the interaction between
environmental factors and inherited biology can lead
to perturbed daily patterns of behaviour and the mole­
cular functioning of cells, which can disrupt the daily

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Key points
• Skeletal muscle has an extensive network of clock-controlled genes, and
dysregulation of its molecular clock can lead to deleterious metabolic consequences.
• Physical strength and skeletal muscle mitochondrial function peak in the late
afternoon, whereas low-energy sensitive signalling peaks in the morning.
• Exercise is a robust Zeitgeber of skeletal muscle clocks, and exercise can reset the
molecular circadian clock, thereby effectively ameliorating the negative effects of
disrupted sleep patterns.
• Optimizing the timing of exercise bouts could aid existing therapeutic interventions
for the management of metabolic disease.
• Divergent modalities of exercise can interact with the circadian rhythm, resulting in
potent metabolic effects.
metabolic processes necessary to maintain health.
Although exercise ameliorates many of the deleterious
processes associated with these phenomena11, research
on optimizing exercise timing is sparse. In other words,
whether there is a right time of the day to trigger an
optimal training response remains unclear.
Finding the optimum time for exercise is an area ripe
for research as skeletal muscle has many clock-controlled
genes17 and exercise capacity is known to fluctuate over
the course of the day18. If the timing of exercise can be
optimized to coincide with the greatest physiological and
molecular response to exercise, perhaps its potency as a
therapeutic tool might be increased even further. In addi-
tion to the metabolic health benefits of exercise, acute
bouts of exercise can be a tool to improve sleep quality19.
These beneficial effects of exercise on sleep might have
relevance for treating disrupted sleep patterns, be they
pathological, geographical (for example, seasonal varia-
tions in light) or a result of shift work. Conversely, there
might also be negative effects of mistimed exercise. For
example, it could be queried whether intense exercise
is beneficial when performed at a time to which the
participant is unaccustomed.
In this Review, we assess the current literature regard-
ing the molecular mechanisms and therapeutic potential
of exercise in regard to circadian rhythms. We summa-
rize the current literature regarding the metabolic con-
sequence of exercise at different times of the day and
the associated beneficial health effects. The interaction
of exercise with the molecular clock machinery and the
role of exercise as a Zeitgeber and the putative health
benefits are also discussed.
insight into the isolated intrinsic skeletal muscle clock
without interference from the SCN or behaviour.
Additionally, the donors involved in this study demon-
strated highly variable, interindividual rhythmic cellular
gene expression, presumably owing to inherited factors.
Putatively, these variable rhythms could derive from
mutations within core clock genes, as demonstrated on
ap­ hysiological level15.
Metabolic flux and the molecular clock
Disruption of the core clock can dysregulate skele-
tal muscle metabolism and alter how an individual
responds to exercise. For example, a CRY1 polymor-
phism (rs2287161) interacts with increased carbo-
hydrate intake to associate with insulin resistance
in individuals who are homozygous for the minor C
allele (CC)21. Although the mechanism of this interac-
tion is unknown, this rs2287161 variant is thought to
modulate the transcription factor binding site of CRY1
(refs21–24). In terms of skeletal muscle, muscle-specific
BMAL1 depletion results in insulin resistance and
obesity in mouse models, alongside decreased GLUT4
and TBC1D1 (ref.5). Additionally, the skeletal muscle
core clock (BMAL1 and REV-ERBα) controls tran-
scriptional programming of lipid and amino acid
metabolism via direct binding to targets in these
pathways25 (Fig. 1).
In primary human skeletal muscle cells, small inter-
fering RNA (siRNA) targeting CLOCK dysregulated
BMAL1 rhythmic transcriptional activity and impaired
insulin-mediated glucose uptake20. In Bmal1−/− mice,
anaerobic glycolysis, mitochondrial respiration and tran-
scription of Hif1a target genes is reduced5. Furthermore,
in human primary skeletal muscle cells, knockdown of
CLOCK reduced the expression of HIF1α target gene
VEGFA20. Thus, in skeletal muscle, the activity of the core
clock machinery seems to be closely aligned to metabolic
flux. Indeed, activity of AMPK, a key energy sensor in
skeletal muscle, can reduce the stability of CRY1 directly
and PER2 through casein kinase 1ε-mediated phospho-
rylation26–28. In addition, CRY1 and CRY2 interact with
the lipid-sensing peroxisome proliferator-activated
receptor-δ (PPARδ) to supress its activity28. CRY2 might
be of particular importance in skeletal muscle as it also
interacts with BCLAF1 to stabilize Tmem176b mRNA,
a myocyte fusion-associated gene29.

Training
Repeated bouts of exercise
resulting in physiological
adaptations.
Diurnal
A diurnal cycle is any pattern
that recurs every 24 hours,
not necessarily biological or
intrinsic.
Zeitgeber
A rhythmically occurring
natural phenomenon that acts
as a cue in the regulation of the
body’s circadian rhythms.
The skeletal muscle molecular clock
Intracellular circadian clocks can modulate physiologi-
cal processes over the course of a day1. These molecular
processes are regulated by an autoregulatory feedback
loop composed of transcriptional activators CLOCK
and BMAL1 and their target genes period (PER),
cryptochrome (CRY) and NR1D1 (which encodes
REV-ERBα), which accumulate temporally and form
a repressor complex that interacts with CLOCK and
BMAL1 to inhibit transcription 1. Data from 2018
demonstrate that synchronized primary human skele-
tal muscle cells share several circadian characteristics
with human skeletal muscle biopsy samples; however,
rhythmic transcriptional activity has a greater magni-
tude in biopsy samples20. These data provide valuable
Physical activity and the muscle clock
Physical activity modulates the molecular clock in skel-
etal muscle, affecting both the amplitude and phase of
circadian rhythms9,10. The skeletal muscle circadian tran-
scriptomic response clusters around the midpoint of the
active phase in mice30. Additionally, a study of dener-
vated skeletal muscle in rodent models demonstrated
that the removal of motor neuron activation mode­
rately dysregulates circadian transcriptional activity31.
In humans, one-legged resistance exercise altered
circadian gene expression and apparently induced a
phase shift of core clock genes when compared with the
contralateral control leg32. HIF1α target genes also have
a temporally dependent response to strenuous exercise
over the course of a circadian cycle in mice8.

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am pm
Glycolysis and
mitochondrial
PPARα respiration

PPARα

sensitivity
Insulin
PER1– CRY1– BMAL1
AMPK CLOCK REV-ERBα
PER2 CRY2
Amplitude
DNM1L

PPARγ
DBP
Exercise
PPARδ
capacity
Glucose
uptake

Strength/exercise
pm

capacity am

Time

Fig. 1 | Skeletal muscle biology and the core clock. A diagram indicating canonical interactions between skeletal
muscle biology and the core clock. Intracellular circadian clocks can modulate physiological processes over the course
of a day. These molecular processes are regulated by an autoregulatory feedback loop composed of transcriptional
activators CLOCK and BMAL1 and their target genes period (PER), cryptochrome (CRY), NR1D1 (which encodes
REV-ERBα) and DBP, which accumulate temporally and form a repressor complex that interacts with CLOCK and BMAL1
to inhibit transcription6. BMAL1−/− myotubes have reduced anaerobic glycolysis, mitochondrial respiration and
transcription of HIF1α target genes9. Modulation of AMPK (a key energy sensor in skeletal muscle) activity can reduce the
stability of CRY1 and PER2 (refs10–12). CRY1 and CRY2 interact with the lipid-sensing peroxisome proliferator-activated
receptor-δ (PPARδ) to supress its activity12. Pharmacologically inhibited DRP1 (DNM1L) increases period length of BMAL1
transcriptional activity by >1 h and is partially regulated by core clock genes26. Dotted lines indicate that the findings are
not established in skeletal muscle. The amplitude of NR1D1 gene expression from human primary myotubes correlates
with insulin sensitivity and is associated with training status18. PPARα has bi-directional regulatory properties of BMAL1,
whereas NR1D1 is a target gene of PPARγ123, although this is not yet established in skeletal muscle.

Oxygen consumption rate
The amount of oxygen
consumed by metabolic
processes in tissues, cells or
organelles. When applied to
measuring mitochondria,
different metabolic states
(states 1–5) of the
mitochondria are used.
These data support the assertion that the core clock
machinery partly regulates the transcriptional response
to exercise. Additionally, genetic ablation of Cry1 and
Cry2 increased exercise capacity in mice and altered the
exercise-induced gene signature28. In human studies,
cultured primary myotubes from endurance-trained
athletes had preserved rhythmic gene expression of
SIRT1 and NAMPT, whereas myotubes derived from
untrained lean or obese individuals, or patients with
T2DM, did not33. Furthermore, the amplitude of NR1D1
gene expression correlated with insulin sensitivity and
the exercise training status of the donor. Therefore, the
status of the core clock machinery in skeletal muscle
seems to be pivotal in regulating the molecular response
to exercise, particularly in terms of gene expression.
Whether these results are fully recapitulated in human
physiology is unclear, but habitual exercise is associated
with inherently altered amplitude of core clock genes in
human myotubes33.
Mitochondria and the muscle clock
Another parameter that seems to relate metabolism and
the skeletal muscle clock is mitochondrial function.
Reduced oxidative capacity of skeletal muscle is asso-
ciated with diminished exercise performance and the
development of T2DM34,35. Isolated mitochondria from
human skeletal muscle biopsy samples have increased
oxidative capacity (state 3 oxygen consumption rate) at
~23:00 h compared with at 04:00 h, 08:00 h, 13:00 h and
18:00 h (ref.36). Nevertheless, the extent to which these
data are the result of the intracellular molecular clock or
external Zeitgebers is unknown.
The researchers who conducted this study36 also
indicated that mitochondrial dynamics (fusion and
fission of mitochondria) can oscillate in a circadian
manner. However, mitochondrial content, as meas-
ured by mitochondrial DNA (mtDNA), levels of pro-
tein, mitochondrial mass or PGC1α expression, is not
rhythmically expressed in human skeletal muscle36,37;
mitochondrial biogenesis might be rhythmic in other
cells or tissue types37,38. Therefore, diurnal changes in
skeletal muscle mitochondrial function are probably a
result of changes to mitochondrial morphology and/or
mitochondrial dynamics and/or mitophagy, which are
potential candidates for circadian regulation37.
Dysregulated mitochondrial fusion and/or fission
(dynamics) might be important in the pathology of
T2DM39, and mitochondrial dynamics seem to be regu­
lated by circadian rhythms in cultured human mac-
rophages40. Interestingly, cultured human fibroblasts

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Chronotype
The interindividual differences
in the circadian phase of
activity patterns and
sleep–wake cycles.
display periodic mitochondrial dynamics driven by
the molecular core clock41. This study identified DRP1
phosphorylation and activity as one possible media­
tor of rhythmic mitochondrial dynamics. When
DRP1 was pharmacologically inhibited by 1 µM P110,
the period length of BMAL1 transcriptional activity
increased by >1 h, indicative of core clock modula-
tion via mitochondrial metabolism. In a 2018 paper42,
siRNA-mediated knockdown of GDAP1 (a protein
involved in mitochondrial fission) in primary human
skeletal muscle was shown to result in increased expres-
sion of NPAS2 (a paralogue of CLOCK) and decreased
DBP expression. These data indicate that the mitochon-
drial dynamic machinery in skeletal muscle might also
participate in retrograde signalling and modulation of
the core clock.
Collectively, these findings41,42 are noteworthy as
they suggest that the core clock in skeletal muscle can
respond to alterations in mitochondrial dynamics in
addition to metabolic stimuli while also driving meta­
bolic outcomes. Exercise potently remodels mitochon-
drial morphology and dynamics, both acutely and
chronically. Therefore, timing exercise bouts to coincide
with the mitochondrial dynamic period might increase
the acute effects of exercise in terms of substrate uptake
and utilization. Furthermore, mitochondrial network
remodelling could also potentially be amplified.
Exercise physiology and the muscle clock
Although it is clear that the molecular clock in skeletal
muscle interacts with cellular physiology, character-
izing the discrete ways in which the clock is involved
in the regulation of human physiology is a challenge.
Numerous factors (such as fatty acid and carbohydrate
metabolic pathways, in addition to secreted factors)
interlink in the regulation of metabolism and physio­
logy by the molecular clock. Animal models are often
vital in elucidating the molecular pathways that regulate
physiology, and they are fundamental to advancing the
field of circadian biology. However, the rodent models
used to study how the molecular clock communicates
with physiological responses are often unable to fully
recapitulate human physiology. For example, rodents
are primarily active at night, often fed ad libitum, have
fragmented daytime sleep and generally do not produce
melatonin17. In addition, although rodent models used
in circadian biology are primarily active at night, their
skeletal muscle molecular clock4 is not simply an inverse
of the human counterpart20.
These issues contribute to a somewhat convo-
luted model, which is made more complex by external
Zeitgebers such as feeding and light exposure. Although
the majority of circadian studies admirably control for
these issues, practical realities prevent the creation
of a perfect model. Potential solutions to counter-
act the practical realities include the creation of more
humanized mouse models43,44, although these models
often do not recapitulate the full spectra of human
physiological phenomena45.
Another solution is to use a species with physio­
logy that is more closely aligned to that of humans; an
elegant attempt has been made to resolve some of the
aforementioned issues by using a primate (baboon)
model17, which should prove an invaluable resource for
this field. Initial findings from this study demonstrate
that skeletal muscle has the highest number of circadian
cycling genes of all tissues in baboons (3,182 cycling
genes versus 2,615 in mice; 649 of these genes overlap),
whereas the liver has the most in mice (3,700 versus 529
in baboons; 150 of these genes overlap). These findings
highlight the importance of skeletal muscle in primate
circadian biology and help inform our interpretation
of circadian rodent studies. Indeed, there was no cor-
relation (R2 = 0.086, P = 0.38) between the number of
tissue-specific cycling genes in mice and baboons.
Furthermore, following an analysis of all tissues, sev-
eral core clock genes had opposite rhythms in mice and
baboons, including Bmal1, Per1 and Cry1. By combining
resources such as primate models with well-controlled
and well-designed rodent models and new technology
in well-controlled human studies, the field of circadian
biology can shine further light on key questions, such as
when the best time to exercise is.
As stated previously, one important, underexplored
area is how the skeletal muscle molecular clock inter-
acts with exercise in terms of metabolic health outcomes.
As it stands currently, the literature cannot support the
assertion that the human skeletal muscle molecular
clock directly modulates the diurnal exercise response,
although accumulating data from rodent models
­partially corroborate this hypothesis8,28.
Exercise physiology and circadian timing
The health outcomes of exercise have not been exten-
sively studied with regard to the optimal diurnal tim-
ing; however, data do exist with regard to the interaction
between diurnal timing and exercise performance (Fig. 2).
For example, more world records are broken by athletes
competing in the early evening, even when environ-
mental conditions and scheduling bias are partially con-
trolled46. Increased strength, power and endurance are
often observed in the afternoon and evening compared
with early morning18,47. Disruptions of diurnal rhythm
can also negatively affect athletic performance. Eastward
trans-meridian travel has a greater negative effect on
intermittent sprint performance and psychological indi-
cators of fatigue than westward travel48. The chronotype
of an athlete can also have a role in exercise performance
at different times of the day47,49. As competing athletes
aim to optimize training and preparation, interest in
the interaction between the circadian rhythm, exer-
cise performance and exercise response is growing;
however, this interaction should also be appraised
when considering exercise as a treatment or preventive
clinical tool.
Different modalities of exercise
Differing modalities of exercise result in varying meta­
bolic perturbations and signalling outcomes, including
the type of skeletal muscle fibre recruited during the
exercise bout. In high-intensity or resistance exer-
cise, a greater amount of type II fibres are recruited
than in low-intensity endurance exercise, which pre-
dominantly recruits type I fibres50. Type II fibres are
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Mitochondrial
function BMAL1

Resistance exercise
(power and strength) NR1D1

00:00
22:00 02:00
NAMPT
20:00 04:00
1,000 m cycling
performance

18:00 06:00

16:00 08:00

14:00 10:00
12:00
Temperature

PER2

Physiological Molecular Temperature

5% 100% Δ0.33°C Blood
10% 150% Δ0.66°C pressure
15% 200% Δ1.00°C Heart rate

Fig. 2 | Human skeletal muscle circadian biology. The plots in this figure represent the extent of diurnal fluctuations in
biological and related physiological parameters in human skeletal muscle over the course of a day. Power and strength
indicate strength or measurements of power during exercise tests28. Mitochondrial function indicates isolated
mitochondria undergoing state 3 respiration22 (state 3 respiration refers to when a respiratory substrate, such as succinate
or pyruvate, is added to the respiratory pathway , which causes respiration to increase markedly to a high and steady rate).
PER2, BMAL1, NAMPT and NR1D1 indicate gene expression in human skeletal muscle biopsy samples or cells18,22.
A 1,000-metre cycling time trial was measured at two time points50; this should be considered as preliminary evidence.
Local temperature of skeletal muscle52,55 is presented as Δ °C. Molecular parameters (such as PER2, BMAL1, NAMPT and
NR1D1) are plotted with a larger scale than physiological parameters for visualization purposes. The figure is primarily
intended to visualize timings of peaks of these parameters. The scale is included to identify the peaks of the various
responses and for comparisons between the scale of peaks and the different parameters. Molecular parameters are
measured by gene expression and thus respond with greater magnitude to acute stimuli than physiological parameters50.
The magnitude of oscillation does not necessarily infer circadian importance. In addition, these parameters have not
necessarily been conclusively and comparatively quantified in regard to their circadian oscillation. The scale represents
the magnitude of peak and trough and diurnal oscillation.

fast-twitch, fatigable and more glycolytic than highly
oxidative type I fibres50. The circadian gene expres-
sion pattern of the core clock is similar in these fibre
types; however, the distinct fibre types display unique
expression of most other diurnally cycling genes51.
Differential recruitment of fibre types during exer-
cise might influence circadian gene expression in an
exercise-specific manner.
Resistance exercise. Resistance exercise is the most sus-
ceptible form of exercise to diurnal rhythms. Daytime
peak force is nearly always demonstrated as being high-
est in the afternoon and evening (16:00–20:00 h), and
lowest in the morning (06:00–10:00 h), with the discrep-
ancy ranging from ~3% to 18% depending on exper-
imental design18,52–73 (although the majority of these
studies found that the discrepancy clusters around ~8%).

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Maximal power output
Maximal intensity of exercise
or skeletal muscle contraction
measured by power output
(Watts).
Maximal sprint
A short burst of intense
exercise after which the
individual is momentarily
unable to continue owing to
fatigue.
Cycle ergometer
A fixed cycling machine often
used in fitness testing to
estimate exercise intensity.
The response to resistance exercise is thought to be
particularly susceptible to time of day, partly owing
to diurnal neuromuscular performance, which can be
somewhat ameliorated by acclimation59,65.
High-intensity exercise. In short-duration, high-intensity
exercise, a similar daily pattern of performance to that
of resistance exercise is observed. Peak and mean power
output vary by ~8% and ~11%, respectively18,66,70, with
peaks and troughs in performance and capacity noted
at similar times to resistance exercise (peaks in the
­afternoon and evening and troughs in the morning).
Moderate and endurance exercise. For long-duration
exercise, the time-of-day effect on performance is
equivocal compared with high-intensity and resistance
training18,71. Although some studies do demonstrate
higher aerobic and endurance performance in the after-
noon and evening than in the morning70, these effects
seem to be moderate and are not consistent between
studies. A finding in some studies of diurnal fluctua-
tions in long-duration exercise is that although overall
performance is not markedly changed, physiological
parameters, such as heart rate, are altered70,72,73, although
directionality of these physiological parameters is vari-
able. The equivocal findings in these studies could be
related to a statistical power issue, and a meta-analysis
might elucidate this further.
Exercise capacity and body temperature
The SCN of the hypothalamus contains the main clock
components1. The main clock components function as
the master circadian clock, whereby they synchronize
and maintain the rhythms of the peripheral clocks3.
Several signals derived from the SCN can influence
peripheral tissue clocks, including the skeletal muscle
clock, in addition to influencing daily variations in body
temperature, the levels of secreted factors (such as insu-
lin) and activity of the autonomic nervous system3,5,74.
Of these, a key factor that can influence exercise per-
formance at specific times of day is body temperature,
but more specifically core body and skeletal muscle
temperature64, which peak in the late afternoon or early
evening. Explicitly, the core body temperature increases
by ~0.8 °C in the afternoon or early evening and the
temperature of skeletal muscle increases by ≥0.35 °C at
these times72,75.
The temperature of skeletal muscles has a multifac-
torial effect on local metabolic processes and contractile
efficiency. ATP turnover, phosphocreatine consump-
tion and fibre conduction velocity are elevated with
increased skeletal muscle temperature (passive heating)
during maximal power output (6-second maximal sprint,
cycle ergometer )76,77. A close relationship also exists
between blood temperature, blood perfusion and aero­
bic metabolism in exercising limbs78. Temperature is a
conserved entraining agent, acting as a Zeitgeber in the
majority of mammals79, and the core clock machinery in
skeletal muscle is strongly responsive to synchronization
by temperature, controlled by the SCN80.
The thermoregulatory response to exercise also oscil-
lates over the circadian cycle, with an apparent reduced
ability to dissipate core body heat in the morning as
compared with the afternoon72. This reduced ability to
dissipate heat could be a driving factor for the generally
increased exercise performance in the afternoon com-
pared with the morning. In support of this theory, cen-
tral and peripheral fatigue, often manifesting in reduced
voluntary contractile activation, are closely associated
with core (and to some extent, peripheral) temperature81.
An active or passive heating of core and peripheral tis-
sues is known to acutely improve strength and power
(although heating above optimal levels of ~38.5 °C is
not very effective and can be detrimental to perfor-
mance)82. However, a 2018 study demonstrated that pas-
sive warming to increase core body and skeletal muscle
temperature did not completely ablate diurnal variation
in repeated sprint performance82. These data suggest
that other factors, independent of heat per se, have a
role in regulating the circadian exercise performance,
particularly in regards to power and/or strength.
Exercise response and hormonal fluctuation
Some other crucial determinants of exercise perfor-
mance are fluctuations in hormonal secretion and
metabolism. For example, 1,000-metre time-trial perfor-
mance for nine male recreational cyclists was improved
in the evening (18:00 h) as compared with the morning
(08:00 h) by ~7%70. Furthermore, the researchers showed
that oxygen uptake and aerobic mechanical power out-
put were higher in the evening trial than in the morning
trial70. Interestingly, in this trial noradrenaline response
to exercise was higher in the morning trial than in the
evening trial, indicating that hormonal response to
­exercise is altered at different times of the day.
Plasma levels of testosterone and cortisol also dis-
play diurnal variations pre-exercise and post-exercise,
although the magnitude of response to exercise seems
similar in evening and morning exercise83. In healthy
young men, the plasma concentrations of testoster-
one and cortisol are higher at 08:00 h than at 22:00 h,
whereas the testosterone:cortisol ratio is higher at
20:00 h than at 08:00 h. It could be speculated that fluc-
tuations in circulating testosterone and/or cortisol are
partly responsible for the acute diurnal fluctuations in
response to resistance exercise; however, the physiologi­
cal relevance of these fluctuations to exercise outcomes
is debatable84.
Diurnal substrate metabolism and exercise
Another key factor affecting diurnal fluctuations in exer-
cise capacity, performance and response is the meta­
bolism and availability of energy substrates. Food and
feeding are Zeitgebers per se, and intrinsic molecular
clocks seem to respond primarily to habitualized, rather
than intrinsically conserved, feeding behaviours85. Given
this factor, distinguishing between teleological and
empirical summations of diurnal feeding patterns
and determining the effect these have on circadian
rhythms is complex. The modern western tradition of
three meals per day is not necessarily pervasive across
modern and historical cultures86–88. These lines of evi-
dence indicate that human physiology is highly adaptive
to different feeding timings, which should be taken into
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Periodized nutrition
The strategic combined use of
exercise training and nutrition,
or nutrition alone, with
the overall aim to improve the
physiological response to
exercise training.
Voluntary muscle force
Skeletal muscle contraction
force produced as a result
of endogenous activation of
motor neurons.
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consideration when interpreting the interaction between
feeding and the circadian rhythm.
The physiological regulation of glucose and triglyc-
erides is an important factor in diurnal rhythms in gen-
eral and in the diurnal exercise response11. The levels
of glucose and triglycerides are partly controlled by
intrinsic clocks in several tissues. For example, in mice,
liver-specific ablation of Bmal1 induces hypoglycaemia
during the fasting phase89, and skeletal-muscle-specific
ablation of Bmal1 robustly modulates glucose uptake
and metabolism90. Therefore, peripheral clocks have criti­
cal roles in maintaining glucose homeostasis. The SCN
also drives diurnal variations in postprandial triglyceride
uptake into skeletal muscle and brown adipose tissue in
rats, probably via a REV-ERBα-mediated pathway91.
Improving our knowledge regarding the interaction
between diurnal feeding patterns and exercise inter-
vention strategies is important to better understand
metabolic regulation. For example, different exercise
intensities seem to profoundly alter postprandial tri-
glyceride metabolism over the course of the subsequent
day92,93. Using high-throughput metabolomics, one
study demonstrated that skeletal muscle and plasma
have unique metabolic signatures that are robustly
reprogrammed by divergent nutritional challenges94.
Putatively, manipulating timing in exercise interven-
tion protocols to protect against subsequent excur-
sions in postprandial metabolites could be a preventive
strategy in combating metabolic disease. Furthermore,
a rapidly growing area of research involves the interaction
between periodized nutrition and exercise responses95–98.
Many periodized nutrition protocols involve manipu-
lating carbohydrate availability before, during or after
exercise bouts, for example, by performing an intense
workout in the evening with subsequent low carbohy-
drate intake resulting in lowered carbohydrate availa-
bility (muscle and liver glycogen) followed by sleep.
This method has demonstrated some benefits in exercise
performance and skeletal muscle signalling response of
the lipid oxidation pathway95–98. This approach has been
primarily researched in an athletic context, but these
studies should also focus on prevention and intervention
strategies for health.
Chronic circadian timing of exercise
Many studies have assessed the acute effect of diurnal
rhythms on exercise physiology18,52–73; one noteworthy
cross-sectional study conducted by Maria Küüsmaa and
colleagues was published in 2016 (ref.99). The researchers
investigated the effect of 24 weeks of combined strength
and endurance training conducted in the morning or
evening on physical performance, muscle hypertro-
phy and serum hormone concentrations. Specifically,
42 (mean of groups range from 30.8 ± 5.0 to 36.1 ± 6.5
years) males were assessed for chronotype (no partici-
pants had an extreme morning or evening chronotype),
matched and assigned to four groups (morning or
evening training and endurance before strength train-
ing or strength training before endurance training).
The researchers reported that the evening training groups
gained more muscle mass than the morning training
groups99. Interestingly, diurnal rhythms in testosterone
Reviews
and cortisol remained unaltered by training. These data
suggest that inherent differences exist in the response to
training in the evening versus morning that acclimation
cannot completely ameliorate. We would like to point
out, however, that although this study was rigorous and
participants were well matched, conventional scientific
process dictates that confirmation of this finding can
come only from a crossover study design — although,
in reality, conducting such a study on this scale would
be impractical.
Another study by Sedliak and colleagues65 assessed
25 young (age of participants in the morning group
was 23 ± 2 years and the age of participants in the after-
noon group was 24 ± 4 years), previously untrained
males who were randomly divided into a morning
exercise group (07:30–08:30 h), an afternoon exercise
group (16:00–17:00 h) and a sedentary control group.
Voluntary muscle force increased in both the morning
and afternoon exercise group after 11 weeks training65.
Compared with the morning group, mean force was
consistently higher in the afternoon exercise training
group before, after and during training; however, these
­differences did not reach statistical significance.
The reason for the difference in morning versus
evening training-induced gains in muscle mass between
these studies65,99 is unknown; however, study cohort size
and length of training might account for the differ-
ences. For example, Küüsmaa and colleagues99 included
a larger total cohort and the duration of training was
longer than in the study by Sedliak and colleagues65,
which might increase the ability to detect diurnal effects.
Furthermore, the exercise protocols were different
between studies. Nevertheless, Sedliak and colleagues65
reported that phosphorylation of p70S6K Thr421/Ser424,
an exercise-responsive signalling molecule involved
in protein synthesis and cell growth, was only acutely
responsive to morning exercise after 11 weeks of training
and was not responsive to afternoon exercise training.
These data indicate that differences in functional
training outcomes between morning or afternoon
exercise can be small once an individual has become
acclimated to morning exercise training; however, sig-
nalling differences related to protein synthesis can per-
sist. Putatively, the effect on protein synthesis might be
mediated by exercising in varying nutritional states.
In addition, the skeletal muscle core clock interacts with
mTOR and downstream signalling100–102, which might
link functional training outcomes to the core clock
machinery. In rats, the fractional synthesis rate of skele-
tal muscle protein synthesis103, and mTOR and p70S6K
activity104, peak during the light phase in these nocturnal
animals. Assuming the inverse holds true for humans
(as discussed previously, this is not always the case) might
mean that protein synthesis rates peak in the evening.
Therapeutic potential for timing exercise
Epidemiological evidence suggests that T2DM and
obesity are associated with loss of sleep quality105,106,
although whether this is a causative phenomenon
is unknown. Furthermore, obesity or T2DM might
intrinsically disrupt the core clock machinery33. Ageing
is associated with a gradual increase in period length
Reviews
Acute exercise
A single exercise bout, rather
than exercise training.
Sleep hygiene
Habits and practices that are
conducive to sleeping well on a
regular basis.
of core clock genes, in addition to the dysregulation of
other rhythmic biological processes107. As exercise
is known to re-set clock genes in skeletal muscle and
other tissues, it could be hypothesized that appropri-
ately, and recurrently, timed exercise can help to re-set
the daily clock and improve pathologically deterio-
rating circadian rhythms. Improving these dysregu-
lated daily rhythms might help ameliorate negative
metabolic consequences.
Exercise and sleep quality
Sleep surveys have documented regular physical activ-
ity as a variable associated with improved overall sleep
quality19,108. Several mechanisms are thought to medi-
ate this effect, including negative-feedback regula-
tion of body temperature after exercise77. In addition,
metabolic perturbations induced by exercise might
regulate the neurotransmitter systems. For example,
high-intensity exercise increased the plasma concen-
trations of the sleep-promoting molecule adenosine
in rats76. In humans, acute exercise performed before
the late evening (before 22:00 h) has been consistently
demonstrated to boost sleep quality109; however, exercise
performed shortly before going to bed might induce a
stress response that attenuates this improvement and
might even be detrimental to sleep quality110.
Habitual exercise is thought to improve sleep quality,
even in the absence of acute exercise110. In addition to
the physiological effects of exercise that promote sleep
quality, performing exercise outside and increasing day-
light exposure might be an additive enhancer of sleep111.
Indeed, exposure to sunlight in the morning improved
sleep quality and circadian entrainment in office work-
ers112. It might be speculated that in terms of optimiz-
ing sleep hygiene specifically, outdoor exercise could be
performed in the morning to maximize the beneficial
results of daylight exposure.
Exercise and shift work
In addition to the exercise response being regulated by
the circadian clock, exercise is also an effective Zeitgeber.
Approximately 13–20% of workers in Europe and the
USA are engaged in shift work that includes some time
working at night113. Epidemiological studies and acute
studies have shown that shift work increases risk factors
for developing metabolic disease6,7. Just 4 days of simu-
lated shift work can reduce insulin sensitivity7, and this
deleterious effect might interact with genetic disposition
to increase the risk of developing T2DM6.
The biological processes that mediate the increased
risk of insulin resistance and T2DM resulting from
disrupted circadian rhythms are multifactorial. For
example, environmental factors interact with circadian
biology; one study reported that reduced meal frequency
and increased snacking are observed in night-shift
workers14. In addition, the normal metabolic response
to food is altered in shift-workers14. Lack of sleep due to
changing diurnal patterns might also have an important
role in the increased risk of insulin resistance result-
ing from disrupted circadian rhythms, and one study
reported that just 1 week of sleep deprivation reduced
insulin sensitivity114.
As with many aspects of metabolic disease patho­
logy, individual differences seem to determine suscep-
tibility to the negative consequences associated with
shift work14. Increased amplitudes of the circadian
rhythm might result in increased tolerance to shift work.
A training-induced increase in amplitude of the skeletal
muscle clock33 could be one method by which habitual
physical activity could improve resistance to shift-work-
induced metabolic phenomena. Alternatively, using acute
or chronic exercise to improve sleep quality109 might also
aid adaptation to shift work and reduce sleep deprivation.
Designing adequate intervention strategies to improve
the acute and chronic health of shift workers is a key issue
in combating the rise in metabolic diseases. Putatively,
correct timing of exercise bouts might ameliorate some
deleterious results of acute and chronic shift work.
As mentioned previously, body temperature and ther-
moregulatory response have a robust circadian rhythm.
In one study115, participants cycled for 15 minutes every
hour during the first three of eight consecutive night
shifts. Exercise facilitated temperature rhythm phase
delays, which better aligned with daytime sleep. Although
this exercise protocol is impractical for the majority of
shift workers, it is proof of principle that correctly timed
­exercise can aid sleep patterns in regard to shift work.
Furthermore, timed exposure to a 5,000-lux bright
light (22:10–23:40 h) might have an additive bene­
ficial effect on hormonal diurnal rhythms, more
specifically on levels of sulfatoxymelatonin, and the
adaptation to shift work when combined with 90 min-
utes of moderate-intensity exercise (04:10–05:40 h)116.
Given that short-duration bouts of exercise improved
the adaptation to shift work115, another promising area
of research that could be applied to shift workers is the
concept of breaking up sedentary time.
Preliminary research suggests that for office workers,
brief periods of activity over the course of a day have
a beneficial effect on health outcomes, which might be
over and above those observed from scheduled exer-
cise per se117. One might speculate that regular bouts of
interventional breaks to sedentary time also have sim-
ilar beneficial results in shift workers. Another inter-
vention that has shown promising health benefits is
time-restricted feeding16; this intervention is based on a
defined daily feeding–fasting rhythm with a determined
window of food consumption, often around 8 h (ref.118).
This approach could be another putative method of
ameliorating the negative health consequences of shift
work, potentially implemented in parallel to physical
activity interventions.
Seasonal disruption of circadian rhythms
Given that daylight is one of the most powerful Zeitgebers
for the majority of tissues, it is interesting to assess the
effect of the change in seasonal daylight variation in
northern latitudes. Sleep quality and daytime fatigue
showed stronger seasonal variations in individuals from
Norway (69°) than in individuals from Ghana (5°)119.
Seasonal variations in daylight might also have a role in
metabolic regulation. Single-nucleotide polymorphisms
(SNPs) at CRY1, CRY2 and MTNR1B seem to interact with
seasonal variations to modulate glucose homeostasis120.
www.nature.com/nrendo
 Reviews

Although lack of daylight in the winter might negatively
affect sleep and metabolic health, levels of physical activ-
ity generally increase in countries with northern latitudes
in the summer121. Introducing winter exercise strategies,
matched with optimal daylight exposure, could be an
important therapeutic intervention for metabolic health.
As a side note, the human thermoregulatory system
also exhibits seasonal variation as a result of ambient
temperature acclimatization122. As diurnal changes in the
thermoregulatory system seem to be a key factor in
the exercise response in terms of circadian rhythm, it
could be important to take note of thermoregulation
seasonality when designing exercise interventions.
Conclusions
The majority of studies assessing high-intensity or
strength training report that exercise performance is
increased in the afternoon and evening compared with
early morning18,52–73. Several factors might influence
this finding, including neuromuscular regulation59,65,
circadian thermoregulation72,75, hormonal metabo-
lism70,83,84, nutritional status11,90,91 and the skeletal mus-
cle molecular clock8,28, among others. How diurnal
exercise performance interacts with the acute exercise
response and health outcomes remains unclear. Finding
an answer to this question is important, particularly
given the challenges of scheduling regular exercise
into a modern lifestyle. Furthermore, exercise might
be a useful therapeutic tool to treat poor sleeping pat-
terns. Using correctly timed exercise as a therapeutic
tool might apply to individuals who work shifts or
have other disturbances to sleep hygiene. Putatively,
synchronizing exercise and nutrient interventions to
the molecular circadian clock might maximize the
health-promoting benefits of exercise to prevent and
treat metabolic disease.
Published online xx xx xxxx

1. Gerhart-Hines, Z. & Lazar, M. A. Circadian metabolism
in the light of evolution. Endocr. Rev. 36, 289–304
(2015).
2. Robinson, I. & Reddy, A. B. Molecular mechanisms of
the circadian clockwork in mammals. FEBS Lett. 588,
2477–2483 (2014).
3. Panda, S. Circadian physiology of metabolism. Science
354, 1008–1015 (2016).
4. Dyar, K. A. et al. Muscle insulin sensitivity and glucose
metabolism are controlled by the intrinsic muscle
clock. Mol. Metab. 3, 29–41 (2014).
5. Schiaffino, S., Blaauw, B. & Dyar, K. A. The functional
significance of the skeletal muscle clock: lessons from
Bmal1 knockout models. Skelet. Muscle 6, 33 (2016).
6. Vetter, C. et al. Night shift work, genetic risk, and
type 2 diabetes in the UK biobank. Diabetes Care 41,
762–769 (2018).
7. Bescos, R. et al. Four days of simulated shift work
reduces insulin sensitivity in humans. Acta Physiol.
(Oxf.) 223, e13039 (2018).
8. Peek, C. B. et al. Circadian clock interaction with HIF1α
mediates oxygenic metabolism and anaerobic glycolysis
in skeletal muscle. Cell Metab. 25, 86–92 (2017).
9. Saner, N. J., Bishop, D. J. & Bartlett, J. D. Is exercise
a viable therapeutic intervention to mitigate
mitochondrial dysfunction and insulin resistance
induced by sleep loss? Sleep Med. Rev. 37, 60–68
(2018).
10. Wolff, G. & Esser, K. A. Scheduled exercise phase
shifts the circadian clock in skeletal muscle. Med. Sci.
Sports Exerc. 44, 1663–1670 (2012).
11. Gabriel, B. M. & Zierath, J. R. The limits of exercise
physiology: from performance to health. Cell Metab.
25, 1000–1011 (2017).
12. Vera, B. et al. Modifiable lifestyle behaviors, but not a
genetic risk score, associate with metabolic syndrome
in evening chronotypes. Sci. Rep. 8, 945 (2018).
13. Huang, W., Ramsey, K. M., Marcheva, B. &
Bass, J. Circadian rhythms, sleep, and metabolism.
J. Clin. Invest. 121, 2133–2141 (2011).
14. Atkinson, G., Fullick, S., Grindey, C. & Maclaren, D.
Exercise, energy balance and the shift worker.
Sports Med. 38, 671–685 (2008).
15. Patke, A. et al. Mutation of the human circadian clock
gene CRY1 in familial delayed sleep phase disorder.
Cell 169, 203–215 (2017).
16. Manoogian, E. N. C. & Panda, S. Circadian rhythms,
time-restricted feeding, and healthy aging.
Ageing Res. Rev. 39, 59–67 (2017).
17. Mure, L. S. et al. Diurnal transcriptome atlas of a
primate across major neural and peripheral tissues.
Science 359, eaao0318 (2018).
18. Chtourou, H. & Souissi, N. The effect of training at a
specific time of day: a review. J. Strength Cond. Res.
26, 1984–2005 (2012).
19. Driver, H. S. & Taylor, S. R. Exercise and sleep.
Sleep Med. Rev. 4, 387–402 (2000).
20. Perrin, L. et al. Transcriptomic analyses reveal
rhythmic and CLOCK-driven pathways in human
skeletal muscle. eLife 7, e34114 (2018).
21. Dashti, H. S. et al. CRY1 circadian gene variant
interacts with carbohydrate intake for insulin
resistance in two independent populations:
Mediterranean and North American. Chronobiol. Int.
31, 660–667 (2014).
22. Raney, B. J. et al. ENCODE whole-genome data in the
UCSC genome browser (2011 update). Nucleic Acids
Res. 39, D871–D875 (2011).
23. Boyle, A. P. et al. Annotation of functional variation in
personal genomes using RegulomeDB. Genome Res.
22, 1790–1797 (2012).
24. Villard, J. et al. A functionally essential domain of
RFX5 mediates activation of major histocompatibility
complex class II promoters by promoting cooperative
binding between RFX and NF-Y. Mol. Cell. Biol. 20,
3364–3376 (2000).
25. Dyar, K. A. et al. Transcriptional programming of lipid
and amino acid metabolism by the skeletal muscle
circadian clock. PLOS Biol. 16, e2005886 (2018).
26. Lamia, K. A. et al. AMPK regulates the circadian clock
by cryptochrome phosphorylation and degradation.
Science 326, 437–440 (2009).
27. Um, J. H. et al. Activation of 5′-AMP-activated kinase
with diabetes drug metformin induces casein kinase
Iepsilon (CKIepsilon)-dependent degradation of clock
protein mPer2. J. Biol. Chem. 282, 20794–20798
(2007).
28. Jordan, S. D. et al. CRY1/2 selectively repress
PPARdelta and limit exercise capacity. Cell Metab. 26,
243–255 (2017).
29. Lowe, M. et al. Cry2 is critical for circadian regulation
of myogenic differentiation by Bclaf1-mediated mRNA
stabilization of cyclin D1 and Tmem176b. Cell Rep.
22, 2118–2132 (2018).
30. Miller, B. H. et al. Circadian and CLOCK-controlled
regulation of the mouse transcriptome and cell
proliferation. Proc. Natl Acad. Sci. USA 104,
3342–3347 (2007).
31. Nakao, R. et al. Atypical expression of circadian clock
genes in denervated mouse skeletal muscle.
Chronobiol. Int. 32, 486–496 (2015).
32. Zambon, A. C. et al. Time- and exercise-dependent
gene regulation in human skeletal muscle.
Genome Biol. 4, R61 (2003).
33. Hansen, J. et al. Synchronized human skeletal
myotubes of lean, obese and type 2 diabetic patients
maintain circadian oscillation of clock genes. Sci. Rep.
6, 35047 (2016).
34. O’Connor, E., Kiely, C., O’Shea, D., Green, S.
& Egana, M. Similar level of impairment in exercise
performance and oxygen uptake kinetics in
middle-aged men and women with type 2 diabetes.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 303,
R70–R76 (2012).
35. Phielix, E. & Mensink, M. Type 2 diabetes
mellitus and skeletal muscle metabolic function.
Physiol. Behav. 94, 252–258 (2008).
36. van Moorsel, D. et al. Demonstration of a day-night
rhythm in human skeletal muscle oxidative capacity.
Mol. Metab. 5, 635–645 (2016).
37. de Goede, P., Wefers, J., Brombacher, E. C.,
Schrauwen, P. & Kalsbeek, A. Circadian rhythms in
mitochondrial respiration. J. Mol. Endocrinol. 60,
R115–R130 (2018).
38. Liu, C., Li, S., Liu, T., Borjigin, J. & Lin, J. D.
Transcriptional coactivator PGC-1α integrates the
mammalian clock and energy metabolism. Nature
447, 477–481 (2007).
39. Yoon, Y., Galloway, C. A., Jhun, B. S. & Yu, T.
Mitochondrial dynamics in diabetes. Antioxid. Redox
Signal. 14, 439–457 (2011).
40. Oliva-Ramirez, J., Moreno-Altamirano, M. M.,
Pineda-Olvera, B., Cauich-Sanchez, P. &
Sanchez-Garcia, F. J. Crosstalk between circadian
rhythmicity, mitochondrial dynamics and macrophage
bactericidal activity. Immunology 143, 490–497
(2014).
41. Schmitt, K. et al. Circadian control of DRP1 activity
regulates mitochondrial dynamics and bioenergetics.
Cell Metab. 27, 657–666 (2018).
42. Lassiter, D. G., Sjogren, R. J. O., Gabriel, B. M.,
Krook, A. & Zierath, J. R. AMPK activation negatively
regulates GDAP1, which influences metabolic
processes and circadian gene expression in skeletal
muscle. Mol. Metab. 16, 12–23 (2018).
43. Xu, Y. et al. Modeling of a human circadian mutation
yields insights into clock regulation by PER2. Cell
128, 59–70 (2007).
44. Zhao, Y. et al. Uncovering the mystery of opposite
circadian rhythms between mouse and human
leukocytes in humanized mice. Blood 130,
1995–2005 (2017).
45. Brehm, M. A., Shultz, L. D., Luban, J. & Greiner, D. L.
Overcoming current limitations in humanized mouse
research. J. Infect. Dis. 208 (Suppl. 2), S125–S130
(2013).
46. Atkinson, G. & Reilly, T. Circadian variation in sports
performance. Sports Med. 21, 292–312 (1996).
47. Facer-Childs, E. & Brandstaetter, R. The impact of
circadian phenotype and time since awakening on
diurnal performance in athletes. Curr. Biol. 25,
518–522 (2015).
48. Fowler, P. M. et al. Greater effect of east versus west
travel on jet lag, sleep, and team sport performance.
Med. Sci. Sports Exerc. 49, 2548–2561 (2017).
49. Facer-Childs, E. & Brandstaetter, R. Circadian
phenotype composition is a major predictor of diurnal
physical performance in teams. Front. Neurol. 6, 208
(2015).
50. Egan, B. & Zierath, J. R. Exercise metabolism and the
molecular regulation of skeletal muscle adaptation.
Cell Metab. 17, 162–184 (2013).
51. Dyar, K. A. et al. The calcineurin-NFAT pathway controls
activity-dependent circadian gene expression in slow
skeletal muscle. Mol. Metab. 4, 823–833 (2015).
52. Atkinson, G., Coldwells, A., Reilly, T. & Waterhouse, J.
A comparison of circadian rhythms in work
performance between physically active and inactive
subjects. Ergonomics 36, 273–281 (1993).
53. Coldwells, A., Atkinson, G. & Reilly, T. Sources of
variation in back and leg dynamometry. Ergonomics
37, 79–86 (1994).
54. Wyse, J. P., Mercer, T. H. & Gleeson, N. P. Time-of-day
dependence of isokinetic leg strength and associated
interday variability. Br. J. Sports Med. 28, 167–170
(1994).

Nature Reviews | Endocrinology

Reviews
55. Gauthier, A., Davenne, D., Martin, A., Cometti, G.
& Van Hoecke, J. Diurnal rhythm of the muscular
performance of elbow flexors during isometric
contractions. Chronobiol. Int. 13, 135–146 (1996).
56. Gauthier, A., Davenne, D., Gentil, C. & Van Hoecke, J.
Circadian rhythm in the torque developed by elbow
flexors during isometric contraction. Effect of sampling
schedules. Chronobiol. Int. 14, 287–294 (1997).
57. Martin, A., Carpentier, A., Guissard, N., van Hoecke, J.
& Duchateau, J. Effect of time of day on force variation
in a human muscle. Muscle Nerve 22, 1380–1387
(1999).
58. Callard, D., Davenne, D., Gauthier, A., Lagarde, D.
& Van Hoecke, J. Circadian rhythms in human
muscular efficiency: continuous physical exercise
versus continuous rest. A crossover study.
Chronobiol. Int. 17, 693–704 (2000).
59. Souissi, N., Gauthier, A., Sesboue, B., Larue, J.
& Davenne, D. Effects of regular training at the same
time of day on diurnal fluctuations in muscular
performance. J. Sports Sci. 20, 929–937 (2002).
60. Souissi, N., Sesboue, B., Gauthier, A., Larue, J.
& Davenne, D. Effects of one night’s sleep deprivation
on anaerobic performance the following day. Eur. J.
Appl. Physiol. 89, 359–366 (2003).
61. Castaingts, V., Martin, A., Van Hoecke, J. & Perot, C.
Neuromuscular efficiency of the triceps surae in induced
and voluntary contractions: morning and evening
evaluations. Chronobiol. Int. 21, 631–643 (2004).
62. Chtourou, H. et al. The effect of strength training at
the same time of the day on the diurnal fluctuations
of muscular anaerobic performances. J. Strength
Cond. Res. 26, 217–225 (2012).
63. Souissi, N. et al. Effect of time of day and partial sleep
deprivation on short-term, high-power output.
Chronobiol. Int. 25, 1062–1076 (2008).
64. Taylor, K., Cronin, J. B., Gill, N., Chapman, D. W.
& Sheppard, J. M. Warm-up affects diurnal variation
in power output. Int. J. Sports Med. 32, 185–189
(2011).
65. Sedliak, M. et al. Morphological, molecular and
hormonal adaptations to early morning versus
afternoon resistance training. Chronobiol. Int. 35,
450–464 (2018).
66. Bernard, T., Giacomoni, M., Gavarry, O., Seymat, M.
& Falgairette, G. Time-of-day effects in maximal
anaerobic leg exercise. Eur. J. Appl. Physiol. Occup.
Physiol. 77, 133–138 (1998).
67. Racinais, S., Perrey, S., Denis, R. & Bishop, D.
Maximal power, but not fatigability, is greater
during repeated sprints performed in the afternoon.
Chronobiol. Int. 27, 855–864 (2010).
68. Lericollais, R., Gauthier, A., Bessot, N., Sesboue, B.
& Davenne, D. Time-of-day effects on fatigue during a
sustained anaerobic test in well-trained cyclists.
Chronobiol. Int. 26, 1622–1635 (2009).
69. Souissi, N. et al. Diurnal variation in Wingate test
performances: influence of active warm-up.
Chronobiol. Int. 27, 640–652 (2010).
70. Fernandes, A. L. et al. Effect of time of day on
performance, hormonal and metabolic response
during a 1000-M cycling time trial. PLOS ONE 9,
e109954 (2014).
71. Deschenes, M. R. et al. Chronobiological effects on
exercise performance and selected physiological
responses. Eur. J. Appl. Physiol. Occup. Physiol. 77,
249–256 (1998).
72. Waterhouse, J. et al. The circadian rhythm of core
temperature: origin and some implications for exercise
performance. Chronobiol. Int. 22, 207–225 (2005).
73. Boukelia, B., Fogarty, M. C., Davison, R. C. &
Florida-James, G. D. Diurnal physiological and
immunological responses to a 10-km run in highly
trained athletes in an environmentally controlled
condition of 6 degrees C. Eur. J. Appl. Physiol. 117,
1–6 (2017).
74. Dibner, C., Schibler, U. & Albrecht, U. The mammalian
circadian timing system: organization and coordination
of central and peripheral clocks. Annu. Rev. Physiol.
72, 517–549 (2010).
75. Edwards, B., Waterhouse, J., Reilly, T. & Atkinson, G.
A comparison of the suitabilities of rectal, gut, and
insulated axilla temperatures for measurement of the
circadian rhythm of core temperature in field studies.
Chronobiol. Int. 19, 579–597 (2002).
76. Gray, S. R., De Vito, G., Nimmo, M. A., Farina, D.
& Ferguson, R. A. Skeletal muscle ATP turnover and
muscle fiber conduction velocity are elevated at
higher muscle temperatures during maximal power
output development in humans. Am. J. Physiol. Regul.
Integr. Comp. Physiol. 290, R376–R382 (2006).
77. Gray, S. R., Soderlund, K. & Ferguson, R. A. ATP and
phosphocreatine utilization in single human muscle
fibres during the development of maximal power
output at elevated muscle temperatures. J. Sports Sci.
26, 701–707 (2008).
78. Gonzalez-Alonso, J. et al. Blood temperature and
perfusion to exercising and non-exercising human
limbs. Exp. Physiol. 100, 1118–1131 (2015).
79. Bass, J. & Lazar, M. A. Circadian time signatures of
fitness and disease. Science 354, 994–999 (2016).
80. Buhr, E. D., Yoo, S. H. & Takahashi, J. S. Temperature
as a universal resetting cue for mammalian circadian
oscillators. Science 330, 379–385 (2010).
81. Racinais, S., Cocking, S. & Periard, J. D. Sports and
environmental temperature: from warming-up to
heating-up. Temperature (Austin) 4, 227–257 (2017).
82. Pullinger, S. A. et al. Diurnal variation in repeated
sprint performance cannot be offset when rectal and
muscle temperatures are at optimal levels (38.5
degrees C). Chronobiol. Int. 35, 1054–1065 (2018).
83. Deschenes, M. R. et al. Biorhythmic influences on
functional capacity of human muscle and physiological
responses. Med. Sci. Sports Exerc. 30, 1399–1407
(1998).
84. Morton, R. W. et al. Neither load nor systemic
hormones determine resistance training-mediated
hypertrophy or strength gains in resistance-trained
young men. J. Appl. Physiol. 121, 129–138 (2016).
85. Atger, F., Mauvoisin, D., Weger, B., Gobet, C. &
Gachon, F. Regulation of mammalian physiology by
interconnected circadian and feeding rhythms.
Front. Endocrinol. (Lausanne) 8, 42 (2017).
86. Mattson, M. P. et al. Meal frequency and timing in
health and disease. Proc. Natl Acad. Sci. USA 111,
16647–16653 (2014).
87. Milton, K. Hunter-gatherer diets-a different
perspective. Am. J. Clin. Nutr. 71, 665–667 (2000).
88. Crittenden, A. N. & Schnorr, S. L. Current views on
hunter-gatherer nutrition and the evolution of the
human diet. Am. J. Phys. Anthropol. 162 (Suppl. 63),
84–109 (2017).
89. Lamia, K. A., Storch, K. F. & Weitz, C. J. Physiological
significance of a peripheral tissue circadian clock.
Proc. Natl Acad. Sci. USA 105, 15172–15177 (2008).
90. Harfmann, B. D. et al. Muscle-specific loss of Bmal1
leads to disrupted tissue glucose metabolism and
systemic glucose homeostasis. Skelet. Muscle 6, 12
(2016).
91. Moran-Ramos, S. et al. The suprachiasmatic nucleus
drives day-night variations in postprandial triglyceride
uptake into skeletal muscle and brown adipose tissue.
Exp. Physiol. 102, 1584–1595 (2017).
92. Gabriel, B., Ratkevicius, A., Gray, P., Frenneaux, M. P.
& Gray, S. R. High-intensity exercise attenuates
postprandial lipaemia and markers of oxidative stress.
Clin. Sci. 123, 313–321 (2012).
93. Gabriel, B. M. et al. The effect of high intensity interval
exercise on postprandial triacylglycerol and leukocyte
activation—monitored for 48h post exercise. PLOS
ONE 8, e82669 (2013).
94. Sato, S., Parr, E. B., Devlin, B. L., Hawley, J. A.
& Sassone-Corsi, P. Human metabolomics reveal daily
variations under nutritional challenges specific to serum
and skeletal muscle. Mol. Metab. 16, 1–11 (2018).
95. Jeukendrup, A. E. Periodized nutrition for athletes.
Sports Med. 47, 51–63 (2017).
96. Marquet, L. A. et al. Enhanced endurance
performance by periodization of carbohydrate intake:
“Sleep Low” strategy. Med. Sci. Sports Exerc. 48,
663–672 (2016).
97. Lane, S. C. et al. Effects of sleeping with reduced
carbohydrate availability on acute training responses.
J. Appl. Physiol. 119, 643–655 (2015).
98. Hawley, J. A., Lundby, C., Cotter, J. D. & Burke, L. M.
Maximizing cellular adaptation to endurance exercise
in skeletal muscle. Cell Metab. 27, 962–976 (2018).
99. Kuusmaa, M. et al. Effects of morning versus evening
combined strength and endurance training on physical
performance, muscle hypertrophy, and serum
hormone concentrations. Appl. Physiol. Nutr. Metab.
41, 1285–1294 (2016).
100. Matsumoto, C. S. et al. PI3K-PTEN dysregulation
leads to mTOR-driven upregulation of the core clock
gene BMAL1 in normal and malignant epithelial cells.
Oncotarget 7, 42393–42407 (2016).
101. Ramanathan, C. et al. mTOR signaling regulates
central and peripheral circadian clock function.
PLOS Genet. 14, e1007369 (2018).
102. Liu, D. et al. mTOR signaling in VIP neurons regulates
circadian clock synchrony and olfaction. Proc. Natl
Acad. Sci. USA 115, E3296–E3304 (2018).
103. Reeds, P. J., Palmer, R. M., Hay, S. M.
& McMillan, D. N. Protein synthesis in skeletal muscle
measured at different times during a 24 hour period.
Biosci. Rep. 6, 209–213 (1986).
104. Chang, S. W., Yoshihara, T., Machida, S. & Naito, H.
Circadian rhythm of intracellular protein synthesis
signaling in rat cardiac and skeletal muscles. Biochem.
Biophys. Rep. 9, 153–158 (2017).
105. Gangwisch, J. E. et al. Sleep duration as a risk factor
for diabetes incidence in a large US sample. Sleep 30,
1667–1673 (2007).
106. Ogilvie, R. P. & Patel, S. R. The epidemiology of sleep
and obesity. Sleep Health 3, 383–388 (2017).
107. Zwighaft, Z. et al. Circadian clock control by polyamine
levels through a mechanism that declines with age.
Cell Metab. 22, 874–885 (2015).
108. Myllymaki, T. et al. Effects of vigorous late-night
exercise on sleep quality and cardiac autonomic
activity. J. Sleep Res. 20, 146–153 (2011).
109. Banno, M. et al. Exercise can improve sleep quality:
a systematic review and meta-analysis. PeerJ 6, e5172
(2018).
110. Youngstedt, S. D., O’Connor, P. J. & Dishman, R. K.
The effects of acute exercise on sleep: a quantitative
synthesis. Sleep 20, 203–214 (1997).
111. Murray, K. et al. The relations between sleep, time
of physical activity, and time outdoors among adult
women. PLOS ONE 12, e0182013 (2017).
112. Figueiro, M. G. et al. The impact of daytime light
exposures on sleep and mood in office workers.
Sleep Health 3, 204–215 (2017).
113. Harrington, J. M. Health effects of shift work and
extended hours of work. Occup. Environ. Med. 58,
68–72 (2001).
114. Buxton, O. M. et al. Sleep restriction for 1 week
reduces insulin sensitivity in healthy men. Diabetes
59, 2126–2133 (2010).
115. Eastman, C. I., Hoese, E. K., Youngstedt, S. D. & Liu, L.
Phase-shifting human circadian rhythms with exercise
during the night shift. Physiol. Behav. 58,
1287–1291 (1995).
116. Youngstedt, S. D. et al. Circadian phase-shifting effects
of bright light, exercise, and bright light + exercise.
J. Circadian Rhythms 14, 2 (2016).
117. Dempsey, P. C. et al. Interrupting prolonged sitting in
type 2 diabetes: nocturnal persistence of improved
glycaemic control. Diabetologia 60, 499–507 (2017).
118. Gabel, K. et al. Effects of 8-hour time restricted
feeding on body weight and metabolic disease risk
factors in obese adults: a pilot study. Nutr. Healthy.
Aging 4, 345–353 (2018).
119. Friborg, O., Bjorvatn, B., Amponsah, B. & Pallesen, S.
Associations between seasonal variations in day
length (photoperiod), sleep timing, sleep quality and
mood: a comparison between Ghana (5 degrees) and
Norway (69 degrees). J. Sleep Res. 21, 176–184
(2012).
120. Renstrom, F. et al. Season-dependent associations
of circadian rhythm-regulating loci (CRY1, CRY2 and
MTNR1B) and glucose homeostasis: the GLACIER
Study. Diabetologia 58, 997–1005 (2015).
121. Atkinson, G. & Drust, B. Seasonal rhythms and
exercise. Clin. Sports Med. 24, e25–e34 (2005).
122. Honma, K., Honma, S., Kohsaka, M. & Fukuda, N.
Seasonal variation in the human circadian rhythm:
dissociation between sleep and temperature rhythm.
Am. J. Physiol. 262, R885–R891 (1992).
123. Chen, L. & Yang, G. PPARs integrate the mammalian
clock and energy metabolism. PPAR Res. 2014,
653017 (2014).
Acknowledgements
The authors are supported by grants from the Novo Nordisk
Foundation (NNF14OC0011493, NNF14OC0009941 and
NNF18CC0034900), the Wenner-Gren Foundation, the
Swedish Research Council (2015–00165), the European
Research Council (233285) and the Strategic Research
Programme in Diabetes at Karolinska Institutet (2009–
1068). The authors are grateful to B. Atkins for his contribu-
tion to figure design.
Author contributions
B.M.G. and J.R.Z. contributed equally to all aspects of
the article.
Competing interests
The authors declare no competing interests.
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