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Exerc Sport Sci Rev. 2013 October ; 41(4): . doi:10.1097/JES.0b013e3182a58a70.

Circadian Rhythms, skeletal muscle molecular clocks and


exercise
Elizabeth A. Schroder1,2 and Karyn A. Esser1,2
1Center for Muscle Biology, University of Kentucky, Lexington, KY 40536

2Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536

Abstract
Skeletal muscle comprises approximately 40 % of total body mass and, as such, contributes to
maintenance of human health. In this review we will discuss the current state of knowledge
regarding the role of molecular clocks in skeletal muscle. In addition we discuss a new function
for exercise as a time setting cue for muscle and other peripheral tissues.
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Keywords
circadian; skeletal muscle; exercise; peripheral tissues; zeitgeber

Introduction
Circadian rhythms are the approximate 24-hour biological cycles that function to prepare the
organism for daily environmental changes. Almost all organisms ranging from single cell
bacteria to plants and animals, exhibit behavioral, physiological and biochemical rhythms
termed circadian rhythms.(7, 9) Underlying circadian rhythms is a molecular clock
mechanism found in most, if not all, cell types including skeletal muscle. At the cellular
level, the presence of a molecular clock is argued to be a necessary timekeeping mechanism
to prepare the cell for daily changes in environmental conditions. The ability to synchronize
the molecular clock and intracellular physiology with external day-night cycles denotes an
evolutionarily conserved adaptation to environmental conditions.(7, 9)

Environmental stimuli capable of shifting the timing of molecular rhythms are critically
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important to understanding the synchronization of oscillators to the environment and to each


other within a multicellular system. The most well understood circadian time cue (termed
zeitgeber) is the photic or light time cue. While lighting conditions have been extensively
studied in many species more recently, non-photic zeitgebers such as time of feeding and
time of physical activity/exercise have been shown to influence molecular rhythms and
behavior.(25, 31) The goal of this review is to present the latest findings demonstrating that
the molecular clock exists in skeletal muscle and support for the concept that exercise plays
a role as a time cue for clocks in peripheral tissues. The existing data, although limited,
suggests the importance of exercise and more importantly, the timing of exercise in adding
stability to the daily rhythms of the circadian system. These observations add a new function
for the role of exercise in human health and suggest new concepts for the benefits of

Copyright © 2013 by the American College of Sports Medicine


Corresponding Author: Karyn A. Esser, University of Kentucky, Department of Physiology, 800 Rose Street, MS508, Lexington, KY
40536-0298, Phone: 859-323-8107; Fax: 859-323-1070; [email protected].
Disclosures: No conflicts of interest, financial or otherwise, are declared by the author(s).
Schroder and Esser Page 2

exercise in potentially postponing or preventing the development of chronic diseases.(25,


31)
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The Molecular Clock in Mammals


The molecular mechanism underlying circadian rhythms is a gene regulatory network
composed of transcriptional-translational feedback loops referred to as the core clock.(11)
The molecular clock components comprising the positive arm of the core clock are two
members of the PAS-bHLH family of transcription factors, Clock (Circadian locomotor
output control kaput) and Bmal1 (Brain muscle arnt-like1). BMAL1 protein is expressed in a
circadian pattern in both the SCN and peripheral tissues.(4, 8) CLOCK protein levels do not
oscillate in the SCN and only in some peripheral tissues.(15) However, the nuclear to
cytosolic distribution of CLOCK is circadian in its pattern with highest levels of CLOCK in
the nucleus occurring in the light phase in mice.(18, 28) The CLOCK:BMAL1 heterodimer
activates transcription of additional core clock genes Period (Per1, Per2 and Per3) and
Cryptochrome (Cry1 and Cry2) by binding to E-box (CACGTG) sequences in the regulatory
region of these genes. The CRY and PER proteins constitute the negative arm of the core
molecular clock by forming multimers that inhibit CLOCK:BMAL1 transcriptional activity
upon translocation to the nucleus. A schematic of the molecular clock mechanism is shown
in Figure 1.

Additional components to the core molecular clock family include the orphan nuclear
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receptors Rora (RAR-related orphan receptor-α) and Rev-erb α/β. These gene products
function to link the feedback loops by activating (Rora) or repressing (Rev-erb) Bmal1
transcription.(21, 24) Most recently, studies have added new elements, known as E3 ligases
(e.g. Fbxl3), to the core molecular clock and these elements function by changing stability of
the PER and CRY proteins.(33) In addition to their role in timekeeping, components of the
core clock (Bmal1 and Clock) have also been shown to transcriptionally regulate the
expression of genes that do not function in timekeeping and these genes are designated as
clock-controlled genes (CCGs).

While the identity of all the direct clock controlled genes in a specific tissue, like skeletal
muscle, have not been defined, they often encode transcription factors (e.g. MyoD1) or
proteins that control rate-limiting steps in cell physiology (e.g. PBEF, the rate-limiting
enzyme in the NAD+ salvage pathway).(17, 18) For more detailed reviews of the molecular
clock mechanism there are several recent reviews by other groups.(16)

Central/Peripheral Clocks in Mammals and Zeitgebers


The first suggestion that the central clock (circadian pacemaker) was located in the
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suprachiasmatic nucleus (SCN) came when it was discovered that surgical ablation of the
SCN resulted in arrhythmic behavior patterns.(27) SCN ablation in hamsters creates an
actively arrhythmic animal and transplantation of a healthy SCN (from either a hamster or
mouse) back into the lesioned hamsters restores activity rhythms with rhythms matching that
of the donor animal (26) demonstrating the role of the SCN as a system-wide circadian
synchronizer. Cell autonomy of the molecular clock in peripheral tissue was first established
almost 15 years ago.(3) The development of a mouse model in which the luciferase cDNA
was knocked into the Per2 coding region to generate a chimeric protein provided the
powerful resource (PER2:LUC mice) to directly test the cell autonomy of the clock
mechanism.(32) For these studies, tissue explants from the SCN, liver and lung from these
PER2:LUC mice were placed in cell culture in the presence of luciferin and real time light
emission was monitored for up to two weeks. While oscillations in luminescence were
expected from the central clock (SCN slice) these findings demonstrated that the clock
mechanism from peripheral tissue explants maintained normal 24hr circadian periodicity in

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the absence of systemic neural or humoral factors.(32) These studies also validated the use
of the PER2::LUC mouse as a valuable resource to study molecular clock function in
multiple tissues including skeletal muscle. (31, 35)
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While studies have established that the molecular clock mechanism is intrinsic to each cell
and that it can run in a cell autonomous manner, a critical feature is that the phase of the
molecular clock can be set or reset by cues from the environment. The ability to reset the
circadian clock is a critical function to be able to adapt to environmental changes. The
timing or phase of the central clock is primarily entrained by cues from light.(29) Recent
studies have demonstrated that the molecular clock in many peripheral tissues, including
skeletal muscle can be dissociated from the rhythm of the SCN by restricting time of
feeding.(4) In addition, Zambon et al.(34) reported that there is an interaction between time
of day and contraction on expression of clock genes in human muscle, suggesting contractile
activity might be a zeitgeber for the molecular clock mechanism in skeletal muscle. In this
study, microarray analysis was used to determine the effects of resistance exercise on gene
expression in the quadriceps at 6 and 18 hours after an acute bout exercise. Gene expression
was also examined in the non-exercised leg at the same time points for comparison. These
results indicate that feeding, and potentially contractile activity, can act as dominant
zeitgebers for setting clocks in peripheral tissues. (Figure 2) They also demonstrate that
circadian rhythms in peripheral tissues can be dissociated from the SCN through non-photic
environmental signals.
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The timing of the molecular clock can also be modulated by post-translational mechanisms
using phosphorylation, acetylation and/or ubiquitination pathways. These modifications
impact the stability and/or translocation of core molecular clock components with the
greatest impact on period length (time for completion of 1 cycle (24h)). The most well-
known regulator of clock function through changing phosphorylation status is casein
kinase1ε (CK1ε). This serine/threonine kinase has been the subject of studies in both
hamster and humans in which the mutations of either CK1ε or PER2 affect period length.
The tau mutant hamster, has a point mutation (Arg178Cys) in the catalytic region of CK1ε,
termed the tau mutation, which results in a hamster that exhibits short circadian periods.(23)
In these hamsters, CK1ε is unable to phosphorylate PER proteins. With diminished levels of
phosphorylation, PER translocates to the nucleus leading to a more rapid repression of the
CLOCK: BMAL1 mediated transcription, effectively shortening the circadian period to 20
hours. (10) In humans, a mutation in PER2 that affects a phosphorylation site (target of
CK1ε) results in the clinical condition, familial advance sleep phase syndrome (FASPS).
Studies of these individuals determined that they have a shortened period length of
approximately 20 hours compared to the normal 24 hours observed in most humans and is
associated with early awake and early to sleep.(30)
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Acetylation of histones unfolds chromatin to expose promoter and regulatory regions of


genes and is associated with activation of gene expression while acetylation results in
silencing of gene expression. An example for a circadian role in acetylation comes from
studies of the histone acetyltransferase p300. The p300 protein associates with CLOCK in a
circadian manner, implicating p300 as a component of the core clock transactivation
complex. In addition, H3 histone acetylation at the promoter region of Per1 and Per2 shows
robust circadian rhythms in phase with the Per1/Per2 mRNA and p300:CLOCK complex
formation. p300 is inhibited by the CRY protein leading to a decrease in CLOCK: BMAL1
mediated transcription at the Per1 promoter. These data suggest that the repressor action of
CRY is mediated in part by its actions on chromatin structure.(6) The most frequently
studied deacetylase involved in circadian regulation is SirtT1. SirT1 deacetylates histone H3.
This activity shows a strong circadian rhythm antiphase to the rhythm of histone H3
acetylation.(17) This antiphase oscillation of acetylation/deacetylation suggest an important

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direct or permissive mechanism for controlling clock gene expression and propose roles for
acetylation/deacetylation in the initiation, duration and termination of both the activating
and repressing phases of the circadian cycle.
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The Molecular Clock in Skeletal Muscle


The skeletal muscle circadian transcriptome was first identified by Miller and colleagues.
(14) This work was followed by a publication which identified ~215 mRNAs that were
expressed in a circadian pattern in the gastrocnemius muscle of wildtype C57BL6 mice.
This list included known core molecular clock components Bmal1, Per2 and Cry1.(13) Gene
ontology analysis identified enrichment in multiple cellular processes including but not
limited to metabolic, transcriptional and degradative processes. The tissue specificity of the
circadian transcriptome in skeletal muscle was underscored by the inclusion of known
muscle specific genes such as Myod1, Ucp3, Fbxo32/atrogin and Myh1(MyHC IIX). The
identification of Myod1 as a gene expressed in a circadian manner was exciting as it is well-
characterized as a transcription factor involved in the skeletal muscle lineage. The fact that it
is expressed in a circadian manner in adult tissue and is under direct control of
CLOCK:BMAL1(1) suggest that it may be critical for daily muscle maintenance. (Figure 1)
To further understand the implications of molecular clock disruption in skeletal muscle
McCarthy et al,(13) compared gene expression changes between skeletal muscle from
wildtype C57Bl6 mice to those from Clock mutant mice. The Clock mutant mice have a
mutation that results in the deletion of exon 19 of CLOCK and this is associated with longer
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behavioral rhythms of 27 hours.(2) We found that several core clock genes including Bmal1
and Per2, no longer oscillated in the muscle of Clock mutant mice. Oscillation was also lost
in several known clock controlled genes in the skeletal muscle such as Tef, Dbp, Myod1 and
Pgc1β. In addition to analysis of the circadian genes, McCarthy et al, found that
approximately 35% of all the expressed genes were differentially expressed in the muscle of
Clock mutant mice demonstrating the substantial impact disruption of the core clock
machinery has on gene expression with implications for normal cellular function and health.
With continued development of analysis tools for time course gene expression studies, the
list of genes expressed in a circadian manner in skeletal muscle has grown to greater than
800. Pizarro et al (2013)(20) have established a valuable website to allow for queries into
circadian expression from time course expression experiments in tissues and cell lines
(http://circadb.org). These new data will open many exciting avenues of research in the
study of skeletal muscle circadian physiology. However, one area that is still understudied is
whether the circadian transcriptome differs among individual skeletal muscles of different
developmental origin (e.g. limb vs. facial muscle) or whether they differ among muscles
with markedly different fiber type, metabolic function and mechanical function.

Exercise and circadian rhythms


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Wheel running or cage activity has long been utilized as a read-out of circadian behavior but
the idea that physical activity/exercise and more importantly the timing of exercise could
serve as an entrainment cue is relatively new. (25, 31) Studies in the late 1980’s and early
90’s were the first to show that novel wheel access at different times of day was sufficient to
shift the phase of circadian activity rhythms in mice and hamsters. (5) Further studies
demonstrated that exercise is a sufficient environmental cue to effect clock gene expression
in the SCN (central clock) located in the hypothalamus of the brain. (12) These studies
established that activity, in the form of access to a novel running wheel, during light
conditions decreased peak expression of the clock genes Per1 and Per2 in the SCN.
Schroeder et al took this idea further examining both timing of exercise as well as multiple
bouts of exercise. They explored effects on the central clock utilizing a scheduled exercise
paradigm in control and mutant mice in which the central molecular clock mechanism was
weakened.(25) In attempts to better mimic the timing of exercise in the human population,

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mice were allowed free access to a wheel, no access to a wheel, or access limited to 6 hour
time frames at the beginning or end of the dark or active phase for a minimum of 16 days.
Similar to previous studies examining single bouts of exercise, they observed changes in the
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properties of the molecular clock in the SCN after 16 days in the control mice suggesting the
phase shifts observed in previous studies were not solely an acute phase response. Moreover,
PER2:LUC amplitude was damped in mice with wheel access scheduled early in the dark
phase but unaffected with scheduled activity late in the dark phase or with free access to
wheel running suggesting that the timing of exercise may be critical for the maintenance of
molecular rhythms in the SCN. Utilizing the vasoactive intestinal polypeptide (VIP) knock-
out mouse, shown to have an unstable clock mechanism, they found that scheduled exercise
functioned to enhance the stability of both activity and heart rate rhythms.

The core molecular clock gene Clock has also been demonstrated to be critical for healthy
skeletal muscle as Clock mutant mice exhibit ~30% reductions in normalized maximal force
at both the muscle and single-fiber level. (1) In addition, myofiber architecture is disrupted
and mitochondrial volume is diminished. Recent work from Pastore et al supports these
results. (19) They demonstrated that CLOCK protein is critical for mitochondrial
maintenance in skeletal muscle. Taking this a step further, they examined the ability of clock
mutant mice to adapt to chronic exercise and found that despite the pathology as a result of
the mutant Clock gene the ability of these mice to adapt to chronic exercise was not
changed. Utilizing endurance training they were able to partially rescue the metabolic
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defects resulting from loss of functional CLOCK protein.

Most studies of exercise and shifting of circadian rhythms have relied on endurance exercise
paradigms. Less is known about the potential for resistance exercise but Zambon et al.,
reported that one bout of 60 contractions was associated with changes in molecular clock
gene expression in skeletal muscle of humans.(34) Experiments in neonatal cardiomyocytes
have shown that contractile activity may modulate the molecular clock through the actions
of the CLOCK protein. Histological and biochemical analysis demonstrated that CLOCK
localizes to the Z-disk in neonatal cardiomyocytes and translocates to the nucleus to
influence gene expression in response to contractile activity. CLOCK localization at the Z-
disk puts CLOCK in an appropriate location to sense mechanical function associated with
contractile activity. (22) While these studies are suggestive that resistance exercise can also
modulate molecular clock function in muscle, there is still much to be determined.

With over 600 different muscles in the human body, comprising approximately 40 percent
total body mass, understanding the effects of exercise on the molecular rhythms in
individual skeletal muscles may provide critical insight into systemic mechanisms
contributing to daily rhythms. At this stage, there is only one study that has examined more
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than one muscle in mice exposed to scheduled bouts of either voluntary or involuntary
endurance exercise for 2 hours/day in the light phase four hours after lights on. In this study,
the authors found a significant shift in clock gene expression (PER2:LUC bioluminescence)
in three different skeletal muscles and the lung from exercised mice, whereas the molecular
clock in the SCN remained unshifted demonstrating that scheduled exercise can alter the
molecular clock in peripheral tissues. In addition, one of the muscles examined, the flexor
digitorum brevis (FDB) was phase advanced more than the other two muscles (soleus and
extensor digitorum longus) suggesting the potential for differential regulation of the
molecular clock in individual muscles.(31) Lumicycle data in combination with data
demonstrating rescue of phenotype resulting from exercise,(19, 25, 31) implicates exercise
as a non-photic time cue in peripheral tissues and suggests that the molecular clock in all
muscle tissues may not respond in a similar manner to non-photic cues. Since muscle is such
a large contributor to systems physiology, these data have broad implications for human
health and disease suggesting the power of exercise, and more specifically the interaction of

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exercise and muscle, as a therapeutic strategy to help stabilize/realign molecular clocks


throughout the body.
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Summary
Circadian rhythms and molecular clocks in skeletal muscle is a new and rapidly emerging
area of research. Studies in the last 15 years have demonstrated that molecular clocks exist
in skeletal muscle and more importantly, studies have demonstrated that the phase of the
clocks in skeletal muscle can be reset by altering time of exercise or time of feeding
independent of the central clock in the brain. In parallel studies it has been shown that
skeletal muscles from mice in which the core clock genes have been disrupted are weaker
and exhibit decreased mitochondrial content and function. These findings suggest a potential
new role for exercise in human health through its role in providing timing information to
skeletal muscle and other peripheral tissue clocks. Although difficult to extrapolate to
humans, exercise studies in mice do suggest an optimal time of day for exercise to enhance
the robust nature of circadian rhythms at the molecular level. Until an optimal time is
determined, consistently timed daily exercise may be a viable alternative. These studies
highlight the recognition that time of day matters for maintenance of proper molecular clock
function and is important for issues of muscle strength and endurance.

Acknowledgments
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This work was supported by the following NIH grants RC1ES018636 and R01AR55246 (KAE).

The authors would like to thank Jonathan England for his help with the figures in the preparation of this manuscript.

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Summary
This review discusses the relationship between the molecular clock, skeletal muscle, and
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exercise.
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Figure 1.
The core circadian clock is an autoregulatory transcriptional feedback loop comprised of a
transcription factors, CLOCK and BMAL1 and their target genes; Per1, Per2, Cry1, and
Cry2. The CLOCK:BMAL1 heterodimer also functions to drive transcription of Rev-erbα
and Rorα which in turn either represses or activates Bmal1 transcription respectively. The
CLOCK:BMAL1 heterodimer also regulates downstream targets known as clock-controlled
genes (CCG). The kinases, casein kinase 1ε (CK1ε) and AMP kinase (AMPK),
phosphorylate PER(CK1ε) and CRY(AMPK) proteins to promote polyubiquitination by E3
ubiquitin ligase complexes. PER and CRY proteins are then degraded by the 26S
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proteasome complex.

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Figure 2.
Central and peripheral clocks can respond to both photic (light) and non-photic (feeding and
exercise) zeitgebers. This schematic demonstrates the interplay between the different
zeitgebers and central and peripheral clocks. It also suggests that central and peripheral
clocks may have differential responses depending upon the zeitgeber present.
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