Download Histone modifications and exercise adaptations

J Appl Physiol 110: 258–263, 2011.
First published October 28, 2010; doi:10.1152/japplphysiol.00979.2010.
Review
HIGHLIGHTED TOPIC
Signals Mediating Skeletal Muscle Remodeling by Activity
Histone modifications and exercise adaptations
Sean L. McGee1 and Mark Hargreaves2
1
Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds; and 2Department of Physiology,
The University of Melbourne, Melbourne, Australia
Submitted 23 August 2010; accepted in final form 21 October 2010
chromatin; gene transcription
is a highly plastic tissue that adapts to exercise/activity interventions by increasing its metabolic capacity
and/or mass. Over the last 10 –20 years, numerous studies have
demonstrated that exercise increases expression of various
myogenic and metabolic genes, usually by increasing rates of
transcription. The importance of chromatin remodeling in regulated gene expression has also become evident, with a focus
on post-translational modifications to histones that determine
the spatial relationships between genomic DNA and the histone
core and access of transcriptional regulators to the promoter
regions of target genes. This review briefly summarizes recent
insights into histone modifications in response to exercise and
implications for exercise/activity-dependent alterations in skeletal muscle gene expression.
SKELETAL MUSCLE
CHROMATIN AND REGULATED GENE EXPRESSION
In all eukaryote cells, DNA is wound around a core of
histone proteins, with the resulting structure referred to as
chromatin. The functional unit of chromatin is the nucleosome,
which is comprised of a 147-bp section of DNA wrapped ⬃1.7
turns around a core octamer of histone proteins that includes
two of each of the histones H2A, H2B, H3, and H4 (20). Early
Address for reprint requests and other correspondence: S. L. McGee, School
of Medicine, Deakin Univ., Waurn Ponds, 3217 Australia (e-mail: sean.mcgee
@deakin.edu.au).
258
research viewed chromatin as a static structure that was primarily involved in DNA packaging and compaction; however,
in recent years this paradigm has changed (33). It is now
recognized that chromatin, and in particular the nucleosome,
exhibits dynamic properties that play a central role in regulated
gene expression. Indeed, it is well recognized that regulated
genes in a transcriptionally repressed state contain nucleosomes at their transcription start site (4). This impairs the
ability of the transcriptional initiation complex (TIC) and RNA
polymerase II (Pol II) to occupy this region and hence impairs
transcription. Nucleosomes within a promoter region also compete with transcription factors for occupancy of cis-regulatory
elements that are critical to the initiation of transcription (4).
Where a cis-regulatory element is located near the middle of a
nucleosome, it is inaccessible to transcription factors (4). In this
situation, modification of chromatin structure that alters the spatial
relationship between histones and DNA must occur to allow
transcription factor binding. Once bound to DNA, transcription
factors can recruit and promote assembly of the TIC on the
promoter region (4; Fig. 1). Transcriptional elongation also
involves chromatin modifications as Pol II requires access to
DNA to traverse and read the coding region of a gene (16).
However, these mechanisms appear to be distinct from those
that regulate chromatin structure at promoter regions (16).
Chromatin structure can be modified through a number of
mechanisms, which together are termed “epigenetics.” These
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McGee SL, Hargreaves M. Histone modifications and exercise adaptations.
J Appl Physiol 110: 258 –263, 2011. First published October 28, 2010;
doi:10.1152/japplphysiol.00979.2010.—The spatial association between genomic
DNA and histone proteins within chromatin plays a key role in the regulation of
gene expression and is largely governed by post-translational modifications to
histone proteins, particularly H3 and H4. These modifications include phosphorylation, acetylation, and mono-, di-, and tri-methylation, and while some are
associated with transcriptional repression, acetylation of lysine residues within H3
generally correlates with transcriptional activation. Histone acetylation is regulated
by the balance between the activities of histone acetyl transferase (HAT) and
histone deacetylase (HDAC). In skeletal muscle, the class II HDACs 4, 5, 7, and 9
play a key role in muscle development and adaptation and have been implicated in
exercise adaptations. As just one example, exercise results in the nuclear export of
HDACs 4 and 5, secondary to their phosphorylation by CaMKII and AMPK, two
kinases that are activated during exercise in response to changes in sarcoplasmic
Ca2⫹ levels and energy status, in association with increased GLUT4 expression in
human skeletal muscle. Unraveling the complexities of the so-called “histone code”
before and after exercise is likely to lead to a greater understanding of the regulation
of exercise/activity-induced alterations in skeletal muscle gene expression and
reinforce the importance of skeletal muscle plasticity in health and disease.
Review
HISTONES AND EXERCISE
259
mechanisms include, but are not limited to, DNA methylation,
histone variants, and histone modifications (12). While these
processes are well studied in a number of cell systems, their
role in skeletal muscle biology is only just beginning to be
explored (1), with the role of histone modifications in the
regulation of skeletal muscle gene expression receiving the
most attention.
HISTONE MODIFICATIONS, ACETYLATION, AND HATs AND
HDACs
Histone modifications involve a number of different posttranslational modifications to the lysine rich tail regions of
histones, in particular H3 and H4 (16). These modifications
include phosphorylation, ubiquitination, methylation, and acetylation (16). Each modification targets different amino acid
residues and can have differential effects on transcription. For
example, methylation at H3 lysine 4 is associated with transcriptional activation (40), while methylation at lysine 36 is
associated with transcriptional repression (13). In addition,
interdependency between different modifications also exists,
such as phosphorylation of H3 serine 10, which facilitates
acetylation of H3 lysine 9 (18). Recognizing and characterizing
all of the potential interdependencies between these histone
modifications in a context-dependent manner, which has been
termed “the histone code,” will be one of the great challenges
to modern biology. However, in general, histone lysine acetylation is associated with transcriptional activation (16). Lysine
acetylation neutralizes the positively charged side chain on
these residues and disrupts the electrostatic interactions with
the negatively charged phosphate backbone of DNA (16). The
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resulting rearrangement in the spatial relationship between the
nucleosome and DNA allows transcription factors access to
cis-regulatory elements and initiation of the transcriptional
cascade (16; Fig. 1). The opposing enzymes that regulate
histone acetylation are histone acetyltransferases (HATs) and
histone deacetylases (HDACs). As their names suggest, HATs
catalyze the addition of acetyl groups to lysine residues, while
HDACs remove them (22). As such, HATs are generally seen
as transcriptional coactivators, while HDACs are considered
transcriptional corepressors. It is thought that a balance in
HAT/HDAC activity at a given promoter determines the level
of histone acetylation and therefore transcription (22). Therefore, understanding the regulation of these enzymes is requisite
to understanding regulated gene expression. While there is a
scarcity of information on HATs, a growing body of evidence
suggests that HDACs, in particular the class IIa subfamily of
HDACs, play a fundamental role in skeletal muscle physiology.
THE CLASS IIa HDACa AND SKELETAL MUSCLE
The class IIa HDACs consist of HDAC4, 5, 7, and 9 and
although ubiquitously expressed, they are enriched in striated
muscle (22). These HDACs function by associating with the
myocyte enhancer factor 2 (MEF2) family of transcription
factors to repress MEF2 dependent transcription (19). The
class IIa HDACs themselves do not possess intrinsic HDAC
activity, but instead recruit a larger repressive complex that
contains HDAC3 for this purpose (11). Whole body knockout
of individual class IIa HDAC isoforms in mice produces
phenotypes related to skeletogenesis (HDAC4; 39), endothelial
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Fig. 1. Histone modifications regulate transcription. Unmodified histones (top) result in a tight interaction with DNA at gene regulatory promoter and coding
regions that mediates transcriptional repression. Histone acetylation (bottom) is one modification that disrupts this interaction, exposing promoter and coding
regions to transcriptional regulators, including RNA polymerase (Pol II) and the various isoforms of the basal transcription factors (TFIIs), which results in
transcriptional activation.
Review
260
HISTONES AND EXERCISE
REGULATION OF THE CLASS IIa HDACs
At present, two main regulatory mechanisms are thought to
govern class IIa HDAC function. The best characterized is
phosphorylation-dependent nuclear export. This mechanism is
initiated when the class IIa HDACs are phosphorylated on
multiple serine residues (21). These phosphate groups serve as
docking domains for the 14 –3-3 family of chaperone proteins,
which export the HDAC out of the nucleus via a CRM-1mediated mechanism (21). When first identified, this was
thought to be a calcium-dependent mechanism, but subsequent
identification of multiple class IIa HDACs has established that
this mechanism is also sensitive to perturbed energy balance
and oxidative stress. Kinases that are known to mediate HDAC
nuclear export include the calcium-calmodulin-dependent protein kinases 1, 2, and 4 (CaMKI, II, IV; 2, 21), protein kinase
D (PKD; 6, 14), the AMP-activated protein kinase (AMPK;
26), and the AMPK related kinases, salt inducible kinase
(SIK1; 3, 37) and Mark2 (6). Exercise is known to activate
some of these kinases in skeletal muscle, suggesting that
phosphorylation-dependent class IIa HDAC nuclear export
could be a mechanism mediating muscle adaptation to exercise. The second regulatory mechanism controlling class IIa
HDAC function is through ubiquitin-mediated proteasomal
degradation. This process involves an E3 ubiquitin ligase
attaching ubiquitin peptides to the HDAC, which then tags this
protein for degradation by the proteasome (31). While this
mechanism has not been extensively studied and the relevant
E3 ubiquitin ligase has not yet been identified (31), it has been
suggested to control skeletal muscle fiber type. Both of these
regulatory mechanisms are thought to reduce the amount of
functional HDAC at a promoter region, which would shift the
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balance of enzymatic activity toward HATs and transcriptional
activation.
HISTONES, HDACs, AND MUSCLE PLASTICITY
As reviewed recently (1), epigenetic modifications have
been implicated in the regulation of muscle development and in
the adaptive responses of mature skeletal muscle to alterations
in activity. In cultured, adult skeletal muscle fibers, electrical
stimulation at 10 Hz, to mimic slow-twitch fiber activity,
resulted in translocation of HDAC4, but not HDAC5, from the
nuclear fraction to the cytoplasm (17, 35). This was associated
with increased CaMKII activation and MEF2 transcriptional
activity and the HDAC4 translocation in response to electrical
stimulation was abolished by the CaMK inhibitor KN-62 (17).
Caffeine, which increases sarcoplasmic reticulum Ca2⫹ release
and activates CaMK, induces HDAC5 efflux from the nucleus
and histone hyperacetylation at the MEF2 site of the GLUT4
promoter in C2C12 myocytes (29). Again, these effects were
completely abolished in the presence of CaMK inhibitors.
Reduced neuromuscular activity, as occurs with denervation,
has been shown to increase the nuclear abundance of HDAC4
and alter the expression of genes encoding myogenic factors
and the acetylcholine receptor (8, 9). These authors observed
expression of both HDAC4 and CaMKII at the neuromuscular
junction and hypothesized that HDAC4 could act as a “sensor”
of local neuromuscular activity (8). HDAC9 also appears to be
regulated by neuromuscular activity and influences chromatin
acetylation and the expression of activity-responsive genes
(28). Finally, recent work from Baldwin and colleagues has
demonstrated that histone H3 acetylation and methylation are
linked to the expression of myosin heavy chain (MHC) genes
under normal conditions and the altered expression of type I,
IIx, and IIb MHC genes in soleus muscle during hindlimb
suspension, a model of reduced muscular activity (30).
HISTONE MODIFICATIONS AND EXERCISE
Our interest in examining the role of histone modifications in
the skeletal muscle adaptation to exercise arose from our
observation that a single bout of exercise increased GLUT4
gene expression in human skeletal muscle (15). The logical
extension to histone modifications came from studies demonstrating the importance of MEF2 for skeletal muscle GLUT4
expression (38) and the regulatory interactions between MEF2
and the class II HDAC5 (10). We observed that a single bout
of exercise reduced nuclear HDAC5 abundance and MEF2associated HDAC5 in human skeletal muscle (24; Fig. 2),
changes that were associated with increased MEF2 DNAbinding activity (26) and GLUT4 mRNA (24). In a subsequent
study, we observed reductions in the nuclear abundance of both
HDAC4 and HDAC5 following exercise (23). This was associated with an increase in global H3 acetylation at lysine 36, a
site linked with transcriptional elongation, but no change in
global H3 acetylation at lysine residues 9 and 14, modifications
that have been linked with transcriptional initiation. However,
this does not rule out these acetylation sites as being important
in the adaptive response to exercise, as global acetylation
patterns might not reflect promoter-specific acetylation. Future
studies need to examine such changes on histones associated
with the promoter regions of specific genes to gain a more
complete understanding of how exercise may differentially
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dysfunction (HDAC7; 7), and exacerbated cardiac hypertrophy
(HDAC5 and 9; 5). However, the class IIa HDACs appear to
have redundant roles in regulating muscle gene expression, as
an increase in the proportion of type I oxidative fibers is
observed only when any two class IIa HDACs are ablated in
skeletal muscle (31). This suggests that the class IIa HDACs
play a fundamental role in muscle phenotype by repressing a
program of oxidative genes. Indeed, some of the genes that are
thought to be regulated by the class IIa HDACs include
peroxisome proliferator activated receptor gamma coactivator
1␣ (PGC-1␣), carnitine palmitoyltransferase 1 (CPT-1), medium chain acyl-CoA dehydrogenase (MCAD), hexokinase II
(HKII), glycogen phosphorylase, and ATP synthase ␤ (10). As
an increase in the expression of many of these oxidative genes
in skeletal muscle is a common response following exercise,
this raises the possibility that the class IIa HDACs could play
a role in skeletal muscle adaptations to exercise. Indeed, this
question has been tested in Eric Olson’s (31) laboratory, where
they examined muscle fiber type transitions in response to 4 wk
of exercise training in wild-type mice or mice overexpressing
HDAC5 in an inducible manner. These experiments showed
that an increase in skeletal muscle HDAC5 was sufficient to
impair the increase in type I oxidative fibers following exercise
training (31). Although fiber type transitions are not often
observed in human training studies, these data provide genetic
evidence to suggest that regulation of the class IIa HDACs
could be important in controlling gene expression responses to
exercise.
Review
HISTONES AND EXERCISE
affect transcription within skeletal muscle. In addition, more
frequent sampling may be required to further assess the temporal relationships between various histone modifications and
activity-induced alterations in gene transcription.
As discussed in previous sections, the nuclear export of class
II HDACs 4 and 5 occurs after their phosphorylation by
upstream kinases. There are well described links between
HDAC4 and CaMKII (2, 6, 9) and exercise increases both
CaMKII activity and phosphorylation (23, 32). Furthermore,
activation of CaMKII appears to be critical for histone hyperacetylation and increased MEF2 binding to the GLUT4 gene
after swimming in rats (36). HDAC5 is not thought to be a
direct target of CaMKII, but may gain responsiveness to this
kinase via oligermization with HDAC4 (2). Of note, we have
observed nuclear export of both HDAC4 and 5 in human
skeletal muscle after exercise (23). In relation to exercise
adaptations, another potentially important HDAC kinase is
AMPK, which increases in nuclear abundance (25) and activation (23) in human skeletal muscle following exercise. We
undertook a number of cell-based experiments and demonstrated that AMPK is indeed an HDAC5 kinase and increases
GLUT4 transcription via this mechanism (27). Thus both
CaMKII and AMPK may be involved in the regulation of
nuclear HDAC4 and 5 levels and histone acetylation during
exercise (23). Any interplay between these kinases in targeting
the class IIa HDACs during exercise could be dependent on a
number of factors, including exercise mode, intensity, and
duration. However, it appears that activation of any one kinase
is sufficient for class IIa HDAC derepression, resulting in the
potential for redundancy between these two kinases. It should
also be noted that exercise fails to increase the activity of other
Fig. 3. Histone modifications regulate transcription in response to exercise. Increases in the AMP:ATP ratio and intracellular calcium concentration activate
AMPK and CaMKII, which in turn phosphorylate the class IIa HDACs, resulting in their nuclear export. In addition, through as yet unidentified mechanisms,
class IIa HDAC ubiquitination by an E3 ubiquitin ligase results in HDAC degradation by the proteasome. Both of these class IIa HDAC regulatory mechanisms
increase histone acetylation around MEF2-dependent genes and activation of MEF2 dependent transcription.
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Fig. 2. MEF2-associated HDAC5 in human skeletal muscle nuclear extracts
obtained before (Rest) and after (60 min) of exercise at 74% V̇O2peak in
untrained men. Values are calculated as fold changes relative to rest and are
reported as means ⫾ SE (n ⫽ 7). #Different from Rest, P ⬍ 0.01. Reproduced
from McGee and Hargreaves (24) by permission of the American Diabetes
Association. Copyright 2004 American Diabetes Association.
261
Review
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HISTONES AND EXERCISE
9.
10.
11.
12.
13.
14.
SUMMARY
Post-translational modifications (acetylation, methylation,
phosphorylation) of histone proteins within chromatin are
important in the regulation of gene expression. It is likely that
exercise results in numerous such modifications, which mediate exercise-induced alterations in gene expression. For example, hyperacetylation of some histone residues, secondary to
nuclear export of the class II HDACs 4 and 5 following
phosphorylation by CaMKII and/or AMPK, is associated with
increased skeletal muscle GLUT4 expression following exercise. Unraveling the complexities of the so-called “histone
code” before and after exercise is challenging, but likely to
lead to a greater understanding of the regulation of exercise/
activity-induced alterations in skeletal muscle gene expression
and reinforce the importance of skeletal muscle plasticity in
health and disease.
15.
16.
17.
18.
19.
20.
21.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
22.
23.
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