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Clinical and Experimental Pharmacology and Physiology (2006) 33, 395–399

McGee Publishing,
Symposium Ltd.

Proceedings of the Australian Physiological Society Symposium: Integrative Aspects

and M gene

of Human Muscle Performance



Sean L McGee and Mark Hargreaves

Department of Physiology, University of Melbourne, Victoria, Australia


1. Skeletal muscle is a highly plastic tissue that has a remark-
Because of its large mass and intrinsic oxidative capacity, the skeletal
able ability to adapt to external demands, such as exercise. Many
muscle is considered an important tissue in maintaining normal
of these adaptations can be explained by changes in skeletal
whole-body metabolism and energy homeostasis. Defects in skeletal
muscle gene expression. A single bout of exercise is sufficient to
muscle function have been linked to diseases such as insulin
induce the expression of some metabolic genes. We have focused
resistance1 and type 2 diabetes.2 Skeletal muscle is a highly plastic
our attention on the regulation of glucose transporter isoform 4
tissue that has a remarkable ability to adapt to external demands,
(GLUT-4) expression in human skeletal muscle.
such as exercise. Regular aerobic exercise is associated with enhanced
2. Glucose transporter isoform 4 gene expression is increased
skeletal muscle oxidative capacity3 and insulin sensitivity.4 These
immediately following a single bout of exercise, and the GLUT-4
alterations in skeletal muscle metabolism can be explained in part by
enhancer factor (GEF) and myocyte enhancer factor 2 (MEF2)
changes in the expression of an array of metabolic genes. Consequently,
transcription factors are required for this response. Glucose
much research of late has sought to examine the molecular mech-
transporter isoform enhancer factor and MEF2 DNA binding
anisms mediating exercise-induced gene expression. An exercise
activities are increased following exercise, and the molecular
responsive gene that has received considerable attention is the
mechanisms regulating MEF2 in exercising human skeletal
glucose transporter isoform 4 (GLUT-4) gene. This gene encodes
muscle have also been examined.
an insulin-regulated glucose transporter that is highly expressed in
3. These studies find possible roles for histone deacetylase
skeletal muscle and adipose tissue.5 Glucose transporter isoform 4
5 (HDAC5), adenosine monophosphate–activated protein kinase
gene expression is increased in the skeletal muscle immediately follow-
(AMPK), peroxisome proliferator-activated receptor gamma
ing a single bout of exercise.6,7 Increasing the expression of this gene
coactivator 1α α (PGC-1α α) and p38 mitogen-activated protein
is of particular interest, as overexpression of GLUT-4 exclusively in
kinase (MAPK) in regulating MEF2 through a series of complex
the skeletal muscle improves whole-body insulin action and glucose
interactions potentially involving MEF2 repression, coactivation
homeostasis.8,9 This phenomenon occurs despite the fact that GLUT-4
and phosphorylation.
expression is not compromised in diabetic skeletal muscle.10,11
4. Given that MEF2 is a transcription factor required for many
This suggests that increasing GLUT-4 in skeletal muscle could be
exercise responsive genes, it is possible that these mechanisms are
an effective therapy in the treatment and management of disease
responsible for regulating the expression of a variety of metabolic
states such as insulin resistance and type 2 diabetes.
genes during exercise. These mechanisms could also provide targets
for the treatment and management of metabolic disease states, such
as obesity and type 2 diabetes, which are characterized by mito- REGULATION OF THE GLUCOSE
chondrial dysfunction and insulin resistance in skeletal muscle. TRANSPORTER ISOFORM 4 GENE
Key words: exercise, gene expression, GLUT-4, histone
From transgenic studies, it has been established that two conserved
deacetylase 5, myocyte enhancer factor 2.
regions on the GLUT-4 promoter are required for normal GLUT-4
expression in the skeletal muscle. The first proximal region contains
a binding site for the myocyte enhancer factor 2 (MEF2) transcrip-
Correspondence: Mark Hargreaves, Department of Physiology, University of tion factor between base pairs −463 and −473.12 Further studies suggest
Melbourne, Victoria 3010, Australia. Email: that a MEF2A/D heterodimer is required to bind to this site for
Presented at the AuPS (AHMRC) Symposium Integrative Aspects of GLUT-4 expression.13 The second more distal region, termed domain
Human Muscle Performance, November 2004. The papers in these proceed-
1, contains a binding domain for the newly identified GLUT-4 enhancer
ings were peer reviewed under the supervision of the AuPS editor. The papers
are being published with the permission of AuPS and were initially published factor (GEF) transcription factor between base pairs −712 and −742.14
on the AuPS website Disruption of either of these binding sites results in reduced GLUT-4
Received 3 November 2005; accepted 8 November 2005. expression. A recent study has also found that MEF2 and GEF
396 SL McGee and M Hargreaves

List of abbreviations:

AMPK Adenosine monophosphate-activated protein kinase MAPK Mitogen-activated protein kinase

CaMKIV Calcium/calmodulin-dependent protein kinase IV MEF2 Myocyte enhancer factor 2
CRM1 Chromosome region maintenance 1 NFAT Nuclear factor of activated T cells
GEF GLUT-4 enhancer factor NRF1 Nuclear respiratory factor 1
GLUT-4 Glucose transporter isoform 4 PGC-1α Peroxisome proliferator-activated
HAT Histone acetyl transferase receptor gamma coactivator 1α
HDAC Histone deacetylase TAD Transcriptional activation domain

physically interact to regulate the GLUT-4 gene.15 As a single bout human skeletal muscle after exercise.23 Following 60 min of cycling,
of exercise increases GLUT-4 gene expression, the effect of exercise HDAC5 association with MEF2 was reduced, as assessed through
on the DNA binding activities of both MEF2 and GEF in skeletal co-immunoprecipitation on nuclear extracts from skeletal muscle
muscle of human subjects following 60 min of cycling was exam- biopsies. This was associated with a decrease in nuclear HDAC5,
ined. Using electrophoretic mobility shift assays on nuclear extracts with no change in whole-cell HDAC5, suggesting that HDAC5 was
from these samples, it was found that MEF2 and GEF DNA binding exported from the nucleus. From these data, it appears that HDAC5
activity was increased (P < 0.05) 1.6- and 1.4-fold, respectively.16 indeed regulates MEF2 during exercise in human skeletal muscle.
These results suggest that both MEF2 and GEF are important in However, it appears that the putative HDAC5 kinase, CaMKIV, is
mediating the GLUT-4 response to exercise and that identifying the not expressed in human skeletal muscle.23,24 Furthermore, pharmaco-
upstream regulators of these transcription factors could be essential logical inhibition of the CaMK pathways in cardiac myocytes does
in understanding GLUT-4 regulation. As GEF has only recently been not inhibit the HDAC5–MEF2 regulatory mechanism,25 suggesting
discovered, very little is known of its regulation. However, MEF2 that HDAC5 could have multiple upstream kinases. This is supported
regulation has been well characterized because of its role in myocyte by studies showing that broad-specificity kinase inhibitors are
differentiation and T-cell proliferation. The MEF2 family of tran- required to totally block HDAC5 phosphorylation.25 However, a
scription factors consists of four isoforms termed A, B, C and D and, potential HDAC5 kinase could be the adenosine monophosphate–
with the exception of MEF2B, are highly expressed in mature activated protein kinase (AMPK), which was recently observed to
skeletal muscle.17 All MEF2 isoforms contain a MADS domain and translocate to the nucleus during exercise.26
MEF2 domain, found towards the amino terminus that mediates Adenosine monophosphate–activated protein kinase is a heterot-
DNA binding and cofactor interactions and a transcriptional activa- rimer that is activated by decreases in the adenosine triphosphate/
tion domain (TAD) towards the carboxyl terminus.17 From a variety adenosine triphosphate (ATP/AMP) ratio through allosteric mecha-
of studies in various different cell types and systems, it appears that nisms and by phosphorylation of Thr172 on its α subunit by
MEF2 regulation is a complex balance between corepression, coac- upstream kinases.27 Exercise of intensities greater than approxi-
tivation and phosphorylation. mately 60% of VO2peak activates AMPK in human skeletal muscle.28
Activation of AMPK has been implicated in the regulation of glucose
uptake, fatty acid oxidation and gene expression.27 Furthermore,
pharmacological activation of AMPK using AICAR is associated
with increased GLUT-4 expression.29–31
In the basal state, MEF2 is associated with the class II histone Given that CaMKIV and AMPK share similar substrate specifi-
deacetylase (HDAC) transcriptional repressors, which include iso- cities, the ability of AMPK to phosphorylate HDAC5 was examined.
forms 4, 5, 7 and 9.18 Despite interacting with the MEF2 DNA bind- Incubating HDAC5 immunoprecipitated from human skeletal
ing domains, HDAC repressors do not inhibit MEF2 DNA binding, muscle with isolated AMPK in the presence of radiolabelled ATP
nor directly bind DNA themselves. Rather, HDACs inhibit transcrip- resulted in HDAC5 phosphorylation (S McGee, K Howlett and
tion by deacetylating lysine side chains on chromatin-forming M Hargreaves, unpubl. obs.). This suggests that AMPK could phos-
histones.18 In the deacetylated state, positively charged histone tails phorylate HDAC5 during exercise, although it is possible that other
interact with the negatively charged DNA phosphate backbone. This kinases are also involved and that AMPK could regulate the GLUT-
close, electrostatic interaction physically restricts the access of 4 gene through regulation of HDAC5–MEF2 interactions.
transcriptional activators to DNA, thereby inhibiting transcription.19
Histone acetylation reverses this situation, thereby allowing transcrip-
tion to proceed. Although MEF2 and the HDAC are physically
associated, MEF2-mediated transcription is inhibited.20 Dissociation
of the HDAC from MEF2 occurs following HDAC phosphorylation.20 Following HDAC5 dissociation, the acetylation state of chromatin
In cardiac myocytes, the calcium/calmodulin-dependent protein surrounding MEF2 must be reversed for transcription to proceed.18
kinase IV (CaMKIV) phosphorylates HDAC5 on serines 259 and This process requires coactivators with intrinsic histone acetyl
498, which dissociates HDAC5 from MEF2 and provides binding transferase (HAT) activity to be recruited to MEF2.19 Work in T cells
sites for the 14-3-3 chaperone protein that results in HDAC5 nuclear has established that the calcineurin/nuclear factor of activated
export21 via a chromosome region maintenance 1 (CRM1)-dependent T-cell (NFAT) pathway, which is also present in skeletal muscle, could
mechanism.22 mediate this response.18 Calcineurin is a calcium/calmodulin phos-
Given the importance of MEF2 in the expression of GLUT-4 and phatase that dephosphorylates NFAT, which unmasks a nuclear
other exercise-responsive genes, this mechanism was examined in localization sequence and results in NFAT nuclear translocation.32
Exercise-induced gene expression 397

Fig. 1 Schematic diagram of the pro-

posed regulation of myocyte enhancer
factor 2 (MEF2) in contracting human
skeletal muscle. At rest, MEF2 is
associated with histone deacetylase
5 (HDAC5), which renders MEF2
transcriptionally inactive. During
exercise, phosphorylation of HDAC5
by adenosine monophosphate–activated
protein kinase (AMPK) results in the
dissociation from MEF2 and nuclear
export. Peroxisome proliferator–
activated receptor gamma coactivator
1α (PGC-1α) associates with MEF2
presumably to recruit cofactors with
HAT activity to MEF2. Exercise in-
creases nuclear p38 phosphorylation
and association with MEF2. Myocyte
enhancer factor 2 is phosphorylated on
various threonine residues in a mitogen-
activated protein kinase (MAPK)
sequence specific manner. These
events result in enhanced MEF2
transcriptional activity.

Once inside the nucleus, NFAT is able to recruit coactivators with which is thought to be involved in the transcriptional response to
intrinsic HAT activity to MEF2.18 Although it is not clear if exercise exercise, as overexpression of PGC-1α increases mitochondrial
activates the calcineurin pathway, calcineurin has been implicated biogenesis in cardiac muscle37 and slow-twitch fibre formation
in converting skeletal muscle fibre type to a slow twitch, oxidative in skeletal muscle,38 both of which are key adaptations to exercise.
phenotype following prolonged muscle contraction.33 Although exercise increases PGC-1α expression39 in the acute
To investigate the role of the calcineurin pathway in the regulation setting, PGC-1α regulates transcription by recruiting coactivators
of MEF2 and the GLUT-4 gene during exercise, the nuclear abun- with intrinsic HAT activity to transcription factors such as the
dance of NFATc1 (NFAT2), the most abundant isoform in skeletal nuclear respiratory factor 1 (NRF1) and MEF240 in a manner similar
muscle,34 was examined following 60 min of exercise in humans.23 to NFAT. In the basal state, PGC-1α is associated with a repressor
After exercise, the nuclear abundance of NFATc1 was unchanged protein. Dissociation from the repressor occurs following phos-
from resting levels. As the nuclear translocation of NFAT is the phorylation of PGC-1α by the p38 mitogen-activated protein kinase
rate-limiting step in this pathway, these data could suggest that the (MAPK).41 However, PGC-1α remains transcriptionally inactive
calcineurin/NFAT pathway is not involved in the acute regulation of until it docks with a transcription factor, which stimulates a con-
MEF2 during exercise. It should be noted, however, that other NFAT formational change in PGC-1α that provides docking domains for
isoforms could be involved. Nonetheless, it seems unlikely that this HAT proteins.42 This suggests that PGC-1α must physically associate
pathway is involved, as calcineurin is sensitive to low amplitude, long with MEF2 in order to regulate MEF2-dependent genes. This mech-
duration calcium transients,35 whereas muscle contraction elicits high anism has been examined in human skeletal muscle after exercise
amplitude, short duration calcium transients.36 using co-immunoprecipitation techniques.23 Following 60 min of
Another potential transcriptional coactivator expressed in skeletal exercise, MEF2-associated PGC-1α was increased 3.7-fold. This
muscle that could play a role in MEF2 regulation is the peroxisome occurred without any change in the nuclear or total abundance of
proliferator–activated receptor gamma coactivator 1α (PGC-1α), PGC-1α protein, although a 1.8-fold increase in the phosphorylation
398 SL McGee and M Hargreaves

of nuclear p38 MAPK was observed. Although not assessed in that 3. Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on
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lases. Proc. Natl Acad. Sci. USA 2000; 97: 4070–5.
they could provide therapeutic targets for the treatment and manage-
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