Sei sulla pagina 1di 5

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

Blackwell
McGee Publishing,
Symposium Ltd.

Proceedings of the Australian Physiological Society Symposium: Integrative Aspects


SL
Exercise-induced
and M gene
Hargreaves
expression

of Human Muscle Performance

EXERCISE AND SKELETAL MUSCLE GLUCOSE TRANSPORTER 4


EXPRESSION: MOLECULAR MECHANISMS

Sean L McGee and Mark Hargreaves


Department of Physiology, University of Melbourne, Victoria, Australia

SUMMARY EXERCISE, SKELETAL MUSCLE AND GENE


EXPRESSION
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: m.hargreaves@unimelb.edu.au 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 http://www.aups.org.au. 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,
HISTONE DEACETYLASE 5 AND MYOCYTE
pharmacological activation of AMPK using AICAR is associated
ENHANCER FACTOR 2
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-
COACTIVATION OF MYOCYTE
tion to proceed. Although MEF2 and the HDAC are physically
ENHANCER FACTOR 2
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
study, this could suggest that PGC-1α was dissociated from its mitochondrial oxygen uptake and respiratory enzyme activity in skeletal
repressor protein. The association of PGC-1α with MEF2 could muscle. J. Biol. Chem. 1967; 242: 2278–82.
4. Mondon CE, Dolkas CB, Reaven GM. Site of enhanced insulin sensitivity
mediate the changes in chromatin acetylation state, which is required
in exercise-trained rats at rest. Am. J. Physiol. 1980; 239: E169 –77.
for active transcription. Indeed, dissociation of HDAC5 and 5. James DE, Strube M, Mueckler M. Molecular cloning and characteri-
association of PGC-1α with MEF2 was associated with an increase zation of an insulin-regulatable glucose transporter. Nature 1989; 338:
in GLUT-4 mRNA following exercise.23 83–7.
6. Neufer PD, Dohm GL. Exercise induces a transient increase in transcrip-
tion of the GLUT-4 gene in skeletal muscle. Am. J. Physiol. 1993; 265:
MYOCYTE ENHANCER FACTOR 2 C1597–603.
PHOSPHORYLATION 7. Kraniou Y, Cameron-Smith D, Misso M, Collier G, Hargreaves M.
Effects of exercise on GLUT-4 and glycogenin gene expression in
Although changes in chromatin acetylation state appear sufficient human skeletal muscle. J. Appl. Physiol. 2000; 88: 794–6.
to induce the transcription of some genes, phosphorylation of MEF2 8. Leturque A, Loizeau M, Vaulont S, Salminen M, Girard J. Improvement
on its TAD is able to dramatically increase the rate of MEF2-mediated of insulin action in diabetic transgenic mice selectively overexpressing
transcription.43 In vitro experiments have established that the p38 GLUT4 in skeletal muscle. Diabetes 1996; 45: 23–7.
MAPK is able to phosphorylate MEF2A on threonine residues 312 9. Ren JM, Marshall BA, Mueckler MM, McCaleb M, Amatruda JM,
Shulman GI. Overexpression of GLUT4 protein in muscle increases
and 319 located within the TAD, whereas MEF2A is in a heterodimer
basal and insulin-stimulated whole body glucose disposal in conscious
with MEF2D.43 This is notable as it has been suggested that the mice. J. Clin. Invest. 1995; 95: 429–32.
MEF2A/D heterodimer is required for GLUT-4 expression.13 10. Pedersen O, Bak JF, Andersen PH et al. Evidence against altered expres-
Exercise is associated with activation of p38 MAPK,44 and as stated sion of GLUT1 or GLUT4 in skeletal muscle of patients with obesity
previously, an increase in p38 MAPK phosphorylation has been or NIDDM. Diabetes 1990; 39: 865–70.
observed in nuclear extracts from human skeletal muscle following 11. Dela F, Ploug T, Handberg A et al. Physical training increases muscle
exercise.23 It has also been hypothesized that p38 MAPK could GLUT4 protein and mRNA in patients with NIDDM. Diabetes 1994;
43: 862–5.
participate in exercise-induced gene expression.45 Crystallographic
12. Thai MV, Guruswamy S, Cao KT, Pessin JE, Olson AL. Myocyte
studies have recently solved the docking domain necessary for enhancer factor 2 (MEF2)-binding site is required for GLUT4 gene
phosphorylation of MEF2A by p38.46 This interaction was assessed in expression in transgenic mice. Regulation of MEF2 DNA binding
human skeletal muscle after exercise. Using co-immunoprecipita- activity in insulin-deficient diabetes. J. Biol. Chem. 1998; 273: 14 285–
tion, exercise increased MEF2 associated p38 MAPK 2.5-fold and 92.
phosphorylated p38 MAPK twofold.23 Myocyte enhancer factor 2 13. Mora S, Pessin JE. The MEF2A isoform is required for striated muscle-
specific expression of the insulin-responsive GLUT4 glucose trans-
phosphorylation was also assessed following MEF2 immunoprecipita-
porter. J. Biol. Chem. 2000; 275: 16 323–8.
tion using a phospho-specific antibody that recognizes phosphorylated 14. Oshel K, Knight J, Cao K, Thai M, Olson A. Identification of a 30-base
threonine residues only when followed by a proline residue, similar pair regulatory element and novel DNA binding protein that regulates
to Thr312 and 319 on the MEF2 TAD. Using this method, it was the human GLUT4 promoter in transgeneic mice. J. Biol. Chem. 2000;
found that exercise was associated with an approximate 2.7-fold 275: 23 666–73.
increase in MEF2 thr-pro phosphorylation.23 Although it is difficult 15. Knight JB, Eyster CA, Griesel BA, Olson AL. Regulation of the human
to determine the effect of MEF2 phosphorylation on gene expression GLUT4 gene promoter: Interaction between a transcriptional activator
and myocyte enhancer factor 2A. Proc. Natl Acad. Sci. USA 2003; 100:
in exercising humans, these data could provide a link between p38
14 725–30.
MAPK and GLUT-4 gene expression through the regulation of MEF2. 16. McGee S, Spasling D, Olson AL, Hargreaves M. Exercise increases
MEF2- and GEF DNA binding activity in human skeletal muscle.
FASEB J 2006; 20: 348–9.
CONCLUSIONS 17. Black BL, Olson EN. Transcriptional control of muscle development
In summary, through analysis of MEF2 regulation, we propose by myocyte enhancer factor-2 (MEF2) proteins. Ann. Rev. Cell Dev.
a model of transcriptional regulation of GLUT-4 during exercise in Biol. 1998; 14: 167–96.
18. McKinsey TA, Zhang CL, Olson EN. MEF2: A calcium-dependent regu-
human skeletal muscle (Fig. 1) that involves derepression by HDAC5
lator of cell division, differentiation and death. Trends Biochem. Sci.
following HDAC5 phosphorylation by AMPK, coactivation by PGC- 2002; 27: 40–7.
1α and finally phosphorylation by p38 MAPK. As consensus MEF2 19. McKinsey TA, Zhang CL, Olson EN. Control of muscle development
binding domains are found on the promoter regions of many exercise by dueling HATs and HDACs. Curr. Opin. Genet. Dev. 2001; 11: 497–504.
responsive genes, it is possible that these same regulatory mechanisms 20. Lu J, McKinsey TA, Nicol RL, Olson EN. Signal-dependent activation
mediate many of the transcriptional responses to exercise. As such, of the MEF2 transcription factor by dissociation from histone deacety-
lases. Proc. Natl Acad. Sci. USA 2000; 97: 4070–5.
they could provide therapeutic targets for the treatment and manage-
21. McKinsey T, Zhang C, Olson E. Signal-dependent nuclear export of a
ment of metabolic diseases such as type 2 diabetes. histone deactylase regulates muscle differentiation. Nature 2000; 408:
106–11.
22. Kao HY, Verdel A, Tsai CC, Simon C, Juguilon H, Khochbin S. Mech-
REFERENCES anism for nucleocytoplasmic shuttling of histone deacetylase 7. J. Biol.
Chem. 2001; 276: 47 496–507.
1. Le Marchand-Brustel Y, Gremeaux T, Ballotti R, Van Obberghen E. 23. McGee SL, Hargreaves M. Exercise and myocyte enhancer factor 2 reg-
Insulin receptor tyrosine kinase is defective in skeletal muscle of insulin- ulation in human skeletal muscle. Diabetes. 2004; 53: 1208–14.
resistant obese mice. Nature 1985; 315: 676 – 9. 24. Rose AJ, Hargreaves M. Exercise increases Ca2+-calmodulin-dependent
2. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. protein kinase II activity in human skeletal muscle. J. Physiol. 2003;
Science 2005; 307: 384 –7. 553: 303–9.
Exercise-induced gene expression 399

25. McKinsey TA, Zhang CL, Olson EN. Signaling chromatin to make 36. Westerblad H, Allen DG, Bruton JD, Andrade FH, Lannergren J. Mech-
muscle. Curr. Opin. Cell Biol. 2002; 14: 763–72. anisms underlying the reduction of isometric force in skeletal muscle
26. McGee SL, Howlett KF, Starkie RL, Cameron-Smith D, Kemp BE, fatigue. Acta Physiol. Scand. 1998; 162: 253–60.
Hargreaves M. Exercise increases nuclear AMPK α(2) in human skeletal 37. Czubryt MP, McAnally J, Fishman GI, Olson EN. Regulation of per-
muscle. Diabetes 2003; 52: 926 – 8. oxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and
27. Kemp B, Mitchelhill K, Stapleton D, Michell B, Chen Z, Witters L. mitochondrial function by MEF2 and HDAC5. Proc. Natl Acad. Sci.
Dealing with energy demand: The AMP-activated protein kinase. TIBS USA 2003; 100: 1711–16.
1999; 24: 22–5. 38. Lin J, Wu H, Tarr PT et al. Transcriptional co-activator PGC-1 alpha
28. Chen ZP, Stephens TJ, Murthy S. et al. Effect of exercise intensity on drives the formation of slow-twitch muscle fibres. Nature 2002; 418:
skeletal muscle AMPK signaling in humans. Diabetes 2003; 52: 2205– 797–801.
12. 39. Baar K, Wende AR, Jones TE et al. Adaptations of skeletal muscle to
29. Holmes B, Kurth-Kraczek E, Winder W. Chronic activation of 5′ AMP- exercise: Rapid increase in the transcriptional coactivator PGC-1.
activated protein kinase increases GLUT4, hexokinase, and glycogen FASEB J 2002; 16: 1879–86.
in muscle. J. Appl. Physiol. 1999; 87: 1990 –5. 40. Knutti D, Kralli A. PGC-1, a versatile coactivator. Trends Endocrinol.
30. Holmes B, Zheng D, MacLean P, Olson A, Dohm G. AICAR increases Metab. 2001; 12: 360–5.
GLUT-4 mRNA transcription in denervated mouse skeletal muscle. 41. Knutti D, Kressler D, Kralli A. Regulation of the transcriptional
Diabetes 2001. coactivator PGC-1 via MAPK-sensitive interaction with a repressor.
31. Zheng D, MacLean PS, Pohnert SC et al. Regulation of muscle GLUT- Proc. Natl. Acad. Sci. USA 2001; 98: 9713–18.
4 transcription by AMP-activated protein kinase. J. Appl. Physiol. 2001; 41. Puigserver P, Adelmant G, Wu Z et al. Activation of PPAR γ coactivator-
91: 1073–83. 1 through transcription factor docking. Science 1999; 286: 1368 –71.
32. Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation 43. Zhao M, New L, Kravchenko VV et al. Regulation of the MEF2 family
by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17: 2205–32. of transcription factors by p38. Mol. Cell. Biol. 1999; 19: 21–30.
33. Kubis HP, Hanke N, Scheibe RJ, Meissner JD, Gros G. Ca2+-transients 44. Widegren U, Jiang XJ, Krook A et al. Divergent effects of exercise on
activate calcineurin/NFATc1 and initiate fast-to-slow transformation in metabolic and mitogenic signaling pathways in human skeletal muscle.
a primary skeletal muscle culture. Am. J. Physiol. Cell Physiol. 2003; FASEB 1998; 12: 1379–89.
285: C56–C63. 45. Widegren U, Ryder JW, Zierath JR. Mitogen-activated protein kinase
34. Olson EN, Williams RS. Remodeling muscles with calcineurin. signal transduction in skeletal muscle: Effects of exercise and muscle
Bioessays 2000; 22: 510 –19. contraction. Acta Physiol. Scand. 2001; 172: 227–38.
35. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation 46. Chang CI, Xu BE, Akella R, Cobb MH, Goldsmith EJ. Crystal struc-
of transcription factors induced by Ca2+ response amplitude and dura- tures of MAP kinase p38 complexed to the docking sites on its nuclear
tion. Nature 1997; 386: 855 – 8. substrate MEF2A and activator MKK3b. Mol. Cell 2002; 9: 1241–9.