CaMK activation during exercise is required for histone hyperacetylation and MEF2A binding at the MEF2 site on the Glut4 gene
Abstract
The role of CaMK II in regulating GLUT4 expression in response to intermittent exercise was investigated. Wistar rats completed 5 × 17-min bouts of swimming after receiving 5 mg/kg KN93 (a CaMK II inhibitor), KN92 (an analog of KN93 that does not inhibit CaMK II), or an equivalent volume of vehicle. Triceps muscles that were harvested at 0, 6, or 18 h postexercise were assayed for 1) CaMK II phosphorylation by Western blot, 2) acetylation of histone H3 at the Glut4 MEF2 site by chromatin immunoprecipitation (ChIP) assay, 3) bound MEF2A at the Glut4 MEF2 cis-element by ChIP, and 4) GLUT4 expression by RT-PCR and Western blot. Compared with controls, exercise caused a twofold increase in CaMK II phosphorylation. Immunohistochemical stains indicated increased CaMK II phosphorylation in nuclear and perinuclear regions of the muscle fiber. Acetylation of histone H3 in the region surrounding the MEF2 binding site on the Glut4 gene and the amount of MEF2A that bind to the site increased approximately twofold postexercise. GLUT4 mRNA and protein increased ∼2.2- and 1.8-fold, respectively, after exercise. The exercise-induced increases in CaMK II phosphorylation, histone H3 acetylation, MEF2A binding, and GLUT4 expression were attenuated or abolished when KN93 was administered to rats prior to exercise. KN92 did not affect the increases in pCaMK II and GLUT4. These data support the hypothesis that CaMK II activation by exercise increases GLUT4 expression via increased accessibility of MEF2A to its cis-element on the gene.
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Active CaMK can increase the capacity for glucose uptake through upregulation of the glucose transporter GLUT4.
“Active CaMK can increase both the capacity for glucose uptake through upregulation of the glucose transporter GLUT4 [31]”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [31]
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“A rat muscle sample obtained from a previous published study was included to serve as control for the MHC IIb isoform on Western blots (Smith et al., 2008).”
MethodSelf-citationPhysical exercise and epigenetic modifications in skeletal muscle, brain, and heart
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Epigenetic regulation of skeletal muscle metabolism
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“Finally, to test the functional consequences of Perm1 overexpression on CaMKII downstream signaling, we assessed the effect of Perm1 on the activity of MEF2, a transcription factor that is activated by CaMKII [9,21].”
BackgroundKoh, J., Hancock, C. R., Han, D.-H., Holloszy, J. O., Nair, K. S., & Dasari, S. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00460.2018 · Cited by 39 · see citing works
Dynamic epigenetic responses to muscle contraction.
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Effect of exercise on DNA methylation and metabolism in human adipose tissue and skeletal muscle.
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MEF2A Binding to the Glut4 Promoter Occurs via an AMPKα2-Dependent Mechanism
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“ChIP assay has already been used to demonstrate the MEF2A binding into the SLC2A4 promoter in response to acute swimming exercise (32), and a calcium/calmodulindependent protein kinase II-dependent increase of histone H3 acetylation was proposed as involved in this response (33).”
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“CaMKII is activated by endurance training (38), and the suppression of MEF2-HDAC4/5 association induces an increase in slow-twitch muscle fibers (37).”
BackgroundBi, F., Gao, C., & Guo, H. (2024) · FASEB BioAdvances · doi:10.1096/fba.2024-00080 · Cited by 26 · see citing works
“For instance, researchers in a study using a rat swimming model observed an increase in H3K9/14 acetylation, which regulates GLUT4 at transcriptional level through action on its promoter, 162 further suggesting a protective role of exercise in heart.”
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The Role of Skeletal Muscle Estrogen Receptors in Metabolic Homeostasis and Insulin Sensitivity
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Yonamine, C. Y., Alves-Wagner, A. B., Esteves, J. V. D. C., Okamoto, M. M., Corrêa‐Giannella, M. L., Giannella‐Neto, D., & Machado, U. F. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.11.006 · Cited by 23 · see citing works
Effects of α-lipoic Acid on mtDNA Damage after Isolated Muscle Contractions
Fogarty, M., VITO, G. D., Hughes, C., Burke, G. A., BROWN, J. C., McEneny, J., Brown, D., McClean, C. M., & Davison, G. W. (2013) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e31828bf31e · Cited by 23 · see citing works
“Previous research has suggested that the oxidation of proteins or amino acids is more likely to occur during exercise lasting 60 min or more (29).”
BackgroundThe relevance of epigenetics to occlusive cerebral and peripheral arterial disease
Krishna, S. M., Trollope, A. F., & Golledge, J. (2015) · Clinical Science · doi:10.1042/cs20140491 · Cited by 22 · see citing works
Zhang, J., Tian, Z., Qin, C., & Momeni, M. R. (2024) · Human Cell · doi:10.1007/s13577-024-01057-y · Cited by 21 · see citing works
“It is of crucial importance to recognize that the phosphorylation of CaMKII appears to be a major component of histone overacetylation and amplified MEF2 binding to the GLUT4 gene in rats that have been engaging in swimming [90].”
Fan, R., Kong, J., Zhang, J., & Zhu, L. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1471642 · Cited by 22 · see citing works
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Mechanisms in Exercise-Induced Increase in Glucose Disposal in Skeletal Muscle
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Self-citationLiu, W., Xia, Y., Kuang, H., Wang, Z., Liu, S., Tang, C., & Yin, D. (2019) · Gerontology · doi:10.1159/000500742 · Cited by 16 · see citing works
Exercise, exerkines and exercise mimetic drugs: Molecular mechanisms and therapeutics
Samant, V., & Prabhu, A. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.123225 · Cited by 15 · see citing works
Exercise and DNA methylation in skeletal muscle
Sharples, A. P., & Seaborne, R. A. E. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816193-7.00010-5 · Cited by 14 · see citing works
Zhang, M., Wei, Y., Liu, Y., Guan, W. X., Zhang, X., Kong, J., Li, H., Yang, S., & Wang, H. (2019) · iScience · doi:10.1016/j.isci.2019.100766 · Cited by 15 · see citing works
Regulation of Mitochondrial Biogenesis and GLUT4 Expression by Exercise
Holloszy, J. O. (2011) · Comprehensive physiology · doi:10.1002/j.2040-4603.2011.tb00346.x · Cited by 14 · see citing works
Caffeine induces cardiomyocyte hypertrophy via p300 and CaMKII pathways
Shi, L., Xu, H., Wei, J., Ma, X., & Zhang, J. (2014) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2014.07.011 · Cited by 14 · see citing works
Esteves, J. V. D. C., Yonamine, C. Y., & Machado, U. F. (2020) · Biomarkers in Medicine · doi:10.2217/bmm-2019-0481 · Cited by 14 · see citing works
Role of Epigenetics in the Pathogenesis and Management of Type 2 Diabetes Mellitus
Yahaya, T. (2019) · Translation The University of Toledo Journal of Medical Sciences · doi:10.46570/utjms.vol6-2019-319 · Cited by 10 · see citing works
“Ca/calmodulin-dependent protein kinase (CaMK) may also modulate the MEF2 activity through histone acetylation after exercising for a short duration (70, 71).”
BackgroundEpigenetics of Glucose Metabolism and the Basis for T2DM Interventions
McLellan, K. C. P., Minoro, R., Sloan, L. A., & Carlos, R. (2013) · InTech eBooks · doi:10.5772/56507 · Cited by 10 · see citing works
“Ca++/Calmodulin dependent protein kinase (CaMK) also seems to modulate MEF activity via histone acetylation in response to acute exercise (Smith et al, 2008).”
BackgroundSuppression of the GLUT4 adaptive response to exercise in fructose-fed rats
Goyaram, V., Kohn, T. A., & Ojuka, E. O. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00342.2013 · Cited by 9 · see citing works
Self-citationGlobal scientific trends in research of epigenetic response to exercise: A bibliometric analysis
Wu, H., Hu, Y., Jiang, C. H., & Chen, C. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e25644 · Cited by 8 · see citing works
“Swimming activated H3K9/14 acetylation in muscle and regulated the transcriptional level of Glut4 and Mef2a [80], which mediated indirect cardiac reprogramming [81,82].”
BackgroundAre Cape Peninsula baboons raiding their way to obesity and type II diabetes? - a comparative study
Leith, D. A., Mpofu, B. S., van Velden, J. L., Reed, C., van Boom, K. M., Breed, D., & Kohn, T. A. (2020) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2020.110794 · Cited by 8 · see citing works
Self-citationEpigenetic Modulation of Gene Expression by Exercise
Goto, S., Kawakami, K., Naito, H., Katamoto, S., & Radák, Z. (2015) · Healthy ageing and longevity · doi:10.1007/978-3-319-14830-4_5 · Cited by 4 · see citing works
“The role of CaMKII activation in H3 hyperacetylation at the MEF2 binding site in the promoter region of GLUT4 was also suggested to be the mechanism by which GLUT4 expression is increased in skeletal muscle after intermittent swimming exercise in rats [20].”
BackgroundMiller, D. L., Greising, S. M., Douglas, E. F., & Call, J. A. (2025) · Physiological Reports · doi:10.14814/phy2.70612 · Cited by 6 · see citing works
Exercise-mediated increase in PGC1α and MEF2 expression in type 2 diabetes mellitus
Benite‐Ribeiro, S. A., Barbosa, H. C., Ramadan, W., & dos Santos, J. M. (2023) · Gene Reports · doi:10.1016/j.genrep.2023.101758 · Cited by 6 · see citing works
CaMKII activity is reduced in skeletal muscle during sepsis
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“Because CaMKII activity is increased in conditions characterized by muscle hypertrophy and stimulated mitochondrial biogenesis and function [Fluck et al., 2000b; Rose and Hargreaves, 2003; Rose et al., 2007; Smith et al., 2008], we hypothesized that sepsis, which is characterized by muscle wasting and reduced mitochon…”
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Caspers, M., Blocquiaux, S., Charlier, R., Knaeps, S., Lefevre, J., de Bock, K., & Thomis, M. (2018) · Twin Research and Human Genetics · doi:10.1017/thg.2018.10 · Cited by 6 · see citing works
“GLUT4 encodesaprotein that functions as an insulin-regulated glucose transporter and thus plays a role in the development of type 2 diabetes (Smith et al., 2008).”
Liu, S., Qi, R., Zhang, J., Zhang, C., Chen, L., Yao, Z., & Niu, W. (2022) · FEBS Letters · doi:10.1002/1873-3468.14428 · Cited by 5 · see citing works
Links between Exercise Capacity, Exercise Training, and Metabolism
Spagnolo, A., Klug, S., Schenkl, C., & Schwarzer, M. (2023) · Comprehensive physiology · doi:10.1002/j.2040-4603.2023.tb00283.x · Cited by 4 · see citing works
“Here, acetylation was found at Glut 4 promoter regions (356) and nuclear respiratory factor 1 (Nrf-1) and Mef2A (159), all relevant for metabolic regulation.”
Cadmium toxicity mediated by the inhibition of SLC2A4 expression in human proximal Tubule cells
Lee, J., Tokumoto, M., & Satoh, M. (2020) · The FASEB Journal · doi:10.1096/fj.202001871r · Cited by 4 · see citing works
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Mechanism of Skeletal Muscle Contraction: Intracellular Signaling in Skeletal Muscle Contraction
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Factors influencing brain recovery from stroke via possible epigenetic changes
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“GLUT4 transcription mediated by the MEF2 binding, after the exer cise, show ed hyperac etylation of hist one H3 at the MEF2 sit e. Aft er physical exercise the increase of GLUT4 mRNA was around tw ofold [ 142 ].”
BackgroundThe Impact of Estrogen Receptor α Expression in the Pathogenesis of the Metabolic Syndrome
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Exercise, epigenetics, and aging
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Epigenetics and Type 2 Diabetes
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- Authors
- Smith, J. A. H., Kohn, T. A., Chetty, A. K., & Ojuka, E. O.
- Affiliations
- University of Cape Town (ZA)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2008-09
- Volume
- 295
- Issue
- 3
- Pages
- E698-E704
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2165038103
- Cited by
- 115
- References
- 46
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 8 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 10 · 2019: 10 · 2018: 5 · 2017: 9 · 2016: 5 · 2015: 6 · 2014: 9 · 2013: 11 · 2012: 6
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- CaMKII, GLUT4, MEF2A, histone H3 acetylation, physical activity, muscle gene expression, KN-93, triceps brachii, transcriptional regulation, swimming training
- MeSH terms
- Acetylation, Animals, DNA, Enzyme Activation, Histones, Male, Phosphorylation, Physical Conditioning, Animal, Protein Binding, Blotting, Western, Rats, Wistar, Myogenic Regulatory Factors, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, MADS Domain Proteins, Glucose Transporter Type 4, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, MEF2 Transcription Factors
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