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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 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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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 10
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
“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
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
CaMKII activity is reduced in skeletal muscle during sepsis
Aversa, Z., Alamdari, N., Castillero, E., Muscaritoli, M., Fanelli, F. R., & Hasselgren, P.-O. J. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24469 · Cited by 6
“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…”
BackgroundXia, X.-H., Hu, Y., Xu, L., & Chen, T. (2014) · European Journal of Sport Science · doi:10.1080/17461391.2012.726652 · Cited by 7
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
“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
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
“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
Ye, M., Huang, C., Gu, Y., Lu, X., Zhu, T., & Zhang, Y. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2026.106529 · Cited by 2
Mechanism of Skeletal Muscle Contraction: Intracellular Signaling in Skeletal Muscle Contraction
Manabe, Y. (2016) · Springer eBooks · doi:10.1007/978-4-431-55720-3_10 · Cited by 2
Factors influencing brain recovery from stroke via possible epigenetic changes
Rroji, O., & Mucignat‐Caretta, C. (2024) · Future Science OA · doi:10.1080/20565623.2024.2409609 · Cited by 2
“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
Hevener, A. L., & Drew, B. G. (2013) · Springer eBooks · doi:10.1007/978-1-4614-8630-5_6 · Cited by 2
Keshishian, H., Many, G. M., Smith, G. R., Clark, N. M., Iyer, G. R., Hart, P., Lindholm, M. E., Montalvo, S., Zhang, Z., Jin, C. A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.04.705181 · Cited by 2
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Exercise, epigenetics, and aging
Chilton, W., Maier, M. C., Akinnibosun, O. A., O’Brien, B. J., & Charchar, F. J. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820682-9.00002-5 · Cited by 1
Epigenetics and Type 2 Diabetes
Ling, C., Rönn, T., & Nitert, M. D. (2011) · Springer eBooks · doi:10.1007/978-1-84882-644-1_9 · Cited by 1
Yonamine, C. Y. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2018.tde-21022018-172243 · Cited by 1
Regulation of skeletal muscle glucose transporter 4 expression in fructose-fed exercised rats
Goyaram, V. (2013) · Open University of Cape Town (University of Cape Town)
Metadata
- 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 › Physiology (medical) › 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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