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Updated: Jul 3, 2026
Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
CaMK activation during exercise is required for histone hyperacetylation and MEF2A binding at the MEF2 site on the
James A H Smith1, Tertius A Kohn, Ashley K Chetty
1Dept. of Human Biology, Univ. of Cape Town, Newlands, 7725 South Africa.
Abstract:
The role of CaMK II in regulating GLUT4 expression in response to intermittent exercise was investigated. Wistar rats completed 5 x 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 approximately 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.
Insights
Calcium-calmodulin-dependent protein kinase II (CaMK II) activation during exercise enhances glucose transporter type 4 (GLUT4) expression by facilitating MEF2A binding to the GLUT4 gene. Inhibiting CaMK II blocked these exercise-induced increases.
Area of Science:
- Molecular Biology
- Exercise Physiology
- Biochemistry
Background:
- Glucose transporter type 4 (GLUT4) is crucial for insulin-independent glucose uptake in muscle.
- Exercise is known to increase GLUT4 expression, but the underlying molecular mechanisms are not fully elucidated.
- Calcium signaling pathways, particularly involving CaMK II, are implicated in cellular responses to stimuli like exercise.
Purpose of the Study:
- To investigate the role of CaMK II in regulating GLUT4 expression following intermittent exercise.
- To determine if CaMK II activation influences the accessibility of transcription factors to the GLUT4 gene promoter.
- To examine the impact of CaMK II inhibition on exercise-induced changes in GLUT4 expression.
Main Methods:
- Wistar rats underwent intermittent swimming exercise.
- CaMK II activity was inhibited using KN93, with KN92 serving as a control.
- Muscle tissue was analyzed for CaMK II phosphorylation, histone acetylation, MEF2A binding via ChIP, and GLUT4 mRNA/protein levels via RT-PCR and Western blot.
Main Results:
- Exercise significantly increased CaMK II phosphorylation, histone H3 acetylation at the Glut4 MEF2 site, and MEF2A binding.
- GLUT4 mRNA and protein levels were elevated post-exercise.
- Administration of KN93 attenuated or abolished exercise-induced increases in CaMK II phosphorylation, histone acetylation, MEF2A binding, and GLUT4 expression.
Conclusions:
- Exercise-induced CaMK II activation is a key regulator of GLUT4 expression in skeletal muscle.
- CaMK II facilitates GLUT4 gene expression by enhancing the binding of MEF2A to its cis-element.
- Targeting CaMK II signaling may offer therapeutic potential for conditions involving impaired glucose metabolism.
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