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MEF2A Binding to the Glut4 Promoter Occurs via an AMPKα2-Dependent Mechanism


Medicine & Science in Sports & Exercise: August 2011 - Volume 43 - Issue 8 - p 1441-1450
doi: 10.1249/MSS.0b013e31820f6093
Basic Sciences

Purpose: The role of AMP-activated protein kinase α2 (AMPKα2) in regulating MEF2A nucleus translocation, nuclear histone deacetylase 5 (HDAC5) association with MEF2, HDAC5 nuclear export, MEF2A binding to the Glut4 promoter, and GLUT4 expression was investigated.

Methods: This was investigated in muscles from AMPKα2 overexpression (OE) mice, AMPKα2 knockout (KO) mice, and corresponding wild-type (WT) mice that had undertaken a 28-d program of treadmill training by: 1) AMPKα-Thr172 phosphorylation by Western blot, 2) total and nuclear MEF2A by Western blot, 3) nuclear HDAC5 association with MEF2 by coimmunoprecipitation, 4) total and nuclear HDAC5 by Western blot, 5) bound MEF2A at the Glut4 MEF2 cis-element by chromatin immunoprecipitation, and 6) GLUT4 expression by real-time polymerase chain reaction and Western blot.

Results: OE or KO of AMPKα2 isoform heightened or attenuated the training-induced increase in nuclear MEF2A content, Glut4 promoter-bound MEF2A. However, OE or KO of the AMPKα2 isoform did not have any effect on the content of nuclear HDAC5 association with MEF2 after 28 d of exercise training, although 35% lower nuclear HDAC5 protein content was found in α2-OE training muscles. Lastly, OE of the α2-isoform was associated with 120% and 155% higher GLUT4 protein and mRNA in training muscles. However, the training-induced increases of GLUT4 protein and mRNA contents were normal in α2-KO muscles despite the reduced AMPK signaling.

Conclusions: Exercise training increases the nuclear MEF2A content and binding of MEF2A to their binding sites on the Glut4 gene by an AMPKα2-dependent mechanism, but intracellular signaling molecules other than AMPKα2 are important in regulating training-induced HDAC5 nuclear export. Furthermore, although AMPKα2 mediates the training-induced increase in Glut4 promoter-bound MEF2A, the present data do not support an essential role of AMPKα2 in regulating training-induced GLUT4 expression in skeletal muscle.

1Beijing Sport University, Beijing, CHINA; and 2Henan Scientific and Technical University, Luoyang, CHINA

Address for correspondence: Ying Zhang, Ph.D., Beijing Sport University, Beijing, 100084, China; E-mail:

Submitted for publication October 2010.

Accepted for publication January 2011.

©2011The American College of Sports Medicine