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Activation of the MEF2 transcription factor in skeletal muscles from myotonic mice
Hai Wu, Eric N. Olson
Hai Wu, Eric N. Olson
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1327-1333. https://doi.org/10.1172/JCI15417.
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Article Genetics

Activation of the MEF2 transcription factor in skeletal muscles from myotonic mice

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Abstract

Becker syndrome, a recessive nondystrophic myotonia caused by mutations in the chloride channel 1 gene (CLCN1), is characterized by delayed muscle relaxation after contraction. The ADR (arrested development of righting response) mouse is an animal model for Becker syndrome. Skeletal muscles from ADR myotonic animals show an increased number of oxidative fibers with a lack of glycolytic fibers as well as signs of muscle hypertrophy. Through breeding ADR myotonic mice with mice harboring a MEF2-dependent reporter gene, we found that the transcriptional activity of MEF2 was dramatically enhanced in myotonic muscles. Post-translational induction of MEF2 transcriptional activity correlated with the activation of p38 MAPK and did not affect MEF2 DNA-binding affinity. Expression of class II histone deacetylases (HDACs), which repress MEF2-dependent gene expression, was significantly reduced in skeletal muscles from myotonic mice. These findings suggest that the combined effects of class II HDAC deficiency and p38 MAPK activation lead to potent upregulation of MEF2 transcriptional activity, which contributes to the long-term changes in gene expression and fiber-type transformation observed in myotonic skeletal muscles. These findings provide new molecular targets for potential treatment of congenital myotonia.

Authors

Hai Wu, Eric N. Olson

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Figure 3

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Immunoblots and assays for DNA-binding of MEF2 using WV muscle extracts ...
Immunoblots and assays for DNA-binding of MEF2 using WV muscle extracts from mice with wild-type (+/+), heterozygous (+/–), and homozygous (–/–) mutant CLCN1 alleles. (a) Western blot analyses of β-galactosidase, major MEF2 isoforms (MEF2A, -2C, and -2D), myoglobin, active form of p38 MAPK (phospho-p38 MAPK), and total p38 MAPK. Tubulin blot showed equivalent loading of each lane. (b) Electrophoretic mobility shift assay of proteins extracted from WV muscles of different mice. The identity of the MEF2 protein-DNA complex (arrow) was confirmed by competition with 100-fold molar excess of unlabeled MEF2-binding oligonucleotides (competitor).
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