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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 2

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Activation of MEF2 in myotonic skeletal muscles. Soleus (SOL), PLA, EDL,...
Activation of MEF2 in myotonic skeletal muscles. Soleus (SOL), PLA, EDL, and WV muscles were dissected from the hind limbs of MEF2 indicator mice that also carry different alleles of the CLCN1 gene, including wild-type alleles (+/+) and heterozygous (+/–) and homozygous (–/–) mutant CLCN1 alleles. Muscles were fixed and stained for β-galactosidase activity. The distribution of β-galactosidase appeared to be uniform along the myofibers. Note that the MEF2-lacZ transgene is specifically activated in PLA, EDL, and WV muscles of the homozygous mutant (×20 magnification; scale bar = 1 mm).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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