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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

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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A model for MEF2 activation in myotonic muscles. CLC-1 chloride channels...
A model for MEF2 activation in myotonic muscles. CLC-1 chloride channels stabilize membrane potential in normal myofibers. In myotonic myofibers, membrane destabilization causes activation of the stress-responsive p38 MAPK, which is a known activator of MEF2. MEF2 activation in myotonic muscles also correlates with severe deficiency of class II HDACs, which function as repressors of MEF2-dependent gene expression. We propose that activated MEF2 is responsible for altered gene expression profiles in myotonic myofibers (shift toward oxidative phenotype and hypertrophy). Calcineurin and CaMK have previously been shown to activate MEF2. In vitro assays for calcineurin and CaMK showed no change of total enzymatic activities in myotonic muscles (data not shown); however, such assays do not measure potential differences in enzyme activation in vivo. Further in vivo experiments will define the roles of these signaling molecules in regulating gene expression in myotonic muscles. Other calcium-independent signaling pathways might also be responsible for the long-term changes of gene expression patterns in myotonic muscles. DHPR, dihydropyridine receptor; RyR, ryanodine receptor; T-tubule, transverse tubule; SR, sarcoplasmic reticulum.