Wu Hai, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas 75390-9148, USA.
J Clin Invest. 2002 May;109(10):1327-33. doi: 10.1172/JCI15417.
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.
贝克尔综合征是一种由氯离子通道1基因（CLCN1）突变引起的隐性非营养不良性肌强直，其特征是收缩后肌肉松弛延迟。ADR（翻正反射发育停滞）小鼠是贝克尔综合征的动物模型。ADR肌强直动物的骨骼肌显示氧化纤维数量增加，缺乏糖酵解纤维以及肌肉肥大的迹象。通过将ADR肌强直小鼠与携带MEF2依赖性报告基因的小鼠杂交，我们发现MEF2的转录活性在肌强直肌肉中显著增强。MEF2转录活性的翻译后诱导与p38 MAPK的激活相关，且不影响MEF2与DNA的结合亲和力。抑制MEF2依赖性基因表达的II类组蛋白去乙酰化酶（HDACs）在肌强直小鼠的骨骼肌中表达显著降低。这些发现表明，II类HDAC缺乏和p38 MAPK激活的联合作用导致MEF2转录活性的强力上调，这有助于在肌强直骨骼肌中观察到的基因表达长期变化和纤维类型转变。这些发现为先天性肌强直的潜在治疗提供了新的分子靶点。
