Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction
Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction
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DOI：
10.1073/pnas.1220068110
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发表时间：
2013-05-28
影响因子：
11.1
通讯作者：
Voss, Andrew A.
中科院分区：
文献类型：
--
作者：
Waters, Christopher W.;Varuzhanyan, Grigor;Voss, Andrew A.
亨廷顿病是一种进行性和致命的遗传性疾病，具有使人衰弱的运动和认知缺陷。舞蹈症、僵硬、肌张力障碍和肌无力是该疾病的特征性运动缺陷，通常归因于中枢神经变性。然而，以前的研究还没有检查过控制亨廷顿病肌肉收缩的膜特性。我们显示了来自亨廷顿病R6/2转基因小鼠模型的离体成人骨骼肌的主要缺陷。患病纤维中的动作电位比WT同窝仔的纤维更容易触发和延长。此外，患病纤维中的一些动作电位会自我触发。这些缺陷的发生是由于静息氯离子和钾离子电导的降低。与此相一致，肌肉氯离子通道ClC-1在亨廷顿病肌肉中的表达受到不适当剪接和总Clcn 1（ClC-1基因）mRNA相应减少的损害。此外，总Kcnj 2（Kir2.1钾通道基因）mRNA在患病肌肉中减少。由此产生的肌肉过度兴奋引起不自主的和延长的收缩，这可能导致舞蹈病、僵硬和肌张力障碍，这些都是亨廷顿病的特征。
Huntington disease is a progressive and fatal genetic disorder with debilitating motor and cognitive defects. Chorea, rigidity, dystonia, and muscle weakness are characteristic motor defects of the disease that are commonly attributed to central neurodegeneration. However, no previous study has examined the membrane properties that control contraction in Huntington disease muscle. We show primary defects in ex vivo adult skeletal muscle from the R6/2 transgenic mouse model of Huntington disease. Action potentials in diseased fibers are more easily triggered and prolonged than in fibers from WT littermates. Furthermore, some action potentials in the diseased fibers self-trigger. These defects occur because of decreases in the resting chloride and potassium conductances. Consistent with this, the expression of the muscle chloride channel, ClC-1, in Huntington disease muscle was compromised by improper splicing and a corresponding reduction in total Clcn1 (gene for ClC-1) mRNA. Additionally, the total Kcnj2 (gene for the Kir2.1 potassium channel) mRNA was reduced in disease muscle. The resulting muscle hyperexcitability causes involuntary and prolonged contractions that may contribute to the chorea, rigidity, and dystonia that characterize Huntington disease.