Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness
Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness
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DOI：
10.1172/jci32638
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发表时间：
2008-04-01
影响因子：
15.9
通讯作者：
Brown, Robert H., Jr.
中科院分区：
文献类型：
--
作者：
Hayward, Lawrence J.;Kim, Joanna S.;Brown, Robert H., Jr.
高钾性周期性麻痹（HyperKPP）会产生肌强直和运动后休息或K+摄入引发的肌无力发作。我们将与人类家族性HyperKPP突变（Met 1592 Val）相对应的错义取代引入编码骨骼肌电压门控Na+通道Na（v）1.4的小鼠基因中。与对照组相比，这种突变的杂合子小鼠在休息时表现出明显的肌强直和肌纤维类型转换为更氧化的表型。孤立的突变体伸趾长肌异常敏感的Na+/K+泵抑制剂哇巴因，并表现出年龄依赖性的变化，包括延迟松弛和改变生成的强直性力量。此外，当细胞外K+浓度从4 mM增加到10 mM时，诱导了分离的突变体肌肉的快速和持续的虚弱，这是在运动期间在人的肌肉组织中观察到的水平。突变体肌肉从刺激诱导的疲劳中恢复的速度比对照肌肉慢，并且在高细胞外K+水平的存在下恢复的程度降低。这些发现表明，小鼠肌肉中Met 1592 Val Na+通道的表达足以产生HyperKPP的重要特征，包括肌强直、K+敏感性麻痹和疲劳恢复期间对延迟性无力的易感性。
Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K+ ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na+ channel Na(v)1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fiber-type switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na+/K+ pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K+ concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, and the extent of recovery was decreased in the presence of high extracellular K+ levels. These findings demonstrate that expression of the Met1592Val Na+ channel in mouse muscle is sufficient to produce important features of HyperKPP, including myotonia, K+-sensitive paralysis, and susceptibility to delayed weakness during recovery from fatigue.