Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and.
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts.
Physiol Genomics. 2014 Jun 1;46(11):385-97. doi: 10.1152/physiolgenomics.00166.2013. Epub 2014 Apr 8.
Hyperkalemic periodic paralysis (HyperKPP) is characterized by myotonic discharges that occur between episodic attacks of paralysis. Individuals with HyperKPP rarely suffer respiratory distress even though diaphragm muscle expresses the same defective Na(+) channel isoform (NaV1.4) that causes symptoms in limb muscles. We tested the hypothesis that the extent of the HyperKPP phenotype (low force generation and shift toward oxidative type I and IIA fibers) in muscle is a function of 1) the NaV1.4 channel content and 2) the Na(+) influx through the defective channels [i.e., the tetrodotoxin (TTX)-sensitive Na(+) influx]. We measured NaV1.4 channel protein content, TTX-sensitive Na(+) influx, force generation, and myosin isoform expression in four muscles from knock-in mice expressing a NaV1.4 isoform corresponding to the human M1592V mutant. The HyperKPP flexor digitorum brevis muscle showed no contractile abnormalities, which correlated well with its low NaV1.4 protein content and by far the lowest TTX-sensitive Na(+) influx. In contrast, diaphragm muscle expressing the HyperKPP mutant contained high levels of NaV1.4 protein and exhibited a TTX-sensitive Na(+) influx that was 22% higher compared with affected extensor digitorum longus (EDL) and soleus muscles. Surprisingly, despite this high burden of Na(+) influx, the contractility phenotype was very mild in mutant diaphragm compared with the robust abnormalities observed in EDL and soleus. This study provides evidence that HyperKPP phenotype does not depend solely on the NaV1.4 content or Na(+) influx and that the diaphragm does not depend solely on Na(+)-K(+) pumps to ameliorate the phenotype.
高钾周期性麻痹（HyperKPP）的特征是肌强直性放电，发生在阵发性瘫痪发作之间。尽管膈肌肌肉表达引起肢体肌肉症状的相同缺陷 Na(+)通道同工型（NaV1.4），但患有 HyperKPP 的个体很少出现呼吸困难。我们检验了以下假设：肌肉中 HyperKPP 表型（低力生成和向氧化型 I 和 IIA 纤维的转变）的程度是 1）NaV1.4 通道含量和 2）通过缺陷通道的 Na(+)内流[即，河豚毒素（TTX）-敏感的 Na(+)内流]的函数。我们测量了 knock-in 小鼠的四个肌肉中的 NaV1.4 通道蛋白含量、TTX 敏感的 Na(+)内流、力生成和肌球蛋白同工型表达，这些小鼠表达的 NaV1.4 同工型对应于人类 M1592V 突变体。HyperKPP 屈趾短肌没有收缩异常，这与其低 NaV1.4 蛋白含量和迄今为止最低的 TTX 敏感的 Na(+)内流密切相关。相比之下，表达 HyperKPP 突变体的膈肌含有高水平的 NaV1.4 蛋白，并表现出 TTX 敏感的 Na(+)内流，与受影响的伸趾长肌（EDL）和比目鱼肌相比，高出 22%。令人惊讶的是，尽管存在这种高的 Na(+)内流负担，但与 EDL 和比目鱼肌中观察到的强大异常相比，突变体膈肌的收缩力表型非常轻微。这项研究提供了证据表明，HyperKPP 表型不仅取决于 NaV1.4 含量或 Na(+)内流，而且膈肌不仅依赖于 Na(+)-K(+)泵来改善表型。
