Novel Approaches to Therapy of Muscle Ion Channelopathies

NIH摘要： 先天性肌强直（MC）和高钾型周期性麻痹（HPP）是一种遗传性骨骼肌疾病 渠道疾病尽管这两种疾病的最初描述多年前，有效和良好的 对这两种疾病的耐受治疗仍然是难以捉摸的。原因是，一个详细的 缺乏对健康和疾病中调节肌肉兴奋性的机制的理解。更好的 了解非营养不良性离子通道病的肌肉功能障碍机制 是为患者开发更好的治疗方法所必需的。 虽然已知先天性肌强直中的肌肉由于ClC-1电流的减少而过度兴奋， 患者所遭受的两种运动症状的潜在机制仍然知之甚少。的 第一种是隐性形式的先天性肌强直（贝克尔病）的短暂无力。而 如果肌肉无力随着持续锻炼而减轻，则它可能是运动功能障碍的重要因素。 虚弱似乎是由于肌肉兴奋性丧失，但机制尚不清楚。第二 症状是牵张诱发（叩击）肌强直。因为肌肉必须交替收缩和伸展 在运动过程中，牵张引起的肌强直可能显著地导致僵硬。目前，无 关于引发牵张性肌强直的机制是已知的。 我们已经发现了新的电流，这些电流是肌无力和牵张诱发的肌强直的基础。目标 1和2我们的目标是表征这些电流，并测试可用阻滞剂的功效，以开发 治疗先天性肌强直运动功能障碍的新方法。在目标3中，我们将这项工作扩展到研究 高钾性周期性麻痹的运动功能障碍

NIH abstract: Myotonia congenita (MC) and hyperkalemic periodic paralysis (HPP) are inherited skeletal muscle ion channel diseases. Despite initial descriptions of both diseases many years ago, effective and well tolerated therapy for both disorders has remained elusive. The reason for this is that a detailed understanding of mechanisms regulating muscle excitability in health and disease is lacking. A better understanding of mechanisms underlying muscle dysfunction in the non-dystrophic ion channelopathies is necessary to develop improved therapy for patients. While it is known that muscle in myotonia congenita is hyperexcitable due to reduction of ClC-1 current, the mechanisms underlying two motor symptoms suffered by patients remain poorly understood. The first is transient weakness in recessive forms of myotonia congenita (Becker disease). While the weakness lessens with continued exercise, it is likely a significant contributor to motor dysfunction. Weakness appears to be due to loss of muscle excitability, but the mechanism is unknown. The second symptom is stretch-induced (percussion) myotonia. As muscles must alternately contract and stretch during movement, stretch-induced myotonia may contribute significantly to stiffness. Currently, nothing is known about the mechanism triggering stretch-induced myotonia. We have discovered novel currents that underlie both weakness and stretch-induced myotonia. In Aims 1 and 2 our goal is characterize these currents and to test the efficacy of available blockers to develop novel therapy for motor dysfunction in myotonia congenita. In Aim 3 we extend this work to study of motor dysfunction in hyperkalemic periodic paralysis.