Novel Approaches to Therapy of Muscle Ion Channelopathies

点击翻译按钮获取中文摘要

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.