Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United States.
Department of Dermatology & Cutaneous Surgery, University of Miami, Miami, United States.
Elife. 2021 Apr 27;10:e65691. doi: 10.7554/eLife.65691.
In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to -25 to -35 mV in the genetic and pharmacologic models of Becker disease. Both Na and Ca currents contribute to plateau potentials. Na persistent inward current (NaPIC) through Na1.4 channels is the key trigger of plateau potentials and current through Ca1.1 Ca channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita.
除了标志性的肌肉僵硬外，隐性先天性肌强直（Becker 病）患者还会经历衰弱性的短暂无力发作，尽管经过多年研究，这种发作仍未得到很好的理解。我们对 Becker 病的遗传和药理学小鼠模型的肌肉进行了细胞内记录，以确定导致短暂无力的机制。我们的记录显示，在遗传和药理学 Becker 病模型中，膜电位会出现短暂去极化（平台电位），达到-25 至-35 mV。Na 和 Ca 电流都有助于平台电位。通过 Na1.4 通道的 Na 持续内向电流（NaPIC）是平台电位的关键触发因素，而 Ca1.1 Ca 通道的电流则有助于平台电位的持续时间。用雷诺嗪抑制 NaPIC 可防止平台电位的发展，并消除体内的短暂无力。这些数据表明，靶向 NaPIC 可能是预防先天性肌强直短暂无力的有效治疗方法。
