The mechanism underlying transient weakness in myotonia congenita.
The mechanism underlying transient weakness in myotonia congenita.
复制标题
先天性肌强直短暂性肌无力的机制。
DOI：
10.7554/elife.65691
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发表时间：
2021-04-27
期刊：
影响因子：
7.7
通讯作者：
Rich MM
中科院分区：
文献类型：
--
作者：
Myers JH;Denman K;DuPont C;Hawash AA;Novak KR;Koesters A;Grabner M;Dayal A;Voss AA;Rich MM
除了标志性的肌肉僵硬外，隐性先天性肌强直（贝克尔病）患者还会出现短暂性虚弱，尽管经过多年的研究，但仍然知之甚少。我们进行了细胞内记录从遗传和药理学小鼠模型的贝克尔病的肌肉，以确定短暂的弱点的机制。我们的记录显示，在贝克病的遗传和药理学模型中，膜电位的瞬时去极化（平台电位）为−25至−35 mV。Na+和Ca 2+电流都有助于平台电位。Na+持续性内向电流（NaPIC）通过NaV1.4通道是触发平台电位的关键，而CaV1.1通道的电流则决定了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，并消除体内短暂的虚弱。这些数据表明，靶向NaPIC可能是预防先天性肌强直一过性无力的有效治疗方法。肌强直是一种神经肌肉疾病，会导致随意运动后肌肉松弛的问题。一种类型的肌强直是贝克尔病，也称为隐性先天性肌强直。这是一种遗传性疾病，会导致肌肉僵硬，这是由于不自主的肌肉活动。患者也可能在开始运动后几秒钟或长达几分钟的短暂虚弱。这些暂时性虚弱的原因尚不清楚，但有迹象表明，这可能与肌肉失去兴奋性有关，即对使其收缩的刺激做出反应的能力。然而，这与贝克尔病中肌肉过度兴奋的研究结果不一致。肌肉兴奋性取决于每个肌肉细胞内外不同浓度的带电离子（带正电的钠、钙和钾离子以及带负电的氯离子）的存在。这些不同浓度的离子在细胞膜上产生一个电势，也称为“膜电势”。当肌肉细胞受到刺激时，细胞膜上被称为离子通道的蛋白质就会打开。这允许离子在细胞内部和外部之间流动，从而产生电流，触发肌肉收缩。为了更好地理解这种肌肉无力背后的原因，Myers等人使用了经过基因操纵或给予药物的小鼠来模拟贝克病。通过测量肌肉力量和驱动收缩的电流，Myers等人发现，运动后虚弱的潜在机制涉及细胞内外正电荷离子浓度的瞬时变化。进一步的实验表明，调节钠和钙进出细胞的蛋白质-称为钠和钙通道-促成了这种浓度的变化。此外，Myers等人发现，使用一种名为雷诺嗪的药物来阻止钠离子进入细胞，可以消除活体小鼠的短暂虚弱。这些发现表明，在贝克尔病中，肌肉在过度兴奋或不能兴奋之间快速循环，并且靶向钠离子流入细胞可能是预防先天性肌强直短暂性无力的有效治疗方法。这项研究为开发新的治疗方法铺平了道路，以治疗贝克尔病以及其他具有短暂性虚弱（如周期性麻痹）的肌肉离子通道疾病。
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 Ca2+ currents contribute to plateau potentials. Na+ persistent inward current (NaPIC) through NaV1.4 channels is the key trigger of plateau potentials and current through CaV1.1 Ca2+ 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. Myotonia is a neuromuscular condition that causes problems with the relaxation of muscles following voluntary movements. One type of myotonia is Becker disease, also called recessive myotonia congenita. This is a genetic condition that causes muscle stiffness as a result of involuntary muscle activity. Patients may also suffer transient weakness for a few seconds or as long as several minutes after initiating a movement. The cause of these bouts of temporary weakness is still unclear, but there are hints that it could be linked to the muscle losing its excitability, the ability to respond to the stimuli that make it contract. However, this is at odds with findings that show that muscles in Becker disease are hyperexcitable. Muscle excitability depends on the presence of different concentrations of charged ions (positively charged sodium, calcium and potassium ions and negatively charged chloride ions) inside and outside of each muscle cells. These different concentrations of ions create an electric potential across the cell membrane, also called the ‘membrane potential’. When a muscle cell gets stimulated, proteins on the cell membrane known as ion channels open. This allows the flow of ions between the inside and the outside of the cell, which causes an electrical current that triggers muscle contraction. To better understand the causes behind this muscle weakness, Myers et al. used mice that had either been genetically manipulated or given drugs to mimic Becker disease. By measuring both muscle force and the electrical currents that drive contraction, Myers et al. found that the mechanism underlying post-movement weakness involved a transient change in the concentrations of positively charged ions inside and outside the cells. Further experiments showed that proteins that regulate the passage of both sodium and calcium in and out of the cell – called sodium and calcium channels – contributed to this change in concentration. In addition, Myers et al. discovered that using a drug called ranolazine to stop sodium ions from entering the cell eliminated transient weakness in live mice. These findings suggest that in Becker disease, muscles cycle rapidly between being hyperexcited or not able to be excited, and that targeting the flow of sodium ions into the cell could be an effective treatment to prevent transient weakness in myotonia congenita. This study paves the way towards the development of new therapies to treat Becker disease as well as other muscle ion channel diseases with transient weakness such as periodic paralysis.