Role of the Transverse Tubular System in Mammalian Skeletal Muscle Excitability

横管系统在哺乳动物骨骼肌兴奋性中的作用

• 批准号: 7571694
• 负责人: Julio L Vergara
• 金额: $ 32.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-11 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571694
• 关键词: Accounting; Address; Adult; Affect; Animal Model; Arts; Back; Biological Preservation; Characteristics; Chloride Channels; Chloride Ion; Chlorides; Control Animal; Coupling; Dependence; Development; Electrophysiology (science); Fiber; Fluorescence Resonance Energy Transfer; Frequencies; Functional disorder; Goals; Human; Hybrids; Hyperkalemic periodic paralysis; Individual; Investigation; Ion Channel; Ions; Knock-in Mouse; Knock-out; Knowledge; Length; Measures; Mediating; Membrane; Membrane Potentials; Methods; Microelectrodes; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Mutant Strains Mice; Mutation; Myopathy; Myotonia; Myotonic Dystrophy; Nature; Optics; Paralysed; Pathogenesis; Pathway interactions; Pattern; Physiological; Play; Process; Property; Radial; Records; Regulation; Relative (related person); Reporting; Research Personnel; Role; Sarcolemma; Signal Transduction; Simulate; Skeletal Muscle; Sodium; Sodium Chloride; Staining method; Stains; Surface; System; Techniques; Testing; Transgenic Animals; Tubular formation; Vacuum; base; electrical property; flexor digitorum brevis; mathematical model; overexpression; programs; research study; response; voltage; voltage clamp

DESCRIPTION (provided by applicant): The central hypothesis of this proposal is that the transverse tubular system (TTS) plays such a preponderant role in the overall properties of mammalian skeletal muscle that, in order to understand the pathophysiology of muscle channelopathies it will be necessary to carefully characterize the electrical properties of this membrane compartment. Changes in membrane potential of the TTS, which are mediated by the activation of ion channels, not only affect the electrical properties of the muscle fiber, but also are responsible for triggering the mechanisms of excitation-contraction coupling (ECC). We will use electrophysiological methods, state-of-the-art optical techniques (which permit to measure TTS voltage changes), and mathematical modeling of the radial spread of the depolarization in this compartment, in order to probe the detailed role that ionic conductances play in these processes. First, we will characterize the passive electrical properties and each of the major conductive pathways in normal mouse muscle fibers under voltage clamp conditions (Aim 1). We will then study the properties and limitations of the TTS propagation in fibers stimulated to elicit repetitive firing and test the effects that alterations in individual conductances (sodium and chloride in particular) have on these properties. The goal is to elucidate the potential role that K accumulation in the lumen of the TTS lumen may play in the phenomenology associated with channelopathies such as periodic paralysis and myotonia (Aim 2). Since a conundrum in the functional investigation of channelopathies is the tenuous demarcation between myotonia and paralysis, in Aim 3 we will investigate whether intricacies of the voltage regulation of the ECC can result in abolition or preservation of the Ca2+ release process depending on the pattern of electrical activity in the TTS. Finally, with the knowledge acquired in previous aims, we will investigate whether the pathogenesis observed in animal models of myotonia and hyperkaelemic periodic paralysis can be understood from alterations in the electrical propagation at the TTS (Aim 4). The knowledge gained with these investigations will not only be relevant towards the understanding of the pathophysiology of channelopathies, but since they will provide basic information about the physiological mechanisms of TTS electrical propagation, they will be of significance for understanding a number of muscle diseases.

描述(申请人提供)：这项建议的中心假设是，横管系统(TTS)在哺乳动物骨骼肌的整体特性中扮演着如此重要的角色，因此，为了了解肌肉通道病的病理生理学，有必要仔细描述这一膜间隔的电特性。TTS膜电位的变化不仅影响肌纤维的电学性质，而且还触发了兴奋收缩偶联(ECC)机制，这种变化是由离子通道激活所介导的。我们将使用电生理学方法、最先进的光学技术(允许测量TTS电压变化)和数学模型来探索离子电导在这些过程中所起的详细作用。首先，我们将表征电压钳条件下正常小鼠肌肉纤维的被动电学特性和每条主要传导通路(目标1)。然后，我们将研究TTS在被刺激以引发重复激发的纤维中传播的特性和限制，并测试单个电导率(特别是钠和氯化物)的变化对这些特性的影响。其目的是阐明TTS管腔中钾的积累在与周期性瘫痪和肌强直等通道病相关的现象学中可能扮演的潜在角色(目标2)。由于通道病的功能研究中的一个难题是肌强直和瘫痪之间的微妙分界，在目标3中，我们将根据TTS中的电活动模式，研究ECC电压调节的复杂性是否会导致钙释放过程的取消或保留。最后，结合在前面的目标中获得的知识，我们将调查在肌强直和高血血症性周期性麻痹动物模型中观察到的发病机制是否可以从TTS的电传播的变化中理解(目标4)。通过这些研究获得的知识不仅与理解经络病的病理生理学有关，而且由于它们将提供关于TTS电传播的生理机制的基本信息，它们将对理解许多肌肉疾病具有重要意义。