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: 7245966
• 负责人: Julio L Vergara
• 金额: $ 33.11万
• 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/7245966
• 关键词: Accounting; Address; Adult; Affect; Animal Model; Arts; Back; Biological Preservation; Characteristics; Chloride Channels; Chloride Ion; Chlorides; Condition; Control Animal; Coupling; Dependence; Development; Electrophysiology (science); Fiber; Fire - disasters; Flexor; 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; Numbers; Optics; Paralysed; Pathogenesis; Pathway interactions; Pattern; Physiological; Play; Process; Property; Protein Overexpression; 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; Today; Transgenic Animals; Tubular formation; Vacuum; base; electrical property; mathematical model; 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（由申请人提供）：该提案的中心假设是，横管系统（TTS）在哺乳动物骨骼肌的整体特性中起着重要作用，为了了解肌肉通道病的病理生理学，有必要仔细表征该膜室的电特性。由离子通道激活介导的TTS膜电位的变化不仅影响肌纤维的电特性，而且还负责触发兴奋-收缩偶联（ECC）机制。我们将使用电生理学方法，国家的最先进的光学技术（允许测量TTS电压变化），和数学建模的径向传播的去极化在这个隔间，为了探测详细的作用，离子电导在这些过程中发挥。首先，我们将表征电压钳条件下正常小鼠肌纤维的被动电特性和每个主要传导通路（目的1）。然后，我们将研究刺激引起重复放电的纤维中TTS传播的特性和局限性，并测试个体电导（特别是钠和氯）的改变对这些特性的影响。目的是阐明TTS腔中K积累可能在与通道病（如周期性麻痹和肌强直）相关的现象中发挥的潜在作用（目的2）。由于一个难题，在功能调查channelopathies是肌强直和瘫痪之间的脆弱的分界线，在目标3中，我们将调查是否复杂的电压调节的ECC可以导致废除或保存的Ca 2+释放过程取决于模式的电活动在TTS。最后，与以前的目标中获得的知识，我们将调查是否可以从TTS（目的4）的电传播的改变理解在动物模型中观察到的发病机制的肌强直和高钾血症性周期性麻痹。这些调查所获得的知识将不仅是相关的对channelopathies的病理生理学的理解，但由于他们将提供有关TTS电传播的生理机制的基本信息，他们将是了解一些肌肉疾病的意义。