Presynaptic active zone alterations that underlie dynapenia at aged mouse neuromuscular junctions

老年小鼠神经肌肉接头处的突触前活性区改变导致无性缺乏

• 批准号: 10718403
• 负责人: STEPHEN D MERINEY
• 金额: $ 45.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718403
• 关键词: Acetylcholine; Adult; Age; Aging; Calcium Channel; Cause of Death; Centers for Disease Control and Prevention (U.S.); Computer Simulation; DNA; Data; Elderly; Electrophysiology (science); Equilibrium; Future; Gait; Global Change; Goals; Heterogeneity; Imaging Techniques; Individual; Injury; Measurement; Measures; Microscopy; Minor; Modeling; Motor; Motor Neurons; Mus; Muscle; Muscle Weakness; Muscle function; Muscular Atrophy; Neurologic; Neuromuscular Junction; Neurotransmitters; Optical reporter; Optics; Persons; Phase; Play; Population; Process; Reporting; Resolution; Risk; Risk Factors; Rodent; Role; Site; Stains; Structure; Synapses; Synaptic Vesicles; Testing; Therapeutic Intervention; Time; Walking; aged; density; equilibration disorder; experience; fall risk; falls; frailty; human old age (65+); imaging approach; mouse model; muscle form; muscle strength; neuromuscular; neurotransmitter release; new therapeutic target; novel strategies; presynaptic; recruit; reduced muscle strength; sarcopenia; superresolution imaging; synaptic function; targeted treatment; therapy development; ultra high resolution; voltage

Project Summary/Abstract: The over-65 population is growing, and over 1/3 of aged people will experience a fall. Falls in the elderly often result from frailty caused by muscle weakness, balance deficits, and gait instability. Previously, these deficits were ascribed to declining muscle mass (sarcopenia), however, simply increasing muscle mass does not necessarily rescue age-induced functional deficits. The term dynapenia has been introduced to denote aging-induced loss of muscle strength, which includes deficits in motoneuron excitability, motor unit recruitment, transmitter release at the neuromuscular junction (NMJ), and muscle mass and function. As such, it is critical to fully understand the changes that occur within NMJs to identity new targets for therapy development. Here, we propose to define heterogeneous changes that occur within the transmitter release sites (active zones; AZs) within NMJs that underlying dynapenia in an aged mouse model. Specifically, we will (1) use a combination of electrophysiology and a new optical quantal analysis approach we developed to study changes in the control of transmitter release within single identified NMJs during aging, (2) use a new super-resolution imaging approach of the density and distribution of presynaptic voltage-gated calcium channels within single AZs and compare these results with our single AZ optical measurements of transmitter release in identified NMJs over the aging time course, and (3) use a realistic computer simulation to test the hypothesis that age-induced changes in AZ voltage-gated calcium channel density and distribution predict single AZ and whole synapse function at the aging NMJ. The results from these aims will elucidate the detailed structural and functional changes that occur within transmitter release sites (AZs) of aging NMJs over the time course of the dynamic alterations that occur as dynapenia develops. This information will guide future studies aimed at targeting these specific aging-induced changes with the goal of treating dynapenia.

项目概要/摘要： 65岁以上的人口正在增长，超过1/3的老年人将经历跌倒。福尔斯 老年人通常是由于肌肉无力、平衡缺陷和步态引起虚弱 不稳定以前，这些缺陷被归因于肌肉质量下降（肌肉减少症）， 然而，简单地增加肌肉质量并不一定能挽救年龄引起的功能性 赤字肌无力一词被用来表示衰老引起的肌肉损失 力量，包括运动神经元兴奋性、运动单位募集、递质 在神经肌肉接头（NMJ）的释放以及肌肉质量和功能。因此，它是 充分了解NMJ内发生的变化以确定新的治疗靶点至关重要 发展在这里，我们建议定义发生在 在老年人中，NMJ内的递质释放位点（活动区; AZ）是神经衰弱的基础。 小鼠模型具体来说，我们将（1）使用电生理学和新的光学 我们开发了一种量子分析方法来研究递质释放控制的变化 在老化过程中单个识别的NMJ中，（2）使用新的超分辨率成像方法， 单个AZ内突触前电压门控钙通道的密度和分布， 比较这些结果与我们的发射器释放的单AZ光学测量， 在老化时间过程中识别的NMJ，以及（3）使用真实的计算机模拟来测试 假设年龄诱导的AZ电压门控钙通道密度的变化， 分布预测单个AZ和整个突触功能在老化NMJ。的结果 这些目标将阐明发生的详细结构和功能变化， 在动态变化的时间过程中老化NMJ的递质释放位点（AZ） 这是在发育不良时发生的。这些信息将指导今后的研究， 这些特定的衰老引起的变化，目的是治疗记忆力减退。