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

项目摘要/摘要： 65岁以上的人口正在增长，超过三分之一的老年人将经历下降。坠落在 老年人通常是由肌肉无力、平衡障碍和步态引起的虚弱所致。 不稳定。以前，这些缺陷被归因于肌肉质量下降(骨质疏松症)， 然而，简单地增加肌肉质量并不一定能挽救年龄诱导的功能性 赤字。“经期减退”一词被用来指代衰老导致的肌肉丧失。 体力，包括运动神经元兴奋性、运动单位招募、递质缺乏 在神经肌肉连接处(NMJ)释放，以及肌肉质量和功能。因此，它是 对充分了解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，我们建议定义在 NMJ内的递质释放部位(活动区；AZs)是老年人月经减退的基础 老鼠模型。具体地说，我们将(1)使用电生理学和一种新的光学 我们开发了定量分析方法来研究发射器释放控制的变化 在老化过程中识别的单个NMJ内，(2)使用新的超分辨率成像方法 突触前电压门控性钙通道在单个AZ和AZ内的密度和分布 将这些结果与我们对发射机释放的单一AZ光学测量结果进行比较 在老化过程中确定NMJ，以及(3)使用真实的计算机模拟来测试 年龄引起AZ电压门控钙通道密度和钙通道密度改变的假说 在NMJ老化时，分布预测单个AZ和整个突触功能。结果来自于 这些目标将阐明内部发生的详细的结构和功能变化 老化NMJ在动态变化过程中的递质释放部位(AZ) 随着经期减退的发展而发生。这一信息将指导未来针对目标的研究 这些特定的衰老诱导的变化的目的是治疗月经过少。

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.