PROJECT 1: Contribution of altered synapse function to muscle atrophy and weakness in aging

摘要-项目1 随着年龄的增长，骨骼肌表现出萎缩和虚弱，限制了行动能力，导致残疾，以及 降低生活质量。据报道，肌肉结构的衰退与衰老之间存在很强的关联 神经肌肉接头(NMJ)的功能和退行性变化；然而， 引发NMJ紊乱的衰老以及肌肉功能和纤维受损的下游机制 损失都是未知的。来自我们小组的研究集体表明，以一种加速的方式概括了 铜锌超氧化物歧化酶缺陷小鼠肌肉衰老的关键属性 老鼠)。使用我们开发的具有组织特异性SOD1调节的新型小鼠模型进行的其他研究 共同提示运动神经元的氧化还原动态平衡是调节维持 NMJ，但骨质疏松症的进展是由两个神经元变化之间的相互作用决定的 和肌肉。项目1的目标是建立运动神经元氧化还原改变的机制 动态平衡导致肌肉突触后的变化。增加活性氧(ROS)的产生 肌肉线粒体是导致NMJ变性和肌肉萎缩的手法的标志，例如 SOD1缺乏、衰老和失神经。因此，我们的假设是，随着年龄的增长，体内氧化还原动态平衡发生变化 外周运动神经元在突触翻转过程中损害NMJ的形成和维持 神经支配的中断会改变肌肉线粒体的功能，从而增加对骨骼肌的氧化损伤 肌肉激活和收缩机械。我们将通过确定氧化的影响来检验这一假说 运动神经元应激对NMJ形成和维持的影响及直接干扰NMJ对KEY的影响 突触后肌肉功能。将使用新的组织特异性诱导氧化应激和NMJ破坏 动物核心提供的小鼠模型。这些功能强大的新鼠标型号与创新的 研究NMJ形成和再生、线粒体功能、钙稳态和作用力的方法 世代，为影响骨骼肌衰老的科学知识提供了一个强有力的范例 成功的预防石棺减少的干预措施。

ABSTRACT – PROJECT 1 With aging, skeletal muscle displays atrophy and weakness that limits mobility, contributes to disability, and reduces quality of life. Strong associations are reported between declines with aging in muscle structure and function and degenerative changes in the morphology of neuromuscular junctions (NMJ); however, events with aging that trigger disruption of NMJs and the downstream mechanisms of impaired muscle function and fiber loss are all unknown. Studies from our groups collectively show a recapitulation, in an accelerated fashion, of key attributes of muscle aging in mice deficient in copper zinc superoxide dismutase (CuZnSOD; Sod1KO mice). Additional studies using novel mouse models we developed with tissue specific modulation of Sod1 collectively suggest that redox homeostasis in motor neurons is a critical factor regulating the maintenance of NMJs, but that the progression of sarcopenia is determined by interactions between changes in both neurons and muscle. The goal of Project 1 is to establish mechanisms by which alterations in motor neuron redox homeostasis cause post-synaptic changes in muscle. Increased production of reactive oxygen species (ROS) by muscle mitochondria is a hallmark of manipulations that cause NMJ degeneration and muscle atrophy, e.g. Sod1 deficiency, aging, and denervation. Thus, our hypothesis is that with aging, altered redox homeostasis in peripheral motor neurons impairs NMJ formation and maintenance during synaptic turnover and the resultant disruption in innervation alters muscle mitochondrial function that causes increased oxidative damage to the muscle activation and contractile machinery. We will test this hypothesis by determining the impact of oxidative stress in motor neurons on NMJ formation and maintenance and the impact of directly disrupting NMJs on key postsynaptic muscle functions. Oxidative stress and NMJ disruption will be induced using novel tissue-specific mouse models provided by the Animal Core. These powerful new mouse models coupled with innovative methods for studying NMJ formation and regeneration, mitochondrial function, calcium homeostasis, and force generation, provide a potent paradigm for impacting scientific knowledge of skeletal muscle aging to drive successful interventions to prevent sarcopenia.