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，骨骼肌显示出萎缩和虚弱，这限制了活动性，导致残疾， 降低生活质量。据报道，肌肉结构随着年龄的增长而下降， 功能和神经肌肉接头（NMJ）形态的退行性变化;然而， 衰老引发NMJ中断以及肌肉功能和纤维受损的下游机制 所有的损失都是未知的。我们小组的研究共同表明，以加速的方式， 铜锌超氧化物歧化酶（CuZnSOD; Sod 1 KO）缺陷小鼠肌肉衰老的关键特征 小鼠）。使用我们开发的组织特异性调节Sod 1的新型小鼠模型进行的其他研究 共同表明，运动神经元的氧化还原稳态是一个关键因素，调节维持 NMJ，但肌肉减少症的进展是由两种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， 体内平衡引起肌肉中突触后变化。增加活性氧（ROS）的产生 是引起NMJ变性和肌肉萎缩的操纵的标志，例如， sod 1缺乏、衰老和去神经支配。因此，我们的假设是，随着年龄的增长， 外周运动神经元损害NMJ的形成和维持在突触周转， 神经支配的中断改变了肌肉线粒体功能，导致对肌肉的氧化损伤增加。 肌肉激活和收缩机制。我们将通过确定氧化的影响来检验这一假设。 运动神经元应激对NMJ形成和维持的影响以及直接破坏NMJ对关键神经元的影响 突触后肌肉功能氧化应激和NMJ破坏将使用新的组织特异性表达来诱导。 动物中心提供的小鼠模型。这些强大的新鼠标模型加上创新的 研究NMJ形成和再生、线粒体功能、钙稳态和力的方法 一代，提供了一个有力的范例，影响骨骼肌老化的科学知识，以推动 预防肌肉减少症的成功干预措施。

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.