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Defining the relative roles of pre- and post-synaptic events in the initiation and progression of sarcopenia

定义突触前和突触后事件在肌肉减少症的发生和进展中的相对作用

基本信息

批准号：
9104587
负责人：
Susan V Brooks
金额：
$ 68.17万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104587
关键词：
Actins Address Adult Aging Atrophic Calcium Calcium Signaling Collaborations Data Denervation Development Effectiveness Elderly Embryo Embryonic Development Event Exhibits Fiber Functional disorder Gastrocnemius Muscle Gene Deletion Generations Goals Homeostasis Human Knock-out Knockout Mice Measures Mitochondria Modeling Morphology Motor Motor Neurons Mus Muscle Muscle Fibers Muscle Mitochondria Muscle Weakness Muscle function Muscular Atrophy Nerve Neuromuscular Junction Neurons Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Pathway interactions Phenotype Production Property Public Health Quality of life Reactive Oxygen Species Risk Role Skeletal Muscle Spinal Cord Structure Superoxides Synapses Tamoxifen Testing Tissues Transgenic Mice Wild Type Mouse Work age related age-related muscle loss base catalase copper zinc superoxide dismutase disability expectation falls frailty functional decline genetic approach improved insight mitochondrial dysfunction muscle form muscular structure nerve supply overexpression oxidative damage postsynaptic presynaptic prevent promoter public health relevance recombinase sarcopenia sciatic nerve skeletal successful intervention therapeutic target young adult

项目摘要

DESCRIPTION (provided by applicant): Drs. Brooks and Van Remmen have a strong record of collaboration in studies on the role of oxidative stress in sarcopenia. Our previous work demonstrated that young adult mice lacking the superoxide anion scavenger CuZnSOD (Sod1KO mice) exhibit age-related muscle atrophy/weakness that closely mimics the sarcopenia phenotype of old wild type (WT) mice, including degeneration of neuromuscular junctions (NMJ), retraction of motor neurons, elevated generation of muscle mitochondrial reactive oxygen species (mtROS), and altered calcium homeostasis. Replacing CuZnSOD specifically in neurons of Sod1KO mice reverses muscle atrophy and weakness, NMJ disruption and muscle oxidative stress, implicating motor neuron deficits as the initiating event in sarcopenia in Sod1KO mice. However, neuronal specific Sod1 knockout (nSod1KO) in mice does not result in atrophy of the gastrocnemius muscle, and although muscle specific Sod1 knockout mice show a loss in contractile force, they show no muscle atrophy. Thus, deletion of Sod1 and induction of oxidative stress in either neurons or muscle alone does not replicate the sarcopenia phenotype of the Sod1KO mice, suggesting that sarcopenia results from an interactive effect requiring both tissues. The goal of this study is to define this interaction. We hypothesize that pre-synaptic oxidative stress and damage initiates alterations in NMJ structure and function that trigger postsynaptic increases in mtROS generation, calcium dysregulation, and oxidative stress/damage in the muscle that further disrupt neuronal and NMJ function to generate the sarcopenia phenotype. We will address this hypothesis in three Specific Aims. First, we will examine the effect of Sod1 deficiencies in both neurons and muscle fibers with the expectation that these double knockout mice will recapitulate the phenotype of Sod1KO mice. We will also determine the effect of muscle or neuronal specific deficiency of Sod1 using conditional deletion of Sod1 during adulthood to determine the impact on sarcopenia, independent of possible developmental compensatory changes. Next, using additional conditional knockout models, we will test whether elevated muscle mtROS without presynaptic oxidative stress is sufficient to induce sarcopenia, and conversely, we will determine whether scavenging post- synaptic mtROS in Sod1KO will delay and/or reduce muscle atrophy and functional declines, despite neuronal changes present in the Sod1KO mice. In each model, we will measure oxidative damage and redox status in sciatic nerve, spinal cord, and muscle, NMJ morphology and function, motor unit properties, and skeletal muscle structure, mitochondrial function, calcium handling, and contractility. These studies will definitively show whether neuronal initiation of NMJ disruption is sufficient for muscle atrophy/weakness or if additional alterations in muscle oxidative stress are required to induce the phenotype. Identifying coordinated roles of neurons and muscle in the initiation and progression of sarcopenia will provide new insights into the pathways that are involved in the onset and propagation of sarcopenia.

描述（由申请人提供）：布鲁克斯博士和货车Remmen博士在氧化应激在肌肉减少症中的作用研究方面有很强的合作记录。我们以前的工作表明，缺乏超氧阴离子清除剂CuZnSOD的年轻成年小鼠（Sod 1 KO小鼠）表现出与年龄相关的肌肉萎缩/无力，与老年野生型（WT）小鼠的肌肉减少症表型非常相似，包括神经肌肉接头（NMJ）变性，运动神经元退缩，肌肉线粒体活性氧（mtROS）生成增加，以及钙稳态改变。在Sod 1 KO小鼠的神经元中特异性地替换CuZnSOD逆转了肌肉萎缩和无力、NMJ破坏和肌肉氧化应激，暗示运动神经元缺陷是Sod 1 KO小鼠肌肉减少症的起始事件。然而，神经元特异性Sod 1敲除（nSod 1 KO）小鼠不会导致腓肠肌萎缩，尽管肌肉特异性Sod 1敲除小鼠显示收缩力丧失，但它们没有显示肌肉萎缩。因此，Sod 1的缺失和氧化应激的诱导，无论是神经元或肌肉单独不复制的Sod 1 KO小鼠的少肌症表型，表明少肌症的结果从一个相互作用的影响，需要两个组织。本研究的目的是确定这种相互作用。我们假设突触前氧化应激和损伤引发NMJ结构和功能的改变，其触发肌肉中的mtROS产生、钙失调和氧化应激/损伤的突触后增加，其进一步破坏神经元和NMJ功能以产生少肌症表型。我们将在三个具体目标中讨论这一假设。首先，我们将研究Sod 1缺陷在神经元和肌纤维中的作用，期望这些双敲除小鼠将重现Sod 1 KO小鼠的表型。我们还将确定肌肉或神经元特异性缺乏的影响，使用条件性删除Sod 1在成年期，以确定对肌肉减少症的影响，独立于可能的发育代偿性变化。接下来，使用额外的条件性敲除模型，我们将测试在没有突触前氧化应激的情况下升高的肌肉mtROS是否足以诱导肌肉减少症，并且相反地，我们将确定清除Sod 1 KO中的突触后mtROS是否会延迟和/或减少肌肉萎缩和功能下降，尽管Sod 1 KO小鼠中存在神经元变化。在每个模型中，我们将测量坐骨神经、脊髓和肌肉中的氧化损伤和氧化还原状态、NMJ形态和功能、运动单位特性和骨骼肌结构、线粒体功能、钙处理和收缩性。这些研究将明确显示NMJ破坏的神经元启动是否足以导致肌肉萎缩/无力，或者是否需要肌肉氧化应激的额外改变来诱导表型。确定神经元和肌肉在肌肉减少症的启动和进展中的协调作用将为肌肉减少症的发病和传播所涉及的途径提供新的见解。