Reactive Oxygen Species: Stress and Damage in Old Muscle

活性氧：旧肌肉的压力和损伤

• 批准号: 7614472
• 负责人: JOHN Arthur FAULKNER
• 金额: $ 119.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614472
• 关键词: Reactive; Oxygen; Species; Stress; Damage

DESCRIPTION (provided by applicant): Frailty represents the summation of the effects of motor neuron degeneration, muscle fiber denervation and degeneration, decreased muscle mass and strength, and mitochondrial dysfunction, but the cause-effect relationships among these variables are unknown. The primary long term goal of the Program Project is to understand the mechanisms underlying the age-related deterioration of motor nerves, muscle fibers, and mitochondria responsible for physical frailty. During our previous five years of support, dozens of knockout (KO) and over-expressor adult and old mice were investigated and superoxide-mediated oxidative stress was identified as a key factor in the age-related changes in the neuromuscular system. The Sod1-/- mouse was identified as the most promising animal model to test hypotheses regarding the role of oxidative stress in the age-related changes in nerves, neuromuscular junctions, muscle fibers, and mitochondria. In addition, CuZnSOD activity was rescued separately in nerves, Sod1-/-(N) mice, and muscles, Sod1-/-(M) mice, to address additional hypotheses related to the specific tissues in which oxidative stress is critical to the age-related changes. The three research groups in Ann Arbor, Liverpool and San Antonio have demonstrated their ability to collaborate with numerous meetings and the publication of major co-authored papers linking their expertise in physiology, biochemistry, molecular and cell biology, and bioengineering in the studies of the structure and function of muscles and mitochondria. The addition of Eva Feldman to Project 1 adds a further dimension in the fields of neurobiology and neurology for studies of the timing and interactions among age-related changes motor neurons, muscle fibers, and mitochondria. The Transgenic Animal Core in San Antonio has linked with that in Ann Arbor to facilitate the provision of KO and transgenic mice. The overall working hypothesis of the Program Project is that impaired regulation of superoxide in the Sod1-/- mouse leads to increased oxidative stress and damage in motor neurons, skeletal muscle fibers and mitochondria that cause acceleration in the development of age-related muscle atrophy and weakness. Testing this working hypothesis will provide insights into the underlying mechanisms associated with 'frailty' and 'failure to thrive' of elderly humans. The investigators in the three Projects have the diverse, well-established investigative skills, productivity, and proven ability in long term collaborations necessary to undertake this challenging task. The relevance to public health of the PPG lies in its focus on the major public health problem among the elderly of 'frailty and failure to thrive', estimated to cost $90 billion per year. Geriatricians cite a lack of understanding of the mechanisms underlying frailty as a major factor contributing to the lack of progress in the treatment of the condition. The scientific outcomes of this PPG should provide substantial scientific insights regarding the underlying causes of the condition and possible treatments.

描述（由申请人提供）：脆弱代表运动神经元变性，肌肉纤维的神经性和变性的影响，肌肉质量和力量降低以及线粒体功能障碍，但这些变量之间的原因效应之间的影响尚不清楚。该计划项目的主要长期目标是了解运动神经，肌肉纤维和线粒体负责物理脆弱的与年龄相关的恶化的基础机制。在我们前五年的支持中，研究了数十个基因敲除（KO）和过表达的成年和老鼠，并将超氧化物介导的氧化应激确定为神经肌肉系统与年龄相关的变化的关键因素。 SOD1 - / - 小鼠被鉴定为最有前途的动物模型，用于检验有关氧化应激在与年龄相关的神经，神经肌肉连接，肌肉纤维和线粒体中与年龄相关的变化中的作用的假设。此外，在神经，SOD1 - / - （N）小鼠和肌肉，SOD1 - / - （M）小鼠中分别挽救了Cuznsod活性，以解决与氧化应激有关的其他假设，这些假设对年龄相关的变化至关重要。安阿伯（Ann Arbor），利物浦（Liverpool）和圣安东尼奥（San Antonio）的三个研究小组已经证明了他们与众多会议合作的能力，并发表了主要的合着论文，这些论文将其在生理学，生物化学，分子和细胞生物学方面的专业知识以及在肌肉和肌肉和线粒体的结构和功能研究中的生物化学方面联系起来。将EVA Feldman添加到项目1中增加了神经生物学和神经病学领域的进一步维度，用于研究与年龄相关的变化运动神经元，肌肉纤维和线粒体之间的时间和相互作用。圣安东尼奥的转基因动物核心与Ann Arbor中的转基因动物核心有关，以促进KO和转基因小鼠的提供。该计划项目的总体工作假设是，SOD1 - / - 小鼠中超氧化物的调节受损会导致运动神经元，骨骼肌纤维和线粒体的氧化应激和损伤增加，从而导致年龄相关肌肉萎缩和弱点的发展加速。检验该工作假设将提供有关与“脆弱”和“未能壮成长”相关的基本机制的见解。这三个项目的调查人员具有多样化，建立了良好的调查技能，生产力和经过证明的能力，可以在承担这项挑战的任务中长期合作。与PPG的公共卫生有关的相关性在于它的重点是“脆弱和未能成长”的老年人，估计每年耗资900亿美元。老年医生认为缺乏对脆弱机制的理解是导致病情治疗中缺乏进展的主要因素。该PPG的科学结果应就疾病和可能的治疗方法提供实质性的科学见解。