Reactive Oxygen Species: Stress and Damage in Old Muscle

描述（由申请人提供）：虚弱是运动神经元变性、肌纤维失神经支配和变性、肌肉质量和力量下降以及线粒体功能障碍的综合影响，但这些变量之间的因果关系尚不清楚。该项目的主要长期目标是了解与年龄相关的运动神经、肌肉纤维和线粒体退化的机制，这些退化会导致身体虚弱。在过去的五年里，我们对数十只基因敲除（KO）和过表达的成年和老年小鼠进行了研究，发现超氧化物介导的氧化应激是神经肌肉系统年龄相关变化的关键因素。Sod1-/-小鼠被认为是最有希望的动物模型，用于测试氧化应激在神经、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。此外，在神经、Sod1-/-(N)小鼠和肌肉、Sod1-/-(M)小鼠中分别恢复了CuZnSOD活性，以解决氧化应激对年龄相关变化至关重要的特定组织相关的其他假设。安娜堡、利物浦和圣安东尼奥的三个研究小组已经证明了他们的合作能力，他们在许多会议上合作，并发表了主要的合著论文，将他们在生理学、生物化学、分子和细胞生物学以及肌肉和线粒体结构和功能研究中的生物工程方面的专业知识联系起来。伊娃·费尔德曼的加入为研究运动神经元、肌肉纤维和线粒体与年龄相关的变化之间的时间和相互作用的神经生物学和神经学领域增加了一个新的维度。圣安东尼奥的转基因动物中心与安娜堡的转基因动物中心建立了联系，以方便提供KO和转基因小鼠。该项目的总体工作假设是，Sod1-/-小鼠体内超氧化物的调节受损，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，从而加速与年龄相关的肌肉萎缩和无力的发展。测试这一有效假设将有助于深入了解与老年人“脆弱”和“无法茁壮成长”相关的潜在机制。这三个项目的调查人员拥有多样化的、成熟的调查技能、生产力和长期合作的能力，以承担这项具有挑战性的任务。PPG与公共卫生的相关性在于其重点关注老年人“虚弱和无法茁壮成长”的主要公共卫生问题，估计每年耗资900亿美元。老年病专家指出，缺乏对虚弱机制的理解是导致治疗进展缓慢的主要因素。该PPG的科学结果应提供有关该疾病的潜在原因和可能的治疗方法的实质性科学见解。

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.