Reactive Oxygen Species: Stress and Damage in Old Muscle

描述(申请人提供)：脆弱性代表运动神经元变性、肌肉纤维失神经和退化、肌肉质量和力量减少以及线粒体功能障碍的影响的总和，但这些变量之间的因果关系尚不清楚。该计划项目的主要长期目标是了解导致身体虚弱的运动神经、肌肉纤维和线粒体因年龄而恶化的潜在机制。在我们之前的五年支持期间，对数十只敲除(KO)和过度表达的成年和老年小鼠进行了研究，超氧化物介导的氧化应激被确定为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测试有关氧化应激在神经、神经肌肉接头、肌肉纤维和线粒体年龄相关变化中的作用的假说的动物模型。此外，在神经SOD1-/-(N)小鼠和肌肉SOD1-/-(M)小鼠中，CuZnSOD活性分别被挽救，以解决与特定组织有关的其他假设，在这些组织中，氧化应激对年龄相关变化至关重要。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有能力与许多会议合作，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生物工程方面的专业知识联系在一起，研究肌肉和线粒体的结构和功能。Eva Feldman加入到项目1中，在神经生物学和神经学领域增加了进一步的维度，用于研究与年龄相关的变化的时间和相互作用，运动神经元、肌肉纤维和线粒体。圣安东尼奥的转基因动物核心已与安娜堡的转基因动物核心联系在一起，以促进提供KO和转基因小鼠。该计划项目的总体工作假设是，SOD1-/-小鼠体内超氧化物歧化调节受损会导致运动神经元、骨骼肌纤维和线粒体氧化应激和损伤增加，从而加速发展与年龄相关的肌肉萎缩和虚弱。检验这一工作假说将为我们深入了解与老年人“虚弱”和“不能茁壮成长”相关的潜在机制。这三个项目中的调查人员拥有多样化的、成熟的调查技能、生产力和长期合作所需的公认能力，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，它关注的是老年人的主要公共卫生问题，即虚弱和不能茁壮成长，估计每年花费900亿美元。老年科医生指出，对虚弱的潜在机制缺乏了解是导致这种疾病治疗缺乏进展的一个主要因素。这项PPG的科学结果应该为这种疾病的根本原因和可能的治疗方法提供实质性的科学见解。

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.