ROLE OF OXIDATIVE STRESS IN AGE-RELATED LOSS OF MOTOR UNITS

对于人类来说，虚弱是衰老和衰老最显著和最一贯的特征之一 代表肌肉萎缩和虚弱的影响的总和。对于老年人来说，身体虚弱 会导致行动不便、摔倒的高风险、肌肉损伤的发生率增加，以及 生活质量下降。尽管在过去十年里做出了相当大的努力，但进展甚微。 减轻了问题的严重性。在我们支持的头五年里，对十几个或 更多品种的基因敲除和转基因小鼠，该计划项目确定Sodl^‘s小鼠是一种 非常有希望的模型来检验项目1的工作假设，即与年龄相关的骨骼肌 萎缩是由于运动单位总数的减少引起的 超氧化物介导的神经元和肌肉的氧化应激，从而：(I)氧化应激在 神经元启动运动神经元的丢失，损害幸存运动的轴突萌发 以及(Ii)肌肉纤维中的氧化应激抑制神经再生。 并导致神经肌肉纤维的收缩能力下降。在工作中 假设将通过在SodfA和SOD1/小鼠、转基因Socf7v“小鼠和 SOD1的表达仅在神经(SOC/FA(N)小鼠)或肌肉(SOC(7~/~(M)小鼠)中被挽救，并且具有组织特异性 仅在神经(Sod1A3，4N)或肌肉(Sod1A3，4^)中缺乏CuZnSOD活性的基因敲除小鼠。这些 模型允许我们测试关于系统性氧化应激的贡献的假设，以及 组织特异性氧化应激对运动神经、肌肉、运动单位和 肌肉纤维。转基因小鼠将在6-8个月和18-20个月进行研究，而 SOD1/小鼠将在6-8个月、18-20个月和28-30个月时进行研究。拟议研究的独特之处在于 来自SOC/f/“小鼠的渗透性单一纤维的运动单位特性和收缩性能的测定， 组织特异性拯救的空白小鼠和组织特异性Sodl基因敲除小鼠。此外，对生物多样性的研究 神经和肌肉变化的相对时间，这些变化以前没有在相同的 动物对于建立与年龄相关的变化的因果关系将特别有启发性 在神经肌肉系统中。与项目2和项目3一起，利用非常强大的鼠标进行研究 以上列出的模型将确定超氧化物诱导肌肉氧化应激的机制作用 和神经与年龄相关的骨骼肌萎缩。公共卫生的意义在于有必要 了解年龄相关性骨骼肌萎缩和虚弱的潜在机制 为卫生专业人员设计和实施科学的战略奠定基础，以确保 通过减少甚至消除老年人口中的身体虚弱而成功地老龄化。

For humans, frailty constitutes of one of the most prominent and consistent features of aging and represents the summation of the effects of muscle atrophy and weakness. For the elderly, physical frailty contributes to impaired mobility, a high risk of falling, an increased incidence of muscle injury, and a decreased quality of life. Despite considerable effort over the past decade, little progress has been made in lessening the magnitude of the problem. During our first five years of support, research on a dozen or more varieties of knockout and transgenic mice, this Program Project identified the Sodl^' mouse as a highly promising model to test the working hypothesis of Project 1 that age-related skeletal muscle atrophy results from a decrease in the total number of motor units caused by increased superoxide-mediated oxidative stress in neurons and muscles, such that: (i) oxidative stress in neurons initiates a loss of motor neurons, impairs axonal sprouting from surviving motor neurons, and inhibits nerve regeneration; and (ii) oxidative stress in muscles fibers inhibits reinnervation and contributes to decreased contractility of innervated muscle fibers. The working hypothesis will be tested through experiments on SodfA and Sod1+/+ mice, transgenic Socf7v" mice with Sod1 expression rescued only in nerves (Soc/fA(N+) mice) or muscles (Soc(7~/~(M+) mice), and tissue-specific knockout mice that lack CuZnSOD activity only in nerves (Sod1A3,4N)N) or muscles (Sod 1 A3,4^). These models allow us to test hypotheses regarding the contribution of systemic oxidative stress, as well as tissue-specific oxidative stress on the structure and function of motor nerves, muscles, motor units and muscle fibers. Genetically modified mice will be studied at 6-8 months and 18-20 months, whereas Sod1+/+ mice will be studied at 6-8, 18-20, and 28-30 months. Unique aspects of the proposed studies are the determination of motor unit properties and contractility of permeabilized single fibers from Soc/f/"mice,, null mice with tissue-specific rescue, and tissue-specific Sodl knockout mice. Furthermore, studies of the relative timing of changes in nerves and muscles that have not been undertaken previously in the same animals will be particularly illuminating for establishing cause-effect relationships of age-related changes in the neuromuscular system. Along with Projects 2 and 3, studies utilizing the very powerful mouse models listed above will determine the mechanistic role of superoxide-induced oxidative stress in muscles and nerves in age-related skeletal muscle atrophy. The Public Health significance is the necessity to understand the mechanisms underlying age-associated skeletal muscle atrophy and weakness to provide the basis for health professionals to design and implement scientifically based strategies to ensure 'successful aging' by reducing and perhaps even eliminating physical frailty in the elderly population.