FAILURE OF ADAPTATIONS TO CONTRACTIONS IN MUSCLES OF CUZNSOD NULL MICE

CUZNSOD 无效小鼠肌肉收缩适应失败

基本信息

批准号：
7436694
负责人：
JOHN Arthur FAULKNER
金额：
$ 21.6万
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：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7436694
关键词：
A Mouse Address Adult Age Aging Am 80 Anterior Binding Characteristics Chronic Cytosol Data Defect Elderly Failure Fiber Fluorescence Microscopy Generations Goals Injection of therapeutic agent Intramuscular Injections Isometric Contraction Knock-out Knockout Mice Measures Motor Neurons Mus Muscle Muscle Fibers Muscle function NF-kappa B Natural regeneration Nerve Neurons Numbers Oxidative Stress Physiological Processes Play Preventive Proteins Protocols documentation Quality of life Reaction Reactive Oxygen Species Recovery Reporting Role Skeletal Muscle Skeletal system Source Specific qualifier value Superoxide Dismutase Superoxides TNFRSF5 gene TNFSF11 gene Techniques Testing Therapeutic Intervention Time Transcription Factor AP-1 Wild Type Mouse Work age effect age related base catalase frailty improved muscle regeneration normal aging programs response sciatic nerve transcription factor

项目摘要

Loss of approximately 40% of skeletal muscle mass and a reduction in the ability of the remaining skeletal muscle to generate maximum force between the ages of 50 and 80 is a major factor contributing to frailty in the elderly. Despite the enormity of the problem, little progress has been made in understanding factors responsible for the physical aspects of frailty. This project has the long term goal of providing mechanistic information aimed at developing preventive and therapeutic interventions to improve strength, mobility, independence and quality of life for elderly people. Increased levels of markers of oxidative damage are associated with the age-related decline in skeletal muscle mass and strength but little direct evidence that an increase in oxidative reactions causes the decline in muscle function. Previous reports from the program project indicated that SooTA mice lacking Cu.Zn superoxide dismutase (CuZnSOD) had increased oxidative damage with advancing age that correlated with an accelerated loss of muscle mass, reduced number of fibers, defects in motor neurons and a decreased muscle force generation in comparison with wild type (WT) mice. Quiescent muscles of adult Soc/f/" mice also had increased DMA binding activity of the transcription factors, NFicB and AP-1 and increased expression of cytoprotective proteins such as MnSOD. Muscles of adult SodT'' mice also failed to fully activate adaptive responses to the increased reactive oxygen species (ROS) generated by isometric contractions. These changes are all characteristic of muscles of old WT mice. In Project 3 we will determine whether the accelerated muscle aging in Sod"/7" mice and normal aging in WT mice are associated with an increase in cytosolic superoxide in muscle fibers and whether this leads to a failure in the adaptive responses of the muscle to non-damaging contractile activity or overt damage. The working hypothesis for this study is that skeletal muscles of SodT'' mice are exposed to a chronic increased cytosolic superoxide throughout their lifetime and that this increased oxidative stress accelerates the normal age-related loss in the adaptive responses of the muscle to non-damaging isometric contractions or overt damage., The following specific aims will be addressed: 1) To determine the effect of age or lack of CuZnSOD on the cytosolic activities of superoxide and other ROS in skeletal muscle; 2) To determine the effect of replacing CuZnSOD in skeletal muscle or motor neurons on the activities of superoxide and other ROS in skeletal muscle fibers of SodT'~ mice; 3) To determine the effect of age'and lack of CuZnSOD on adaptive responses of skeletal muscle to nondamaging isometric contractions; 4) To determine whether, during regeneration from damage, skeletal muscles from old WT mice and those from mice lacking CuZnSOD show a failure of activation of NFxB and AP-1 and a lack of complete skeletal muscle regeneration compared with adult WT mice.

骨骼肌质量损失约 40%，其余骨骼的能力下降 50岁至80岁之间肌肉产生最大力量是导致身体虚弱的一个主要因素老年人。尽管问题很严重，但在理解因素方面进展甚微造成身体虚弱的原因。该项目的长期目标是提供机械旨在制定预防和治疗干预措施以提高力量、活动能力、老年人的独立性和生活质量。氧化损伤标志物水平升高与年龄相关的骨骼肌质量和力量下降有关，但几乎没有直接证据表明氧化反应的增加导致肌肉功能下降。该计划之前的报道项目表明，缺乏 Cu.Zn 超氧化物歧化酶 (CuZnSOD) 的 SooTA 小鼠的氧化水平增加随着年龄的增长，损伤与肌肉质量加速损失、肌肉数量减少相关与野生型（WT）相比，纤维、运动神经元缺陷和肌肉力量产生减少老鼠。成年 Soc/f/" 小鼠的静止肌肉也具有增加的转录 DMA 结合活性因子、NFicB 和 AP-1 以及细胞保护蛋白（如 MnSOD）的表达增加。肌肉成年 SodT'' 小鼠也未能完全激活对增加的活性氧的适应性反应（ROS）由等长收缩产生。这些变化都是老年WT小鼠肌肉的特征。在项目3中，我们将确定Sod"/7"小鼠的肌肉老化是否加速，而WT小鼠的肌肉老化是否正常小鼠与肌纤维中胞质超氧化物的增加有关，这是否会导致肌肉对非破坏性收缩活动或明显损伤的适应性反应失败。这这项研究的工作假设是 SodT'' 小鼠的骨骼肌暴露于慢性增加的细胞质超氧化物在其整个一生中都会产生，这种增加的氧化应激会加速正常的与年龄相关的肌肉对非破坏性等长收缩或明显收缩的适应性反应丧失将解决以下具体目标： 1) 确定年龄或缺乏 CuZnSOD 对超氧化物和其他物质胞质活性的影响骨骼肌中的ROS； 2) 确定替代 CuZnSOD 对骨骼肌或运动的影响神经元对SodT'~小鼠骨骼肌纤维中超氧化物和其他ROS活性的影响； 3) 至确定年龄和缺乏 CuZnSOD 对骨骼肌对非损伤的适应性反应的影响等长收缩； 4) 确定在损伤再生过程中骨骼是否老WT小鼠和缺乏CuZnSOD小鼠的肌肉显示NFxB和NFxB激活失败与成年 WT 小鼠相比，AP-1 和缺乏完整的骨骼肌再生。