REACTIVE OXYGEN SPECIES: STRESS AND DAMAGE IN OLD MUSCLE

活性氧：老肌肉的压力和损伤

• 批准号: 7067469
• 负责人: JOHN Arthur FAULKNER
• 金额: $ 1.76万
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067469
• 关键词: aging; free radical oxygen; oxidative stress; striated muscles

The annual cost of physical frailty in the United States is enormous, $80 billion, yet the cause of muscle atrophy and weakness is unknown. The working hypothesis of this Program Project is that the atrophy and weakness of skeletal muscles in old animals is caused by the imbalance between the generation of reactive oxygen species (ROS), particularly during demanding protocols of aerobic contractions, and in the presence of deficiencies in antioxidant systems. The purpose of the Program Project is to determine the effect of a demanding isometric contraction protocol on the generation of ROS, ROS-induced damage and adaptations of heat shock proteins in skeletal muscles of 8-month old (young/adult) and 28-month-old (old) mice. Comparisons will be made among wild type (WT) mice and mice with mitochondrial or cytosolic antioxidant systems deficiencies due to partial (Sod+/- and Sod1+/-) or complete (Sod2D3-/- and Sod1-/-) knockouts, or mice enhanced by transgenic procedures (Sod2Tg+/-) or by aerobic conditioning. In aerobic organisms, ROS are generated constantly with 85% generated in the mitochondria and the remainder from extra-mitochondrial sources. Particularly for skeletal muscles of young healthy animals with intact or enhanced antioxidant systems, even with the increased ROS generation of a demanding aerobic contraction protocol, the generation of superoxide anions produces an ROS stress and adaptations in HSPs, but no ROS damage. In contrast, for skeletal muscles of old animals, or animals with impaired antioxidant systems, ROS stress has the potential to produce sufficient damage at rest or with contract protocols to cause atrophy, weakness and loss of power. The working hypothesis will be tested rigorously through experiments on four Group Hypotheses tested collaboratively, and specific hypotheses, and specific hypotheses tested on young/adult and old mice by Project #1 on conditions of ROS stress and damage following a demanding aerobic contraction protocol; by Project #2 regarding mitochondrial function of muscles from WT and Sod2 deficient and enhanced mice, and by Project #3 comparing expression patterns of satellite stem cells from different groups. The projects will be assisted by Administrative, Transgenic Animal, and Biochemistry Cores and a Statistical Unit.

美国的年身脆弱成本是巨大的，耗资800亿美元，但肌肉萎缩和弱点的原因尚不清楚。该计划项目的工作假设是，老动物中骨骼肌的萎缩和弱点是由活性氧（ROS）产生的不平衡引起的，尤其是在有氧收缩苛刻的方案中，以及在抗氧化系统中存在缺陷的情况下。该计划项目的目的是确定苛刻的等距收缩方案对8个月大的（年轻/成人）和28个月大的（老）小鼠的骨骼肌中ROS的产生，ROS诱导的损伤和热休克蛋白的适应作用。比较将在野生型（WT）小鼠和小鼠中与线粒体或胞质抗氧化剂系统缺陷，这是由于部分（SOD +/-和SOD1 +/-）或完整（SOD2D3 - / - 和SOD1-和SOD1--------------）敲除或通过Transgenic erentenic Protifure（SOD2D3 - / - 和SOD1-/ - - ）淘汰（SOD2D3 - / - 和SOD1-----）或通过跨基因级别（SOD2D3 - / - - - - - - ）或通过eribice（SOD1-/ - - - ）或 - 或通过SOD2TG +/------或 - ）进行了比较。在有氧生物中，ROS不断产生，线粒体中产生了85％，其余产生来自线粒体外来源。特别是对于具有完整或增强抗氧化剂系统的年轻健康动物的骨骼肌，即使ROS的产生增加了苛刻的有氧收缩方案，超氧化物阴离子的产生也会产生HSP的ROS应力和适应性，但没有ROS损害。相比之下，对于老动物的骨骼肌或具有抗氧化剂系统受损的动物，ROS应力有可能在休息时或使用合同方案产生足够的损害，以引起萎缩，弱点和权力损失。将通过项目＃1通过项目＃1对年轻/成人和旧小鼠测试的特定假设进行的四个组假设进行实验，并通过对苛刻的有氧运动收缩方案后的ROS应激和损害的条件进行测试的特定假设来严格检验。通过项目＃2，介绍了来自WT和SOD2缺乏和增强小鼠的肌肉的线粒体功能，以及通过项目＃3比较来自不同组的卫星干细胞的表达模式。这些项目将得到行政，转基因动物和生物化学核心以及统计单位的协助。