REACTIVE OXYGEN SPECIES: STRESS AND DAMAGE IN OLD MUSCLE

在美国，身体虚弱每年造成的损失是巨大的，达800亿美元，但肌肉萎缩和虚弱的原因尚不清楚。该计划项目的工作假设是，老年动物骨骼肌的萎缩和虚弱是由活性氧物种(ROS)的产生失衡引起的，特别是在要求苛刻的有氧收缩过程中，以及在抗氧化系统存在缺陷的情况下。本项目的目的是确定严格的等长收缩方案对8月龄(幼年/成年)和28月龄(老年)小鼠骨骼肌中ROS的产生、ROS诱导的损伤和热休克蛋白的适应的影响。将在野生型(WT)小鼠和由于部分(Sod+/-和Sod1+/-)或完全(Sod2D3-/-和Sod1-/-)基因敲除而导致线粒体或胞质抗氧化系统缺陷的小鼠，或通过转基因程序(Sod2Tg+/-)或有氧调节增强的小鼠之间进行比较。在好氧生物中，ROS不断产生，85%产生在线粒体中，其余来自线粒体外来源。特别是对于具有完整或增强的抗氧化系统的年轻健康动物的骨骼肌，即使在严格的有氧收缩方案中ROS生成增加，超氧阴离子的生成也会在HSP中产生ROS压力和适应，但不会造成ROS损伤。相比之下，对于老年动物的骨骼肌，或抗氧化系统受损的动物，ROS应激有可能在休息或收缩协议下产生足够的损伤，导致萎缩、虚弱和丧失动力。工作假说将通过四组共同测试的假说以及特定假说和特定假说在年轻/成年和老年小鼠上进行测试，通过项目#1关于ROS应激和遵循严格的有氧收缩方案的损伤条件的实验，通过项目#2关于WT和Sod2缺乏和增强的小鼠肌肉的线粒体功能的实验，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，来严格检验工作假说。这些项目将得到行政、转基因动物和生化核心以及一个统计股的协助。

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.