REACTIVE OXYGEN SPECIES: STRESS AND DAMAGE IN OLD MUSCLE

在美国，每年因身体虚弱而造成的损失是巨大的，高达800亿美元，但肌肉萎缩和虚弱的原因尚不清楚。本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（ROS）生成之间的不平衡引起的，特别是在有氧收缩的要求协议期间，以及抗氧化系统的缺陷。该计划项目的目的是确定一个苛刻的等长收缩协议对ROS的产生，ROS诱导的损伤和热休克蛋白在8个月大（年轻/成年）和28个月大（老）小鼠骨骼肌适应的影响。将在野生型（WT）小鼠和由于部分（Sod+/-和Sod 1 +/-）或完全（Sod 2D 3-/-和Sod 1-/-）敲除而导致线粒体或细胞溶质抗氧化系统缺陷的小鼠之间进行比较，或通过转基因程序（Sod 2 Tg +/-）或通过有氧调节增强的小鼠之间进行比较。在需氧生物中，ROS不断产生，其中85%在线粒体中产生，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，即使在要求严格的有氧收缩方案的增加的ROS产生的情况下，超氧阴离子的产生产生在HSP中产生ROS应激和适应，但没有ROS损伤。相比之下，对于老年动物或抗氧化系统受损的动物的骨骼肌，活性氧应激有可能在休息时或使用合同协议时产生足够的损伤，导致萎缩、虚弱和失去动力。工作假设将通过对四个群体假设的实验进行严格测试，这些群体假设是合作测试的，具体假设是由项目#1在ROS应激和损伤条件下在要求严格的有氧收缩方案后对年轻/成年和老年小鼠进行测试的具体假设;项目#2关于WT和Sod 2缺陷和增强小鼠肌肉的线粒体功能，以及项目#3比较来自不同群体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。

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.