REDOX MECHANISMS OF RESPIRATORY MUSCLE STRESS ADAPTATION

呼吸肌应激适应的氧化还原机制

• 批准号: 6628974
• 负责人: THOMAS Lindsay CLANTON
• 金额: $ 36.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628974
• 关键词: biological signal transduction; biomechanics; confocal scanning microscopy; diaphragm; environmental adaptation; environmental stressor; fatigue; fluorescent dye /probe; free radical oxygen; heat stimulus; hypoxia; laboratory mouse; mitochondria; muscle contraction; muscle metabolism; muscle stress; muscle tone; oxidative stress; respiratory muscles; superoxides

DESCRIPTION: During intense exercise, skeletal muscles must withstand stress in the form of heat, tissue hypoxia, reactive oxygen, steep osmotic gradients, elevated tissue pressure, sheer stress and over-stimulation. Few cells of the body could survive such punishment and yet skeletal muscles survive and adapt to it. To accomplish this, they must be pre-programmed in some primordial way to sense when the environment is threatening and make rapid adaptations in contractile and metabolic activity to reduce the threat to survival. We hypothesize that reactive oxygen is an important signal used for this purpose, particularly under conditions of metabolic stress, such as high energy demand (over-stimulation), low energy supply (hypoxia) or overheating (thermal stress). In this funding period, we will investigate the mechanisms by which reactive oxygen participates in muscle adaptation to stress. The study will focus on isolated, perfused mouse diaphragm. SPECIFIC AIM 1 will test the hypothesis that reactive oxygen is formed as an acute response to hypoxia, heat stress and over-stimulation (resulting in fatigue) and that conditions of disordered O2 supply and demand are necessary prerequisites for this response. Both tissue fluorescence and confocal imaging techniques will be used in these experiments. SPECIFIC AIM 2 will test the hypothesis that reactive oxygen plays an important role as a signaling agent to modify metabolic pathways during stress in such a way as to favor of accumulation of metabolites, preservation of ATP and reduction of creatine phosphate. This will be tested by blocking the effects or reactive oxygen with antioxidants and by using transgenic species with antioxidant over-expression. Measures phosphate metabolism, mitochondrial function, creatine kinase function and activity of other metabolic enzymes will be assessed. SPECIFIC AIM 3 will test the hypothesis that reactive oxygen plays a role in acute changes in the cytoskeleton during stress that promote an increase in muscle "stiffness" and favor preservation of muscle structural integrity. Biophysical measurements of the viscoelastic properties of muscle will be tested before and during stress. These studies should provide new information regarding the adaptive mechanisms muscle in stressful environments.

描述：在激烈的运动中，骨骼肌必须承受压力， 热的形式，组织缺氧，活性氧，陡峭的渗透压梯度， 组织压力升高、剪切应力和过度刺激。少数细胞的 身体可以在这样的惩罚中幸存下来，而骨骼肌却能存活并适应 要做到这一点，它们必须以某种原始的方式预先编程， 当环境受到威胁时， 收缩和代谢活动，以减少对生存的威胁。我们 假设活性氧是用于此目的重要信号， 特别是在代谢应激的条件下，例如高能量需求， （过度刺激）、低能量供应（缺氧）或过热（热 应力）。在这一资助期间，我们将调查 活性氧参与肌肉对应激的适应。这项研究将 集中在离体灌注的小鼠膈肌上。具体目标1将测试 假设活性氧是作为对缺氧、热 压力和过度刺激（导致疲劳）以及 混乱的O2供应和需求是这种反应的必要先决条件。 组织荧光和共聚焦成像技术将用于这些研究。 实验SPECIFIC AIM 2将检验活性氧在 作为一种信号传导剂， 以有利于代谢物积累、保存 ATP和磷酸肌酸的减少。这将通过阻塞 影响或活性氧与抗氧化剂和通过使用转基因物种 抗氧化剂过度表达。测量磷酸盐代谢，线粒体 肌酸激酶功能和其他代谢酶的活性将 进行评估。SPECIFIC AIM 3将检验活性氧在 在应激过程中细胞骨架的急性变化中发挥作用， 增加肌肉“硬度”并有利于保持肌肉结构 完整肌肉粘弹性的生物物理测量 将在压力前和压力期间进行测试。这些研究将提供新的 关于压力环境中适应机制肌肉的信息。