REDOX MECHANISMS OF RESPIRATORY MUSCLE STRESS ADAPTATION

描述：在高强度运动中，骨骼肌必须承受压力。 高温、组织缺氧、活性氧、陡峭的渗透梯度、 组织压力升高，绝对压力和过度刺激。几个细胞的细胞 身体可以挺过这样的惩罚，但骨骼肌仍能存活并适应 为它干杯。要做到这一点，必须以某种原始的方式对它们进行预编程 当环境受到威胁时，能够感知并迅速做出适应 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的重要信号， 特别是在代谢压力大的情况下，如高能量需求 (过度刺激)、低能量供应(缺氧)或过热(过热) 压力)。在这一资助期间，我们将调查通过哪些机制 活性氧参与肌肉对压力的适应。这项研究将 专注于隔离的、灌流的小鼠横隔膜。特定的AIM 1将测试 认为活性氧是对低氧、高温的急性反应而形成的假说 压力和过度刺激(导致疲劳)以及 无序的氧气供需是这一反应的必要前提。 组织荧光和共聚焦成像技术将在这些 实验。特定的AIM 2将检验活性氧起作用的假设 一个重要的作用，作为一个信号媒介，以改变代谢途径在 应激方式有利于代谢物的积累、保存 降低三磷酸腺苷和降低磷酸肌酸水平。这将通过阻止 使用抗氧化剂和转基因物种对活性氧的影响 抗氧化剂过度表达。测量磷酸盐代谢，线粒体 肌酸激酶的功能和其他代谢酶的活性将 被评估。特定的AIM 3将检验活性氧发挥作用的假设 在应激过程中细胞骨架的急剧变化中所起的作用 增加肌肉“僵硬”，有利于肌肉结构的保存 正直。肌肉粘弹性特性的生物物理测量 将在压力前和压力期间进行测试。这些研究应该提供新的 关于肌肉在压力环境中的适应机制的信息。

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.