Redox Signaling in Skeletal Muscle Biology

描述（由申请人提供）：骨骼肌持续摄取葡萄糖，这是调节血糖水平和向工作肌肉输送能量的关键过程。机械负荷导致葡萄糖摄取增加。在运动过程中，骨骼肌以更高的速率产生ROS，并且暴露于过氧化氢刺激葡萄糖摄取。初步数据显示，抗氧化剂预处理减少了运动肌肉对葡萄糖的摄取。综上所述，这些数据表明，肌肉来源的ROS可能作为第二信使，以促进葡萄糖的摄取在机械负荷。目前的项目就是针对这一模式。目标1.评估肌肉来源的ROS作为机械负荷期间葡萄糖摄取的介质。骨骼肌不断产生过氧化氢和相关的ROS分子，这是一个在收缩活动期间增加的过程。过氧化氢已被用作刺激葡萄糖摄取的工具，但肌肉来源的ROS的生理作用尚未确定。我们将通过测试两个假设来做到这一点：A。骨骼肌纤维中的ROS水平通过外部机械负荷而增加。B.）肌肉来源的ROS介导机械负荷诱导的葡萄糖摄取增加。目标2.确定细胞外钙离子内流是否刺激ROS依赖性葡萄糖转运。在收缩活动期间，细胞外钙似乎进入肌纤维并刺激细胞内ROS产生。我们假设这是一个局部反应，发生在细胞膜附近，由机械负荷引起，并刺激葡萄糖摄取。我们的模型将通过测试两个假设来评估：A。机械负荷增加肌膜下钙浓度。B。细胞外钙刺激ROS的产生和葡萄糖的摄取响应负荷。

DESCRIPTION (provided by applicant): Skeletal muscle continually takes up glucose, a process critical for regulation of blood sugar levels and for energy delivery to working muscle. Mechanical loading causes glucose uptake to increase. Skeletal muscles produce ROS at higher rates during exercise and exposure to hydrogen peroxide stimulates glucose uptake. Preliminary data show that antioxidant pretreatment decreases glucose uptake by exercising muscle. Taken together, these data suggest muscle-derived ROS might function as second messengers to promote glucose uptake during mechanical loading. The current project addresses this model. Aim 1. To evaluate muscle-derived ROS as mediators of glucose uptake during mechanical loading. Skeletal muscle continually generates hydrogen peroxide and related ROS molecules, a process that increases during contractile activity. Hydrogen peroxide has been used as a tool to stimulate glucose uptake but the physiological effects of muscle-derived ROS have not been determined. We will do so by testing two hypotheses: A.) ROS levels in skeletal muscle fibers are increased by external mechanical loading. B.) Muscle-derived ROS mediate the increase in glucose uptake induced by mechanical loading. Aim 2. To determine if influx of extracellular calcium stimulates ROS-dependent glucose transport. During contractile activity, extracellular calcium appears to enter muscle fibers and stimulate intracellular ROS production. We postulate this is a localized response that occurs near the cell membrane, is induced by mechanical loading, and stimulates glucose uptake. Our model will be evaluated by testing two hypotheses: A.) Mechanical loading increases subsarcolemmal calcium concentration. B. Extracellular calcium stimulates ROS production and glucose uptake in response to loading.