Redox Signaling in Skeletal Muscle Biology

描述(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。机械负荷会导致葡萄糖摄取增加。骨骼肌在运动中产生RO的速率更高，暴露在过氧化氢中会刺激葡萄糖的摄取。初步数据显示，抗氧化剂的预处理减少了肌肉运动对葡萄糖的摄取。综上所述，这些数据表明，肌肉来源的ROS可能在机械负荷过程中作为第二信使促进葡萄糖摄取。当前的项目针对的是这个模型。目的1.评价肌源性ROS在机械负荷过程中对葡萄糖摄取的调节作用。骨骼肌不断产生过氧化氢和相关的ROS分子，这一过程在收缩活动期间会增加。过氧化氢已被用作刺激葡萄糖摄取的工具，但肌源性ROS的生理效应尚未确定。我们将通过检验两个假设来实现这一点：a.)骨骼肌纤维中的ROS水平通过外部机械负荷而增加。B.)肌源性ROS介导机械负荷引起的葡萄糖摄取增加。目的2.确定细胞外钙内流是否刺激ROS依赖的葡萄糖转运。在收缩活动中，细胞外钙似乎进入肌肉纤维并刺激细胞内ROS的产生。我们推测这是一种发生在细胞膜附近的局部反应，由机械负荷诱导，并刺激葡萄糖摄取。我们的模型将通过检验两个假设进行评估：A.)机械负荷可增加肌膜下钙离子浓度。B.细胞外钙刺激ROS的产生和葡萄糖的摄取，以响应负荷。

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.