Redox Signaling in Skeletal Muscle Biology

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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.