REDOX MECHANISMS OF RESPIRATORY MUSCLE STRESS ADAPTATION

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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.