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Pulmonary Division, Department of Medicine, Case Western Reserve University, and MetroHealth Medical Center, Cleveland, Ohio 44109
Contraction-induced respiratory muscle fatigue and sepsis-related reductions in respiratory muscle force-generating capacity are mediated, at least in part, by reactive oxygen species (ROS). The subcellular sources and mechanisms of generation of ROS in these conditions are incompletely understood. We postulated that the physiological changes associated with muscle contraction (i.e., increases in calcium and ADP concentration) stimulate mitochondrial generation of ROS by a phospholipase A2 (PLA2)-modulated process and that sepsis enhances muscle generation of ROS by upregulating PLA2 activity. To test these hypotheses, we examined H2O2 generation by diaphragm mitochondria isolated from saline-treated control and endotoxin-treated septic animals in the presence and absence of calcium and ADP; we also assessed the effect of PLA2 inhibitors on H2O2 formation. We found that 1) calcium and ADP stimulated H2O2 formation by diaphragm mitochondria from both control and septic animals; 2) mitochondria from septic animals demonstrated substantially higher H2O2 formation than mitochondria from control animals under basal, calcium-stimulated, and ADP-stimulated conditions; and 3) inhibitors of 14-kDa PLA2 blocked the enhanced H2O2 generation in all conditions. We also found that administration of arachidonic acid (the principal metabolic product of PLA2 activation) increased mitochondrial H2O2 formation by interacting with complex I of the electron transport chain. These data suggest that diaphragm mitochondrial ROS formation during contraction and sepsis may be critically dependent on PLA2 activation.
free radicals; skeletal muscle; diaphragm; respiratory muscles; mitochondria; phospholipase
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