Increased mitochondrial ROS production is required for ventilator‐induced myonuclear apoptosis in the diaphragm

Abstract

Prolonged mechanical ventilation (MV) results in diaphragm atrophy that is accompanied by myonuclear apoptosis and increased mitochondrial production of reactive oxygen species (ROS). However, it is unknown if this increased mitochondrial ROS production is essential for MV‐induced myonuclear apoptosis in the diaphragm. We tested the hypothesis that during MV, mitochondrial ROS induce the mitochondrial‐mediated apoptotic pathway in the diaphragm.MethodsCause‐and‐effect was determined by using a selective mitochondrial targeted antioxidant (SS‐31) that prevents MV‐induced mitochondrial ROS emission. Sprague‐Dawley rats were divided into three groups: 1) control, 2) mechanically ventilated for 12 hrs and 3) mechanically ventilated for 12 hrs with SS‐31.ResultsCompared to control, MV induced a significant increase in diaphragmatic active caspase‐9 and cytosolic cytochrome‐c. Treatment with SS‐31 prevented the MV‐induced increases in these upstream signals of myonuclear apoptosis. Additionally, SS‐31 significantly decreased the MV‐induced presence of diaphragmatic TUNEL positive nuclei, a positive indicator for apoptotic cell death.ConclusionThese results provide evidence that MV‐induced increases in mitochondrial ROS promote mitochondrial‐mediated myonuclear apoptosis in diaphragm during MV. Supported by the NIH RO1 HL087839 awarded to SKP.