Azumolene administration during prolonged mechanical ventilation does not prevent mitochondrial reactive oxygen species emission or diaphragm atrophy

Abstract

Although mechanical ventilation (MV) is a life‐saving measure in patients suffering from respiratory failure, prolonged MV causes the rapid development of diaphragm atrophy. MV‐induced diaphragm atrophy is due, in part, to increased production of reactive oxygen species (ROS) in diaphragm mitochondria. Moreover, increased cytosolic calcium in diaphragm fibers, perhaps from leakage of the ryanodine receptor (RyR), may be responsible for this increase in mitochondrial ROS production during MV and the subsequent activation of calpain and caspase‐3. Therefore, we hypothesized that blocking the RyR in diaphragm fibers with azumolene (Az) would prevent MV‐induced increases in mitochondrial ROS production, protease activation, and diaphragm atrophy. However, our results reveal that Az treatment did not attenuate the MV‐induced increase in mitochondrial ROS emission or prevent the MV‐induced activation of calpain and caspase‐3 in the diaphragm. Further, Az treatment did not prevent MV‐induced diaphragmatic fiber atrophy. We conclude that inhibition of the RyR in diaphragm muscle fibers is not sufficient to prevent MV‐induced diaphragm atrophy.Supported by NIH R01 HL087839 (SKP) and AHA 11PRE6520001 (EET).