Exercise‐induced protection against ventilator‐induced diaphragm atrophy is dependent upon increased diaphragmatic levels of manganese superoxide dismutase

Abstract

Mechanical ventilation (MV) is a life‐saving intervention for patients unable to sustain adequate pulmonary gas exchange on their own. Unfortunately, prolonged MV results in rapid atrophy and contractile dysfunction of the diaphragm, collectively termed ventilator‐induced diaphragm dysfunction (VIDD). Although the mechanisms responsible for VIDD remain elusive, it is established that increased mitochondrial production of reactive oxygen species is required for the development of VIDD. Notably, recent evidence reveals that endurance exercise training performed prior to MV is sufficient to protect the diaphragm against VIDD. While the mechanisms responsible for exercise‐induced prevention of VIDD remain unknown, evidence suggests that endurance exercise training may reduce diaphragm oxidative damage by elevating endogenous antioxidant enzyme expression. Therefore, these experiments tested the hypothesis that endurance exercise‐induced protection against VIDD is dependent upon increased diaphragmatic levels of the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD). Cause and effect was determined by administering an antisense oligonucleotide against MnSOD to prevent the exercise‐induced increase in diaphragmatic MnSOD. Our data confirm that exercise training performed prior to prolonged MV results in protection against VIDD. Importantly, prevention of the exercise‐induced increases in diaphragmatic MnSOD resulted in a loss of exercise‐mediated protection against MV‐induced diaphragm atrophy. In contrast, prevention of exercise‐induced increases in MnSOD did not result in a loss of exercise‐induced protection against MV‐induced diaphragm contractile dysfunction. Collectively, these results reveal that while increases in diaphragmatic levels of MnSOD contribute to exercise induced protection against VIDD, increased MnSOD is not the sole mechanism responsible for exercise‐induced protection against VIDD.Support or Funding InformationSupported by NIH R01 AR064189 awarded to SKP