Diaphragm muscle weakness following acute sustained hypoxic stress in the mouse is prevented by pretreatment with N-acetyl cysteine
O'Leary, Andrew J.
Drummond, Sarah E.
O'Halloran, Ken D.
Oxygen deficit (hypoxia) is a major feature of cardiorespiratory diseases characterized by diaphragm dysfunction, yet the putative role of hypoxic stress as a driver of diaphragm dysfunction is understudied. We explored the cellular and functional consequences of sustained hypoxic stress in a mouse model. Adult male mice were exposed to 8 hours of normoxia, or hypoxia (FiO(2) = 0.10) with or without antioxidant pretreatment (N-acetyl cysteine, 200 mg/kg i.p.). Ventilation and metabolism were measured. Diaphragm muscle contractile function, myofibre size and distribution, gene expression, protein signalling cascades, and oxidative stress (TBARS) were determined. Hypoxia caused pronounced diaphragm muscle weakness, unrelated to increased respiratory muscle work. Hypoxia increased diaphragm HIF-1 alpha protein content and activated MAPK, mTOR, Akt, and FoxO3a signalling pathways, largely favouring protein synthesis. Hypoxia increased diaphragm lipid peroxidation, indicative of oxidative stress. FoxO3 and MuRF-1 gene expression were increased. Diaphragm 20S proteasome activity and muscle fibre size and distribution were unaffected by acute hypoxia. Pretreatment with N-acetyl cysteine substantially enhanced cell survival signalling, prevented hypoxia-induced diaphragm oxidative stress, and prevented hypoxia-induced diaphragm dysfunction. Hypoxia is a potent driver of diaphragm weakness, causing myofibre dysfunction without attendant atrophy. N-acetyl cysteine protects the hypoxic diaphragm and may have application as a potential adjunctive therapy.
Hypoxic stress , Cardiorespiratory diseases , Hypoxia , Respiratory muscle , Signalling pathways
O’Leary, A. J., Drummond, S. E., Edge, D., and O'Halloran, K. D. (2018) 'Diaphragm muscle weakness following acute sustained hypoxic stress in the mouse is prevented by pretreatment with N-acetyl cysteine', Oxidative Medicine and Cellular Longevity, 2018, 4805493 (19pp). doi: 10.1155/2018/4805493