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Oxidative Medicine and Cellular Longevity
Volume 2018 (2018), Article ID 4805493, 19 pages
Research Article

Diaphragm Muscle Weakness Following Acute Sustained Hypoxic Stress in the Mouse Is Prevented by Pretreatment with N-Acetyl Cysteine

1Department of Physiology, School of Medicine, University College Cork, Cork, Ireland
2Department of Physiology, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin, Ireland

Correspondence should be addressed to Ken D. O’Halloran

Received 2 June 2017; Revised 29 October 2017; Accepted 12 December 2017; Published 19 February 2018

Academic Editor: Andrey J. Serra

Copyright © 2018 Andrew J. O’Leary et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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 (FiO2 = 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-1α 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.