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

• Published in: Oxidative medicine and cellular longevity 2018-01, Vol.2018 (2018), p.1-19
• Main Authors: O’Halloran, Ken D., Edge, Deirdre, Drummond, Sarah E., O’Leary, Andrew J.
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Acetylcysteine - therapeutic use; Analysis; Animals; Antioxidants; Atrophy; Autophagy - drug effects; Autophagy - genetics; Biomechanical Phenomena; Carbon dioxide; Carbon Dioxide - metabolism; Chymotrypsin - metabolism; Cystine; Diagnostic reagents industry; Diaphragm - drug effects; Diaphragm - pathology; Diaphragm - physiopathology; Forkhead Box Protein O3 - metabolism; Gene expression; Gene Expression Regulation - drug effects; Hypoxia; Hypoxia - complications; Hypoxia - genetics; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kinases; Male; MAP Kinase Signaling System - drug effects; Metabolism; Mice, Inbred C57BL; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - pathology; Muscle weakness; Muscle Weakness - drug therapy; Muscle Weakness - etiology; Muscle Weakness - genetics; Muscle Weakness - prevention & control; Musculoskeletal system; Oxidative stress; Oxidative Stress - drug effects; Phosphorylation; Phosphorylation - drug effects; Physiology; Prevention; Proteasome Endopeptidase Complex - metabolism; Protein biosynthesis; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary Ventilation - drug effects; Respiration; Respiratory distress syndrome; Rodents; Sepsis; Stress, Physiological - drug effects; Thiobarbituric Acid Reactive Substances - metabolism; Thiols; TOR Serine-Threonine Kinases - metabolism; Ventilators
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2018/4805493

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.