Reactive oxygen species mediated diaphragm fatigue in a rat model of chronic intermittent hypoxia. Issue 4 (13th February 2014)

• Record Type: Journal Article
• Authors: Shortt, Christine M.; Fredsted, Anne; Chow, Han Bing; Williams, Robert; Skelly, J. Richard; Edge, Deirdre; Bradford, Aidan; O'Halloran, Ken D.
• Is Part Of: Experimental physiology. Volume 99:Issue 4(2014:Apr.)
• Page Start: 688
• Page End: 700
• Publication Date: 2014-02-13
• Subjects: Physiology, Experimental -- Periodicals; 571.0724
• DOI: 10.1113/expphysiol.2013.076828
• Languages: English
• ISSNs: 0958-0670

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="eph1420-sec-0010" sec-type="section"> <title>New Findings</title> <p> <list id="eph1420-list-0001" list-type="bullet"> <list-item> <p> <bold>What is the central question of this study?</bold> </p> <p>The effects of chronic intermittent hypoxia (CIH) on respiratory muscles are relatively underexplored. It is speculated that muscle dysfunction and other key morbidities associated with sleep apnoea are the result of CIH‐induced oxidative stress. We sought to investigate the putative role of CIH‐induced reactive oxygen species in the development of respiratory muscle dysfunction.</p> </list-item> <list-item> <p> <bold>What is the main finding and its importance?</bold> </p> <p>The CIH‐induced diaphragm muscle fatigue is time and intensity dependent and is associated with a modest oxidative stress. Supplementation with <italic>N</italic>‐acetyl cysteine prevents CIH‐induced diaphragm muscle dysfunction, suggesting that antioxidant supplementation may have therapeutic value in respiratory muscle disorders characterized by CIH, such as obstructive sleep apnoea.</p> </list-item> </list> </p> </sec> <sec id="eph1420-sec-0020" sec-type="section"> <p>Respiratory muscle dysfunction documented in sleep apnoea patients is perhaps due to oxidative stress secondary to chronic intermittent hypoxia (CIH). We sought to explore the effects of different CIH protocols on respiratory muscle form and function in a rodent model. Adult male Wistar rats were exposed to CIH (<italic>n</italic> = 32) consisting of 90 s normoxia–90 s hypoxia (either 10 or 5% oxygen at the nadir; arterial O<sub>2</sub> saturation ∼90 or 80%, respectively] for 8 h per day or to sham treatment (air–air, <italic>n</italic> = 32) for 1 or 2 weeks. Three additional groups of CIH‐treated rats (5% O<sub>2</sub> for 2 weeks) had free access to water containing <italic>N</italic>‐acetyl cysteine (1% NAC, <italic>n</italic> = 8), tempol (1 m<sc>m</sc>, <italic>n</italic> = 8) or apocynin (2 m<sc>m</sc>, <italic>n</italic> = 8). Functional properties of the diaphragm muscle were examined <italic>ex vivo</italic> at 35°C. The myosin heavy chain and sarco(endo)plasmic reticulum Ca<sup>2+</sup>‐ATPase isoform distribution, succinate dehydrogenase and glyercol phosphate dehydrogenase enzyme activities, Na<sup>+</sup>–K<sup>+</sup>‐ATPase pump content, concentration of thiobarbituric acid reactive substances, DNA oxidation and antioxidant capacity were determined. Chronic intermittent hypoxia (5% oxygen at the nadir; 2 weeks) decreased diaphragm muscle force and endurance. All three drugs reversed the deleterious effects of CIH on diaphragm endurance, but only NAC prevented CIH‐induced diaphragm weakness. Chronic intermittent hypoxia increased diaphragm muscle myosin heavy chain 2B areal density and oxidized glutathione/reduced glutathione (GSSG/GSH) ratio. We conclude that CIH‐induced diaphragm dysfunction is reactive oxygen species dependent. <italic>N</italic>‐Acetyl cysteine was most effective in reversing CIH‐induced effects on diaphragm. Our results suggest that respiratory muscle dysfunction in sleep apnoea may be the result of oxidative stress and, as such, antioxidant treatment could prove a useful adjunctive therapy for the disorder.</p> </sec> </abstract>