Skeletal muscles, including the striated muscles of breathing, have a remarkable capacity for remodelling as evident in various physiological and pathophysiological settings. Hypoxia – a dominant feature of respiratory system malfunction – can drive phenotypic change in physiological systems including the respiratory control system with potential ‘adaptive’ or ‘maladaptive’ consequences for respiratory homeostasis. Despite the clinical relevance however, surprisingly little is known about the effects of chronic hypoxia on respiratory muscle physiology. We are exploring the effects of long-term hypoxia on respiratory muscle form, function and control in translational animal models of chronic sustained hypoxia (CSH) – a feature of chronic lung disease such as COPD, and chronic intermittent hypoxia (CIH) – a dominant feature of sleep-disordered breathing. In adult male Wistar rats, we examined the effects of CSH (ambient pressure = 380mmHg for 1-6 weeks) [1] and CIH (20 cycles of hypoxia [5 or 10%] per hour; 8 hours a day for 1-2 weeks) on respiratory pump and upper airway muscle contractile and endurance properties, fibre type and size, oxidative capacity, relative area of fibres expressing sarco/endoplasmic reticulum calcium ATPase (SERCA2), and Na+-K+ ATPase pump content. Moreover, we tested the hypotheses that NO is critically involved in CSH-induced respiratory muscle ‘adaptation’ whereas oxidative stress is implicated in CIH-induced respiratory muscle ‘maladaptation’. The major findings of our studies are: 1) CSH improves diaphragm (but not sternohyoid) muscle endurance; 2) CSH-induced muscle plasticity is time- and intensity-dependent and differentially expressed in respiratory muscles; 3) CSH causes diaphragm muscle fibre atrophy but does not alter fibre areal density; 4) CSH does not alter respiratory muscle oxidative capacity; 5) CSH does not increase the relative area of diaphragmatic fibres expressing SERCA2 protein; 6) CSH increases diaphragm Na+-K+ pump content; 7) Chronic NOS blockade attenuates CH-induced increases in Na+-K+ pump content and prevents CH-induced functional remodelling in the diaphragm; 8) CIH increases diaphragm muscle fatgiue; 9) CIH-induced muscle plasticity is time- and intensity-dependent; 10) CIH causes slow-to-fast fibre transition; 11) CIH does not affect respiratory muscle oxidative and glycolytic capacity; 12) CIH increases the relative area of diaphragmatic fibres expressing SERCA1 protein after 7 but not 14 days; 13) CIH does not affect respiratory muscle Na+-K+ pump content; 14) Chronic antioxidant treatments prevent CIH-induced functional remodelling in the diaphragm. To summarize, chronic hypoxia drives structural and functional remodelling in respiratory muscle. Sustained hypoxia is associated with NO-dependent ‘adaptation’ in diaphragm increasing Na+-K+ pump content concomitant with increased muscle endurance. Conversely, intermittent hypoxia increases rat diaphragm fatigue, most likely due to increased oxidative stress as antioxidant treatment (N-acetyl cysteine and Tempol) or NADPH-oxidase inhibition prevents CIH-induced diaphragm dysfunction. We conclude that hypoxia-induced muscle plasticity is dependent upon the duration, intensity and pattern of hypoxic exposure and is differentially expressed in muscles with complementary function (i.e. airway dilator muscles vs. diaphragm). In separate studies we have established that hypoxic remodelling in respiratory muscle is dependent on age and sex. Our studies are providing novel insight into mechanisms involved in chronic hypoxia-induced respiratory muscle remodelling. The results may have relevance to respiratory disorders characterized by chronic hypoxia such as COPD and sleep apnoea where respiratory muscle remodelling is known to occur.