The effects of chronic hypoxia (CH) on respiratory muscle are poorly understood. The aim of the present study was to examine the effects of CH on respiratory muscle structure and function, and to determine whether nitric oxide is implicated in respiratory muscle adaptation to CH.Male Wistar rats were exposed to CH for 1-6 weeks. Sternohyoid and diaphragm muscle contractile properties, muscle fibre type and size, the density of fibres expressing sarco/ endoplasmic reticulum calcium-ATPase (SERCA) 2 and sodium-potassium ATPase (Na + ,K + -ATPase) pump content were determined. Muscle succinate dehydrogenase (SDH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) dehydrogenase activities were also assessed. Acute and chronic blockade of nitric oxide synthase (NOS) was employed to determine whether or not NO is critically involved in functional remodelling in CH muscles. CH improved diaphragm, but not sternohyoid, fatigue tolerance in a time-dependent fashion. This adaptation was not attributable to increased SDH or NADPH dehydrogenase activities. The areal density of muscle fibres and relative area of fibres expressing SERCA2 were unchanged. Na + ,K + -ATPase pump content was significantly increased in CH diaphragm. Chronic NOS inhibition decreased diaphragm Na + ,K + -ATPase pump content and prevented CH-induced increase in muscle endurance. This study provides novel insight into the mechanisms involved in CH-induced muscle plasticity. The results may be of relevance to respiratory disorders characterised by CH, such as chronic obstructive pulmonary disease.KEYWORDS: Chronic obstructive pulmonary disease, fatigue, myosin heavy chain isoforms, nitric oxide synthase, sarco/endoplasmic reticulum calcium-ATPase 2 S keletal muscle has enormous capacity for remodelling, as evident in various physiological and pathophysiological settings. Chronic hypoxia (CH), a feature of respiratory disease, is known to affect skeletal muscle structure and function. Alterations include changes in capillarity [1,2], fibre size and distribution [3][4][5][6][7][8][9][10], oxidative capacity [5,6,11,12] and contractile performance [5,9,[13][14][15][16]. CH induces reflex hyperventilation. Thus respiratory muscles are unique in that they must increase their workload in the face of a reduction in oxygen availability, necessary for aerobic metabolism. Respiratory muscle remodelling is a feature of chronic obstructive pulmonary disease (COPD) [17][18][19][20][21][22][23][24][25][26][27], which may be the result of hypoxic adaptation. Surprisingly, there is a general paucity of information concerning the effects of CH on respiratory muscle structure and function despite the clinical relevance. Translational animal models permit examination of the effects of CH on skeletal muscle independent of other confounding factors that are present in disease. Furthermore, they permit a thorough exploration of the molecular mechanisms that underpin muscle adaptation. As such, the major aim of the present study was to conduct a compreh...