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...

New findings r What is the central question of this study?Co-ordinated activity of the thoracic pump and pharyngeal dilator muscles is critical for maintaining airway calibre and respiratory homeostasis. Whilst postnatal maturation of the diaphragm has been well characterized, surprisingly little is known about the developmental programme in the airway dilator muscles. r What is the main finding and its importance?Developmental increases in force-generating capacity and fatigue in the sternohyoid and diaphragm muscles are attributed to a maturational shift in muscle myosin heavy chain phenotype. This maturation is accelerated in the sternohyoid muscle relative to the diaphragm and may have implications for the control of airway calibre in vivo.The striated muscles of breathing, including the thoracic pump and pharyngeal dilator muscles, play a critical role in maintaining respiratory homeostasis. Whilst postnatal maturation of the diaphragm has been well characterized, surprisingly little is known about the developmental programme in airway dilator muscles given that co-ordinated activity of both sets of muscles is needed for the maintenance of airway calibre and effective pulmonary ventilation. The form and function of sternohyoid and diaphragm muscles from Wistar rat pups [postnatal day (PD) 10, 20 and 30] was determined. Isometric contractile and endurance properties were examined in tissue baths containing Krebs solution at 35• C. Myosin heavy chain (MHC) isoform composition was determined using immunofluorescence. Muscle oxidative and glycolytic capacity was assessed by measuring the activities of succinate dehydrogenase and glycerol-3-phosphate dehydrogenase using semi-quantitative histochemistry. Sternohyoid and diaphragm peak isometric force and fatigue increased significantly with postnatal maturation. Developmental myosin disappeared by PD20, whereas MHC 2B areal density increased significantly from PD10 to PD30, emerging earlier and to a much greater extent in the sternohyoid muscle. The numerical density of fibres expressing MHC 2X and MHC 2B increased significantly during development in the sternohyoid. Diaphragm succinate dehydrogenase activity and sternohyoid glycerol-3-phosphate dehydrogenase activity increased significantly with age. Developmental increases in force-generating capacity and fatigue in the sternohyoid and diaphragm muscles are attributed to a postnatal shift in muscle MHC phenotype. The accelerated maturation of the sternohyoid muscle relative to the diaphragm may have implications for the control of airway calibre in vivo.

Background: Age, obesity and male sex are risk factors for the development of obstructive sleep apnoea syndrome. Objective: We examined structural and functional properties of the sternohyoid muscle in young lean and aged obese male rats. We hypothesized that the aged muscle would be vulnerable to oxidative stress (hypoxia). Methods: Isometric contractile and endurance properties of the sternohyoid muscle were assessed in vitro with or without the superoxide scavenger Tempol (10 mM). Muscle fibre size and density were determined by myosin heavy chain immunofluorescence. Succinate dehydrogenase (SDH) and glycerol-3- phosphate dehydrogenase (GPDH) enzyme activities were determined. Results: Fibre hypertrophy, increased fast twitch (type 2X) fibre density, decreased SDH activity and increased GPDH activity, together with increased force and fatigue, were observed in aged obese muscles compared to young lean muscles. Tempol treatment increased strength and sensitivity to stimulation. Hypoxic depression of force was ameliorated by antioxidant treatment with equivalent effects in young lean and aged obese muscle. Conclusions: We conclude that the rat sternohyoid exhibits indefinite growth and is protected from oxidative stress as the animal ages.