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...
Sustained hypoxia is a dominant feature of respiratory disease. Despite the clinical significance, the effects of sustained hypoxia on the form and function of respiratory muscle during development are relatively underexplored.Wistar rats were exposed to 1 week of sustained hypoxia (ambient pressure 450 mmHg) or normoxia at various time points during development. Sternohyoid and diaphragm muscle contractile and endurance properties were assessed in vitro. Muscle succinate dehydrogenase and myosin heavy chain composition were determined. The role of reactive oxygen species in hypoxia-induced muscle remodelling was assessed.Sustained hypoxia increased sternohyoid muscle force and fatigue in early but not late development, effects that persisted after return to normoxia. Hypoxia-induced sternohyoid muscle fatigue was not attributable to fibre type transitions or to a decrease in oxidative capacity. Chronic supplementation with the superoxide scavenger tempol did not prevent hypoxia-induced sternohyoid muscle fatigue, suggesting that mechanisms unrelated to oxidative stress underpin hypoxia-induced maladaptation in sternohyoid muscle. Sustained hypoxia had no effect on diaphragm muscle fatigue.We conclude that there are critical windows during development for hypoxia-induced airway dilator muscle maladaptation. Sustained hypoxia-induced impairment of upper airway muscle endurance may persist into later life. Upper airway muscle dysfunction could have deleterious consequences for the control of pharyngeal airway calibre in vivo. @ERSpublications There are critical windows during development for hypoxia-induced airway dilator muscle maladaptation
The effects of chronic hypoxia (CH) on respiratory muscle performance have hardly been investigated, despite clinical relevance. Results from recent studies are indicative of unique adaptive strategies in hypoxic diaphragm. Respiratory muscle tolerance of acute severe hypoxic stress was examined in normoxic and CH diaphragm in the presence and absence of a nitric oxide (NO) synthase inhibitor. We tested the hypothesis that improved tolerance of severe hypoxic stress in CH diaphragm is NO-dependent. Wistar rats were exposed to normoxia (sea-level, n = 6) or CH (ambient pressure = 380 mmHg, n = 6) for 6 weeks. Diaphragm muscle functional properties were determined ex vivo under severe hypoxic conditions (gassed with 95%N2/5% CO2) with and without 1 mM L-N(G)-nitroarginine (L-NNA, nNOS inhibitor). Fatigue tolerance, but not force, was significantly improved in CH diaphragm (p = 0.008). CH exposure did not affect diaphragm muscle fibre oxidative capacity determined from cluster analysis of area-density plots of muscle fibre succinate dehydrogenase activity. Acute NOS inhibition reduced diaphragm peak tetanic force (p = 0.018), irrespective of gas treatment, and completely reversed improved fatigue tolerance of the CH diaphragm. We conclude that CH exposure improves fatigue tolerance during acute severe hypoxic stress in an NO-dependent manner, independent of muscle fibre oxidative capacity.
Oxidative stress is associated with skeletal muscle fatigue. This study tests the hypotheses that N-acetylcysteine (NAC) reduces fatigue and accelerates recovery of the rat external anal sphincter (EAS). Fifteen female Wistar rats were killed humanely. The EAS was mounted as a ring preparation and electrically stimulated with 50 Hz trains of 200 ms in duration every 4 s for three and a half minutes. Three groups were analysed: a control group (n = 5), a group pretreated with NAC (10(-4) mol L(-1); n = 5) and a group pretreated with NAC (10(-3) mol L(-1); n = 5). A novel fatigue index was formulated and was compared to a conventional method of expressing fatigue. There was no significant difference at concentrations of NAC (10(-4) mol L(-1); P > 0.05). At high concentrations of NAC (10(-3) mol L(-1)) there was a significant depression in peak twitch amplitude before fatigue (P = 0.04). N-acetylcysteine in both concentrations used, did not alter fatigue or recovery of the rat EAS. There was a significant positive correlation between the two methods of expressing fatigue but the conventional method produced a higher fatigue index (22.4% on average). N-acetylcysteine does not ameliorate fatigue or accelerate recovery of the EAS and may not be a useful medical therapy for faecal incontinence.
Nitric Oxide (NO), a highly reactive second messenger, plays an important role in skeletal muscle physiology. The aim of this study was to investigate the effects of the NO synthase inhibitor, N‐nitro‐L‐arginine (L‐NNA) on the contractile and endurance properties of the sternohyoid (upper airway dilator) muscle under hyperoxic and hypoxic conditions in vitro.Adult male Wistar rats were killed humanely and sternohyoid muscle strips were mounted isometrically in an organ bath containing aerated physiological salt solution maintained at 30degC. Four groups were assessed: control muscle strips exposed to hyperoxic (95%O2, 5% CO2; n=9) or hypoxic (95%N2, 5%CO2; n=8) conditions and L‐NNA‐treated strips (1mM) studied under hyperoxic (n=9) or hypoxic conditions (n=8). Force‐frequency relationship was assessed.L‐NNA had no effect on sub‐maximal forces but significantly decreased peak tetanic force at 100Hz under both hyperoxic (17+/−1.5 vs. 13.8+/−1.2 N/cm2; mean+/−SEM, control vs. L‐NNA, P<0.05 ANOVA) and hypoxic conditions (9.3+/−0.9 vs. 6.6+/−0.7, control vs. L‐NNA, P<0.05).We conclude that NO facilitates rat sternohyoid muscle contractile function especially under hypoxic conditions. Although NO is reported to inhibit diaphragm contractile function, a positive inotropic effect of NO donors has been observed in limb muscle.
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