The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Ken D Ohalloran - One of the best experts on this subject based on the ideXlab platform.
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sex differences in murine Sternohyoid Muscle tolerance of acute severe hypoxic stress
Physiological Research, 2016Co-Authors: Philip Lewis, Ken D OhalloranAbstract:Given that sex differences inherent to Muscle might at least contribute to male risk for obstructive sleep apnoea syndrome (OSAS), our objective was to test the hypothesis that male Sternohyoid Muscle exhibits greater susceptibility to severe hypoxic stress compared with female Muscle. Adult male and female C57Bl6/J mouse Sternohyoid isometric and isotonic functional properties were examined ex vivo at 35 °C in tissue baths under control and severe hypoxic conditions. Hypoxia was detrimental to peak force (Fmax), work (Wmax) and power (Pmax), but not shortening velocity (Vmax). Two-way analysis of variance revealed a significant sex x gas interaction for Fmax (p<0.05), revealing inferior hypoxic tolerance in male Sternohyoid Muscle. However, increases in male shortening velocity in severe hypoxia preserved power-generating capacity which was equivalent to values determined in female Muscle. Fmax decline in hypoxic female Sternohyoid was considerably less than in male Muscle, illustrating an inherent tolerance of force-generating capacity mechanisms to hypoxic stress in female airway dilator Muscle. We speculate that this could confer a distinct advantage in vivo in terms of the defense of upper airway caliber.
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early life exposure to chronic intermittent hypoxia primes increased susceptibility to hypoxia induced weakness in rat Sternohyoid Muscle during adulthood
Frontiers in Physiology, 2016Co-Authors: Fiona B Mcdonald, Eugene M Dempsey, Ken D OhalloranAbstract:Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway Muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory Muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting Muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, Sternohyoid and diaphragm Muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory Muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused Sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on Muscle function. Persistent susceptibility in pCIH-exposed airway dilator Muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.
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early life exposure to chronic intermittent hypoxia causes upper airway dilator Muscle weakness which persists into young adulthood
Experimental Physiology, 2015Co-Authors: Fiona B Mcdonald, Ken D Ohalloran, Robert Williams, David SheehanAbstract:New Findings What is the central question of this study? Chronic intermittent hypoxia (CIH) is a dominant feature of respiratory control disorders, which are common. We sought to examine the effects of exposure to CIH during neonatal development on respiratory Muscle form and function in male and female rats. What is the main finding and its importance? Exposure to CIH during neonatal development caused Sternohyoid Muscle weakness in both sexes; an effect that persisted into young adult life upon return to normoxia. Upper airway dilator Muscle dysfunction in vivo could predispose to airway collapse, leading to impaired respiratory homeostasis. Chronic intermittent hypoxia (CIH) is a feature of sleep-disordered breathing, which is very common. Exposure to CIH is associated with aberrant plasticity in the respiratory control system including the final effector organs, the striated Muscles of breathing. We reasoned that developmental age and sex are key factors determining the functional response of respiratory Muscle to CIH. We tested the hypothesis that exposure to CIH causes persistent impairment of Sternohyoid Muscle function due to oxidative stress and that males are more susceptible to CIH-induced Muscle impairment than females. Wistar rat litters (with respective dams) were exposed to intermittent hypoxia for 12 cycles per hour, 8 h per day for 3 weeks from the first day of life [postnatal day (P) 0]. Sham experiments were run in parallel. Half of each litter was studied on P22; the other half was returned to normoxia and studied on P42. Functional properties of the Sternohyoid Muscle were determined ex vivo. Exposure to CIH significantly decreased Sternohyoid Muscle force in both sexes; an effect that persisted into young adult life. Chronic intermittent hypoxia had no effect on Sternohyoid Muscle endurance. Chronic intermittent hypoxia did not affect Sternohyoid myosin fibre type, succinate dehydrogenase or glycerol-3-phosphate dehydrogenase activities, or protein free thiol and carbonyl content. Muscles exposed to CIH had smaller cross-sectional areas, consistent with the observation of Muscle weakness. In human infants with disordered breathing, CIH-induced upper airway dilator Muscle weakness could increase the propensity for airway narrowing or collapse, which could serve to perpetuate impaired respiratory homeostasis.
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chronic sustained hypoxia induced redox remodeling causes contractile dysfunction in mouse Sternohyoid Muscle
Frontiers in Physiology, 2015Co-Authors: Philip Lewis, David Sheehan, Renata Soares, Ana Varela Coelho, Ken D OhalloranAbstract:Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory Muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the Sternohyoid - a representative upper airway dilator Muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse Sternohyoid Muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2=0.1) for one, three, or six weeks. A second cohort of animals was exposed to CH for six weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signalling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of Sternohyoid Muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to Sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator Muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease.
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chronic intermittent hypoxia increases rat Sternohyoid Muscle nadph oxidase expression with attendant modest oxidative stress
Frontiers in Physiology, 2015Co-Authors: Robert Williams, Fiona B Mcdonald, David Sheehan, Paul Lemaire, Philip Lewis, Eric F Lucking, Sean Hogan, Vincent Healy, Ken D OhalloranAbstract:Chronic intermittent hypoxia (CIH) causes upper airway Muscle dysfunction. We hypothesized that the superoxide generating NADPH oxidase (NOX) is upregulated in CIH-exposed Muscle causing oxidative stress. Adult male Wistar rats were exposed to intermittent hypoxia (5% O2 at the nadir for 90 s followed by 210 s of normoxia), for 8 hours per day for 14 days. The effect of CIH exposure on the expression of NOX subunits, total myosin and 4-hydroxynonenal (4-HNE) protein adducts in Sternohyoid Muscle was determined by western blotting and densitometry. Sternohyoid protein free thiol and carbonyl group contents were determined by 1D electrophoresis using specific fluorophore probes. Aconitase and glutathione reductase activities were measured as indices of oxidative stress. HIF-1a content and key oxidative and glycolytic enzyme activities were determined. Contractile properties of Sternohyoid Muscle were determined ex vivo in the absence and presence of apocynin (putative NOX inhibitor). We observed an increase in NOX 2 and p47 phox expression in CIH-exposed Sternohyoid Muscle with decreased aconitase and glutathione reductase activities. There was no evidence, however, of increased lipid peroxidation or protein oxidation in CIH-exposed Muscle. CIH exposure did not affect Sternohyoid HIF-1a content or aldolase, lactate dehydrogenase, or glyceraldehyde-3-phosphate dehydrogenase activities. Citrate synthase activity was also unaffected by CIH exposure. Apocynin significantly increased Sternohyoid force and power. We conclude that CIH exposure upregulates NOX expression in rat Sternohyoid Muscle with concomitant modest oxidative stress but it does not result in a HIF-1a-dependent increase in glycolytic enzyme activity. Constitutive NOX activity decreases Sternohyoid force and power. Our results implicate NOX-dependent reactive oxygen species in CIH-induced upper airway Muscle dysfunction which likely relates to redox modulation of key regulatory proteins.
Aidan Bradford - One of the best experts on this subject based on the ideXlab platform.
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effects of sustained hypoxia on Sternohyoid and diaphragm Muscle during development
European Respiratory Journal, 2014Co-Authors: Jayne C Carberry, Aidan Bradford, James F X Jones, Clodagh Mcmorrow, Ken D OhalloranAbstract: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 .
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tempol ameliorates pharyngeal dilator Muscle dysfunction in a rodent model of chronic intermittent hypoxia
American Journal of Respiratory Cell and Molecular Biology, 2012Co-Authors: Richard J Skelly, Aidan Bradford, James F X Jones, Christine M Shortt, Deirdre Edge, Ken D OhalloranAbstract:Respiratory Muscle dysfunction is implicated in the pathophysiology of obstructive sleep apnea syndrome (OSAS), an oxidative stress disorder prevalent in men. Pharmacotherapy for OSAS is an attractive option, and antioxidant treatments may prove beneficial. We examined the effects of chronic intermittent hypoxia (CIH) on breathing and pharyngeal dilator Muscle structure and function in male and female rats. Additionally, we tested the efficacy of antioxidant treatment in preventing (chronic administration) or reversing (acute administration) CIH-induced effects in male rats. Adult male and female Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; Fi(O(2)) = 5% O(2) at nadir; Sa(O(2)) ∼ 80%) or sham treatment for 8 h/d for 9 days. Tempol (1 mM, superoxide dismutase mimetic) was administered to subgroups of sham- and CIH-treated animals. Breathing was assessed by whole-body plethysmography. Sternohyoid Muscle contractile and endurance properties were examined in vitro. Muscle fiber type and cross-sectional area and the activity of key metabolic enzymes were determined. CIH decreased Sternohyoid Muscle force in male rats only. This was not attributable to fiber transitions or alterations in oxidative or glycolytic enzyme activity. Muscle weakness after CIH was prevented by chronic Tempol supplementation and was reversed by acute antioxidant treatment in vitro. CIH increased normoxic ventilation in male rats only. Sex differences exist in the effects of CIH on the respiratory system, which may contribute to the higher prevalence of OSAS in male subjects. Antioxidant treatment may be beneficial as an adjunct OSAS therapy.
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respiratory control and Sternohyoid Muscle structure and function in aged male rats decreased susceptibility to chronic intermittent hypoxia
Respiratory Physiology & Neurobiology, 2012Co-Authors: Richard J Skelly, Aidan Bradford, James F X Jones, Christine M Shortt, Deirdre Edge, Ken D OhalloranAbstract:Obstructive sleep apnoea syndrome (OSAS) is a common respiratory disorder characterized by chronic intermittent hypoxia (CIH). We have shown that CIH causes upper airway Muscle dysfunction in the rat due to oxidative stress. Ageing is an independent risk factor for the development of OSAS perhaps due to respiratory Muscle remodelling and increased susceptibility to hypoxia. We sought to examine the effects of CIH on breathing and pharyngeal dilator Muscle structure and function in aged rats. Aged (18-20 months), male Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; F(I)O(2)=5% O(2) at nadir) or sham treatment for 8h/day for 9 days. Following CIH exposure, breathing was assessed by whole-body plethysmography. In addition, Sternohyoid Muscle contractile and endurance properties were examined in vitro. Muscle fibre type and cross-sectional area, and the activity of key oxidative and glycolytic enzymes were determined. CIH had no effect on basal breathing or ventilatory responses to hypoxia or hypercapnia. CIH did not alter succinate dehydrogenase or glycerol phosphate dehydrogenase enzyme activities, myosin heavy chain fibre areal density or cross-sectional area. Sternohyoid Muscle force and endurance were unaffected by CIH exposure. Since we have established that this CIH paradigm causes Sternohyoid Muscle weakness in adult male rats, we conclude that aged rats have decreased susceptibility to CIH-induced stress. We suggest that structural remodelling with improved hypoxic tolerance in upper airway Muscles may partly compensate for impaired neural regulation of the upper airway and increased propensity for airway collapse in aged mammals.
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the effects of chronic episodic hypercapnic hypoxia on rat upper airway Muscle contractile properties and fiber type distribution
Chest, 2002Co-Authors: Michelle Mcguire, Marry Macdermott, Aidan BradfordAbstract:Objective: Obstructive sleep apnea (OSA) is caused by episodes of upper airway (UA) obstruction due to an inability of UA Muscles such as the geniohyoids and Sternohyoids to maintain airway patency. This results in chronic episodic hypercapnic hypoxia. Chronic continuous hypoxia and episodic hypocapnic hypoxia affect skeletal Muscle structure and function, but the effects of chronic episodic hypercapnic hypoxia on UA Muscle structure and function are unknown. Design: Rats breathed air and hypercapnic hypoxic gas twice per minute for 8 h/d for 5 weeks in order to mimic the intermittent hypercapnic hypoxia of OSA in humans. Isometric contractile properties were determined using strips of isolated geniohyoid and Sternohyoid Muscles in physiologic saline solution at 30°C. Fiber-type distribution was determined by adenosine triphosphatase staining. Results: For both Muscles, chronic episodic hypercapnic hypoxia had no significant effect on twitch or tetanic tension, twitch/tetanic tension ratio, and tension-frequency relationship. There was a significant (p < 0.05) increase in geniohyoid fatigue (50.5 6.6% vs 43.6 5.8% of initial tension), but Sternohyoid fatigue was reduced (31.5 5.2% vs 37.8 6.0% of initial tension). Geniohyoid type 1 fibers were reduced and type 2B fibers increased, whereas Sternohyoid Muscle had an increase in type 1 and 2A fibers and a decrease in type 2B fibers. Conclusions: Chronic episodic hypercapnic hypoxia alters UA Muscle structure and function, changes that may affect the regulation of UA patency. (CHEST 2002; 122:1400 –1406)
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Contractile and electrical properties of Sternohyoid Muscle in streptozotocin diabetic rats.
Clinical and experimental pharmacology & physiology, 2001Co-Authors: Michelle Mcguire, M Dumbleton, M Macdermott, Aidan BradfordAbstract:SUMMARY 1. The effects of diabetes on the electrical and contractile function of skeletal Muscle are variable, depending on Muscle fibre type distribution. The Muscles of the upper airway have a characteristic fibre distribution that differs from previously studied Muscles, but the effects of diabetes on upper airway Muscle function are unknown. Normally, contraction of upper airway Muscles, such as the Sternohyoids, dilates and/or stabilizes the upper airway, thereby preventing its collapse. Diabetes is associated with obstructive sleep apnoea in which there is collapse of the upper airway due to failure of the upper airway musculature to maintain airway patency. Therefore, the purpose of the present study was to determine the effects of diabetes on the electrical and contractile characteristics of upper airway Muscle. 2. Rats were treated with vehicle (sodium citrate buffer; pH 4.5) or with streptozotocin to induce diabetes, confirmed by the presence of hyperglycaemia, and the contractile and electrical properties of the Sternohyoid were compared in these two groups. Isometric contractile properties and membrane potentials were determined in isolated Sternohyoid Muscles in physiological saline solution at 25°C. 3. Streptozotocin had no effect on Sternohyoid Muscle fatigue, the tension–frequency relationship or membrane potentials, but did increase contraction time, half-relaxation time, twitch tension and tetanic tension. 4. Streptozotocin-induced diabetes has no effect on Sternohyoid Muscle fatigue or the tension–frequency relationship, but does reduce contractile kinetics and increases force generation. These effects are not due to changes in resting membrane potential. These data are evidence that the association of sleep apnoea and diabetes is not due to effects on upper airway Muscle contractile properties.
Fiona B Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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early life exposure to chronic intermittent hypoxia primes increased susceptibility to hypoxia induced weakness in rat Sternohyoid Muscle during adulthood
Frontiers in Physiology, 2016Co-Authors: Fiona B Mcdonald, Eugene M Dempsey, Ken D OhalloranAbstract:Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway Muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory Muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting Muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, Sternohyoid and diaphragm Muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory Muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused Sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on Muscle function. Persistent susceptibility in pCIH-exposed airway dilator Muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.
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early life exposure to chronic intermittent hypoxia causes upper airway dilator Muscle weakness which persists into young adulthood
Experimental Physiology, 2015Co-Authors: Fiona B Mcdonald, Ken D Ohalloran, Robert Williams, David SheehanAbstract:New Findings What is the central question of this study? Chronic intermittent hypoxia (CIH) is a dominant feature of respiratory control disorders, which are common. We sought to examine the effects of exposure to CIH during neonatal development on respiratory Muscle form and function in male and female rats. What is the main finding and its importance? Exposure to CIH during neonatal development caused Sternohyoid Muscle weakness in both sexes; an effect that persisted into young adult life upon return to normoxia. Upper airway dilator Muscle dysfunction in vivo could predispose to airway collapse, leading to impaired respiratory homeostasis. Chronic intermittent hypoxia (CIH) is a feature of sleep-disordered breathing, which is very common. Exposure to CIH is associated with aberrant plasticity in the respiratory control system including the final effector organs, the striated Muscles of breathing. We reasoned that developmental age and sex are key factors determining the functional response of respiratory Muscle to CIH. We tested the hypothesis that exposure to CIH causes persistent impairment of Sternohyoid Muscle function due to oxidative stress and that males are more susceptible to CIH-induced Muscle impairment than females. Wistar rat litters (with respective dams) were exposed to intermittent hypoxia for 12 cycles per hour, 8 h per day for 3 weeks from the first day of life [postnatal day (P) 0]. Sham experiments were run in parallel. Half of each litter was studied on P22; the other half was returned to normoxia and studied on P42. Functional properties of the Sternohyoid Muscle were determined ex vivo. Exposure to CIH significantly decreased Sternohyoid Muscle force in both sexes; an effect that persisted into young adult life. Chronic intermittent hypoxia had no effect on Sternohyoid Muscle endurance. Chronic intermittent hypoxia did not affect Sternohyoid myosin fibre type, succinate dehydrogenase or glycerol-3-phosphate dehydrogenase activities, or protein free thiol and carbonyl content. Muscles exposed to CIH had smaller cross-sectional areas, consistent with the observation of Muscle weakness. In human infants with disordered breathing, CIH-induced upper airway dilator Muscle weakness could increase the propensity for airway narrowing or collapse, which could serve to perpetuate impaired respiratory homeostasis.
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chronic intermittent hypoxia increases rat Sternohyoid Muscle nadph oxidase expression with attendant modest oxidative stress
Frontiers in Physiology, 2015Co-Authors: Robert Williams, Fiona B Mcdonald, David Sheehan, Paul Lemaire, Philip Lewis, Eric F Lucking, Sean Hogan, Vincent Healy, Ken D OhalloranAbstract:Chronic intermittent hypoxia (CIH) causes upper airway Muscle dysfunction. We hypothesized that the superoxide generating NADPH oxidase (NOX) is upregulated in CIH-exposed Muscle causing oxidative stress. Adult male Wistar rats were exposed to intermittent hypoxia (5% O2 at the nadir for 90 s followed by 210 s of normoxia), for 8 hours per day for 14 days. The effect of CIH exposure on the expression of NOX subunits, total myosin and 4-hydroxynonenal (4-HNE) protein adducts in Sternohyoid Muscle was determined by western blotting and densitometry. Sternohyoid protein free thiol and carbonyl group contents were determined by 1D electrophoresis using specific fluorophore probes. Aconitase and glutathione reductase activities were measured as indices of oxidative stress. HIF-1a content and key oxidative and glycolytic enzyme activities were determined. Contractile properties of Sternohyoid Muscle were determined ex vivo in the absence and presence of apocynin (putative NOX inhibitor). We observed an increase in NOX 2 and p47 phox expression in CIH-exposed Sternohyoid Muscle with decreased aconitase and glutathione reductase activities. There was no evidence, however, of increased lipid peroxidation or protein oxidation in CIH-exposed Muscle. CIH exposure did not affect Sternohyoid HIF-1a content or aldolase, lactate dehydrogenase, or glyceraldehyde-3-phosphate dehydrogenase activities. Citrate synthase activity was also unaffected by CIH exposure. Apocynin significantly increased Sternohyoid force and power. We conclude that CIH exposure upregulates NOX expression in rat Sternohyoid Muscle with concomitant modest oxidative stress but it does not result in a HIF-1a-dependent increase in glycolytic enzyme activity. Constitutive NOX activity decreases Sternohyoid force and power. Our results implicate NOX-dependent reactive oxygen species in CIH-induced upper airway Muscle dysfunction which likely relates to redox modulation of key regulatory proteins.
David Sheehan - One of the best experts on this subject based on the ideXlab platform.
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early life exposure to chronic intermittent hypoxia causes upper airway dilator Muscle weakness which persists into young adulthood
Experimental Physiology, 2015Co-Authors: Fiona B Mcdonald, Ken D Ohalloran, Robert Williams, David SheehanAbstract:New Findings What is the central question of this study? Chronic intermittent hypoxia (CIH) is a dominant feature of respiratory control disorders, which are common. We sought to examine the effects of exposure to CIH during neonatal development on respiratory Muscle form and function in male and female rats. What is the main finding and its importance? Exposure to CIH during neonatal development caused Sternohyoid Muscle weakness in both sexes; an effect that persisted into young adult life upon return to normoxia. Upper airway dilator Muscle dysfunction in vivo could predispose to airway collapse, leading to impaired respiratory homeostasis. Chronic intermittent hypoxia (CIH) is a feature of sleep-disordered breathing, which is very common. Exposure to CIH is associated with aberrant plasticity in the respiratory control system including the final effector organs, the striated Muscles of breathing. We reasoned that developmental age and sex are key factors determining the functional response of respiratory Muscle to CIH. We tested the hypothesis that exposure to CIH causes persistent impairment of Sternohyoid Muscle function due to oxidative stress and that males are more susceptible to CIH-induced Muscle impairment than females. Wistar rat litters (with respective dams) were exposed to intermittent hypoxia for 12 cycles per hour, 8 h per day for 3 weeks from the first day of life [postnatal day (P) 0]. Sham experiments were run in parallel. Half of each litter was studied on P22; the other half was returned to normoxia and studied on P42. Functional properties of the Sternohyoid Muscle were determined ex vivo. Exposure to CIH significantly decreased Sternohyoid Muscle force in both sexes; an effect that persisted into young adult life. Chronic intermittent hypoxia had no effect on Sternohyoid Muscle endurance. Chronic intermittent hypoxia did not affect Sternohyoid myosin fibre type, succinate dehydrogenase or glycerol-3-phosphate dehydrogenase activities, or protein free thiol and carbonyl content. Muscles exposed to CIH had smaller cross-sectional areas, consistent with the observation of Muscle weakness. In human infants with disordered breathing, CIH-induced upper airway dilator Muscle weakness could increase the propensity for airway narrowing or collapse, which could serve to perpetuate impaired respiratory homeostasis.
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chronic sustained hypoxia induced redox remodeling causes contractile dysfunction in mouse Sternohyoid Muscle
Frontiers in Physiology, 2015Co-Authors: Philip Lewis, David Sheehan, Renata Soares, Ana Varela Coelho, Ken D OhalloranAbstract:Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory Muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the Sternohyoid - a representative upper airway dilator Muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse Sternohyoid Muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2=0.1) for one, three, or six weeks. A second cohort of animals was exposed to CH for six weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signalling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of Sternohyoid Muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to Sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator Muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease.
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chronic intermittent hypoxia increases rat Sternohyoid Muscle nadph oxidase expression with attendant modest oxidative stress
Frontiers in Physiology, 2015Co-Authors: Robert Williams, Fiona B Mcdonald, David Sheehan, Paul Lemaire, Philip Lewis, Eric F Lucking, Sean Hogan, Vincent Healy, Ken D OhalloranAbstract:Chronic intermittent hypoxia (CIH) causes upper airway Muscle dysfunction. We hypothesized that the superoxide generating NADPH oxidase (NOX) is upregulated in CIH-exposed Muscle causing oxidative stress. Adult male Wistar rats were exposed to intermittent hypoxia (5% O2 at the nadir for 90 s followed by 210 s of normoxia), for 8 hours per day for 14 days. The effect of CIH exposure on the expression of NOX subunits, total myosin and 4-hydroxynonenal (4-HNE) protein adducts in Sternohyoid Muscle was determined by western blotting and densitometry. Sternohyoid protein free thiol and carbonyl group contents were determined by 1D electrophoresis using specific fluorophore probes. Aconitase and glutathione reductase activities were measured as indices of oxidative stress. HIF-1a content and key oxidative and glycolytic enzyme activities were determined. Contractile properties of Sternohyoid Muscle were determined ex vivo in the absence and presence of apocynin (putative NOX inhibitor). We observed an increase in NOX 2 and p47 phox expression in CIH-exposed Sternohyoid Muscle with decreased aconitase and glutathione reductase activities. There was no evidence, however, of increased lipid peroxidation or protein oxidation in CIH-exposed Muscle. CIH exposure did not affect Sternohyoid HIF-1a content or aldolase, lactate dehydrogenase, or glyceraldehyde-3-phosphate dehydrogenase activities. Citrate synthase activity was also unaffected by CIH exposure. Apocynin significantly increased Sternohyoid force and power. We conclude that CIH exposure upregulates NOX expression in rat Sternohyoid Muscle with concomitant modest oxidative stress but it does not result in a HIF-1a-dependent increase in glycolytic enzyme activity. Constitutive NOX activity decreases Sternohyoid force and power. Our results implicate NOX-dependent reactive oxygen species in CIH-induced upper airway Muscle dysfunction which likely relates to redox modulation of key regulatory proteins.
James F X Jones - One of the best experts on this subject based on the ideXlab platform.
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effects of sustained hypoxia on Sternohyoid and diaphragm Muscle during development
European Respiratory Journal, 2014Co-Authors: Jayne C Carberry, Aidan Bradford, James F X Jones, Clodagh Mcmorrow, Ken D OhalloranAbstract: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 .
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upper airway dilator Muscle weakness following intermittent and sustained hypoxia in the rat effects of a superoxide scavenger
Physiological Research, 2013Co-Authors: J R Skelly, Simon C Rowan, James F X Jones, Ken D OhalloranAbstract:Summary Obstructive sleep apnoea syndrome (OSAS) is a common disorder associated with upper airway Muscle dysfunction. Agents that improve respiratory Muscle performance may have considerable therapeutic value. We examined the effects of acute exposure to sustained and intermittent hypoxia on rat pharyngeal dilator Muscle function. Additionally, we sought to test the efficacy of antioxidant treatment in ameliorating or preventing hypoxia-related Muscle dysfunction. Isometric contractile and endurance properties of isolated rat Sternohyoid Muscle bundles were examined at 35 °C in vitro. Muscle bundles were exposed to one of four gas treatments: hyperoxia (control), sustained hypoxia (SH), intermittent hypoxia (IH) or hypoxia/reoxygenation (HR), in the absence or presence of the superoxide scavenger – Tempol (10 mM). Stress-frequency relationship was determined in response to electrical stimulation (10-100 Hz in increments of 10-20 Hz, train duration: 300 ms). Muscle performance was also assessed during repetitive Muscle stimulation (40 Hz, 300 ms every 2 s for 2.5 min). Compared to control, IH and HR treatments significantly decreased Sternohyoid Muscle force. The negative inotropic effect of the two gas protocols was similar, but both were of lesser magnitude than the effects of SH. SH, but not IH and HR, increased Muscle fatigue. Tempol significantly increased sensitivity to stimulation in all Muscle preparations and caused a leftward shift in the stressfrequency relationship of IH and SH treated Muscles. Tempol did not ameliorate Sternohyoid Muscle fatigue during SH. We conclude that Tempol increases upper airway Muscle sensitivity to stimulation but only modestly ameliorates respiratory Muscle weakness during intermittent and sustained hypoxic conditions in vitro. Respiratory Muscle fatigue during sustained hypoxia appears unrelated to oxidative stress.
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tempol ameliorates pharyngeal dilator Muscle dysfunction in a rodent model of chronic intermittent hypoxia
American Journal of Respiratory Cell and Molecular Biology, 2012Co-Authors: Richard J Skelly, Aidan Bradford, James F X Jones, Christine M Shortt, Deirdre Edge, Ken D OhalloranAbstract:Respiratory Muscle dysfunction is implicated in the pathophysiology of obstructive sleep apnea syndrome (OSAS), an oxidative stress disorder prevalent in men. Pharmacotherapy for OSAS is an attractive option, and antioxidant treatments may prove beneficial. We examined the effects of chronic intermittent hypoxia (CIH) on breathing and pharyngeal dilator Muscle structure and function in male and female rats. Additionally, we tested the efficacy of antioxidant treatment in preventing (chronic administration) or reversing (acute administration) CIH-induced effects in male rats. Adult male and female Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; Fi(O(2)) = 5% O(2) at nadir; Sa(O(2)) ∼ 80%) or sham treatment for 8 h/d for 9 days. Tempol (1 mM, superoxide dismutase mimetic) was administered to subgroups of sham- and CIH-treated animals. Breathing was assessed by whole-body plethysmography. Sternohyoid Muscle contractile and endurance properties were examined in vitro. Muscle fiber type and cross-sectional area and the activity of key metabolic enzymes were determined. CIH decreased Sternohyoid Muscle force in male rats only. This was not attributable to fiber transitions or alterations in oxidative or glycolytic enzyme activity. Muscle weakness after CIH was prevented by chronic Tempol supplementation and was reversed by acute antioxidant treatment in vitro. CIH increased normoxic ventilation in male rats only. Sex differences exist in the effects of CIH on the respiratory system, which may contribute to the higher prevalence of OSAS in male subjects. Antioxidant treatment may be beneficial as an adjunct OSAS therapy.
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respiratory control and Sternohyoid Muscle structure and function in aged male rats decreased susceptibility to chronic intermittent hypoxia
Respiratory Physiology & Neurobiology, 2012Co-Authors: Richard J Skelly, Aidan Bradford, James F X Jones, Christine M Shortt, Deirdre Edge, Ken D OhalloranAbstract:Obstructive sleep apnoea syndrome (OSAS) is a common respiratory disorder characterized by chronic intermittent hypoxia (CIH). We have shown that CIH causes upper airway Muscle dysfunction in the rat due to oxidative stress. Ageing is an independent risk factor for the development of OSAS perhaps due to respiratory Muscle remodelling and increased susceptibility to hypoxia. We sought to examine the effects of CIH on breathing and pharyngeal dilator Muscle structure and function in aged rats. Aged (18-20 months), male Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; F(I)O(2)=5% O(2) at nadir) or sham treatment for 8h/day for 9 days. Following CIH exposure, breathing was assessed by whole-body plethysmography. In addition, Sternohyoid Muscle contractile and endurance properties were examined in vitro. Muscle fibre type and cross-sectional area, and the activity of key oxidative and glycolytic enzymes were determined. CIH had no effect on basal breathing or ventilatory responses to hypoxia or hypercapnia. CIH did not alter succinate dehydrogenase or glycerol phosphate dehydrogenase enzyme activities, myosin heavy chain fibre areal density or cross-sectional area. Sternohyoid Muscle force and endurance were unaffected by CIH exposure. Since we have established that this CIH paradigm causes Sternohyoid Muscle weakness in adult male rats, we conclude that aged rats have decreased susceptibility to CIH-induced stress. We suggest that structural remodelling with improved hypoxic tolerance in upper airway Muscles may partly compensate for impaired neural regulation of the upper airway and increased propensity for airway collapse in aged mammals.
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structural and functional properties of an upper airway dilator Muscle in aged obese male rats
Respiration, 2011Co-Authors: Richard J Skelly, James F X Jones, R A Oconnell, Ken D OhalloranAbstract: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.