77 research outputs found

    A paradigm shift in oxygen sensing with a twist in the tale!

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    AMP-activated protein kinase (AMPK) is pivotal to metabolic homeostasis in eukaryotes, serving as a critical energy sensor. Increased AMPK activity during oxygen deprivation (hypoxia) protects against potentially catastrophic deficits in ATP supply. Whilst the nervous system circuitry for elaboration of the complex cardiorespiratory response to hypoxia has been understood in some detail for many decades, there is continued and considerable interest in the molecular machinery underpinning the mechanism(s) of oxygen sensing. In this issue of the Biochemical Journal, Evans et al. (2016) review their recent work, which points to a pivotal role for AMPK in the transduction of cellular hypoxic stress to integrated ventilatory behaviour, critical in the defence of whole-body oxygen homeostasis. Of great surprise, there is profound blunting of the hyperventilatory response to hypoxic stress in AMPK deficient mice, with resultant dysregulated breathing arising in spite of normal peripheral oxygen sensing and appropriate sensory input to the brain! Their pointedly provocative review challenges current dogma, and in doing so raises intriguing questions that probe fundamental aspects of our understanding of the mammalian ventilatory response to hypoxic stress. The engaging review by Evans et al. (2016) is an interesting read that is sure to encourage colourful debate

    “Double-Trouble” for Respiratory Control in Pompe Disease

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    A commentary on ‘Hypoglossal neuropathology and respiratory activity in Pompe mice’, by Lee, K.-Z., Qiu, K., Sandhu, M. S., Elmullah, M. K., Falk, D. J., Lane, M. A., Reier, P. J., Byrne, B. J., and Fuller, D. D. (2011). Front. Physiol. 2:31. doi: 10.3389/fphys.2011.00031

    Chronic intermittent hypoxia and renovascular hypertension: A case of one plus one equals one-half!

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    The homeostatic regulation of blood pressure depends on an exquisite interplay between multimodal sensors, several brain regions and long-range control systems that serve to maintain and defend cardiovascular constancy

    Sympathetic vasomotor activity during dynamic exercise with resistive breathing: Sex differences and the nerve to show it!

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    Respiratory muscle metaboreflexes exert substantial influence over cardiorespiratory and autonomic control, exemplified during heavy dynamic exercise in health, and in obstructive airways disease even at rest

    Sex, stress and sleep apnoea: decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females

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    Obstructive sleep apnoea syndrome (OSAS) is a devastating respiratory control disorder more common in men than women. The reasons for the sex difference in prevalence are multifactorial, but are partly attributable to protective effects of oestrogen. Indeed, OSAS prevalence increases in post-menopausal women. OSAS is characterized by repeated occlusions of the pharyngeal airway during sleep. Dysfunction of the upper airway muscles controlling airway calibre and collapsibility is implicated in the pathophysiology of OSAS, and sex differences in the neuro-mechanical control of upper airway patency are described. It is widely recognized that chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoea, drives many of the morbid consequences characteristic of the disorder. In rodents, exposure to CIH-related redox stress causes upper airway muscle weakness and fatigue, associated with mitochondrial dysfunction. Of interest, in adults, there is female resilience to CIH-induced muscle dysfunction. Conversely, exposure to CIH in early life, results in upper airway muscle weakness equivalent between the two sexes at 3 and 6 weeks of age. Ovariectomy exacerbates the deleterious effects of exposure to CIH in adult female upper airway muscle, an effect partially restored by oestrogen replacement therapy. Intriguingly, female advantage intrinsic to upper airway muscle exists with evidence of substantially greater loss of performance in male muscle during acute exposure to severe hypoxic stress. Sex differences in upper airway muscle physiology may have relevance to human OSAS. The oestrogen–oestrogen receptor α axis represents a potential therapeutic target in OSAS, particularly in post-menopausal women

    Effects of gestational and postnatal exposure to chronic intermittent hypoxia on diaphragm muscle contractile function in the rat

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    Alterations to the supply of oxygen during early life presents a profound stressor to physiological systems with aberrant remodeling that is often long-lasting. Chronic intermittent hypoxia (CIH) is a feature of apnea of prematurity, chronic lung disease, and sleep apnea. CIH affects respiratory control but there is a dearth of information concerning the effects of CIH on respiratory muscles, including the diaphragm—the major pump muscle of breathing. We investigated the effects of exposure to gestational CIH (gCIH) and postnatal CIH (pCIH) on diaphragm muscle function in male and female rats. CIH consisted of exposure in environmental chambers to 90 s of hypoxia reaching 5% O2 at nadir, once every 5 min, 8 h a day. Exposure to gCIH started within 24 h of identification of a copulation plug and continued until day 20 of gestation; animals were studied on postnatal day 22 or 42. For pCIH, pups were born in normoxia and within 24 h of delivery were exposed with dams to CIH for 3 weeks; animals were studied on postnatal day 22 or 42. Sham groups were exposed to normoxia in parallel. Following gas exposures, diaphragm muscle contractile, and endurance properties were examined ex vivo. Neither gCIH nor pCIH exposure had effects on diaphragm muscle force-generating capacity or endurance in either sex. Similarly, early life exposure to CIH did not affect muscle tolerance of severe hypoxic stress determined ex vivo. The findings contrast with our recent observation of upper airway dilator muscle weakness following exposure to pCIH. Thus, the present study suggests a relative resilience to hypoxic stress in diaphragm muscle. Co-ordinated activity of thoracic pump and upper airway dilator muscles is required for optimal control of upper airway caliber. A mismatch in the force-generating capacity of the complementary muscle groups could have adverse consequences for the control of airway patency and respiratory homeostasis

    Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

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    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

    Combined xIL-6R and urocortin-2 treatment restores mdx diaphragm muscle force

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    Introduction: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration leading to immobility, respiratory failure, and premature death. As chronic inflammation and stress are implicated in DMD pathology, the efficacy of an anti-inflammatory and anti-stress intervention strategy in ameliorating diaphragm dysfunction was investigated. Methods: Diaphragm muscle contractile function was compared in wild-type and dystrophin-deficient mdx mice treated with saline, anti-interleukin-6 receptor antibodies (xIL-6R), the corticotrophin-releasing factor receptor 2 (CRFR2) agonist, urocortin 2, or both xIL-6R and urocortin 2. Results: Combined treatment with xIL-6R and urocortin 2 rescued impaired force in mdx diaphragms. Mechanical work production and muscle shortening was also improved by combined drug treatment. Conclusions: Treatment which neutralizes peripheral IL-6 signaling and stimulates CRFR2 recovers force-generating capacity and the ability to perform mechanical work in mdx diaphragm muscle. These findings may be important in the search for therapeutic targets in DMD
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