Key points Respiratory muscle weakness is a major feature of Duchenne muscular dystrophy (DMD), yet little is known about the neural control of the respiratory muscles in DMD and animal models of dystrophic disease. Substantial diaphragm muscle weakness is apparent in young (8‐week‐old) mdx mice, although ventilatory capacity in response to maximum chemostimulation in conscious mice is preserved. Peak volume‐ and flow‐related measures during chemoactivation are equivalent in anaesthetized, vagotomized wild‐type and mdx mice. Diaphragm and T3 external intercostal electromyogram activities are lower during protracted sustained airway occlusion in mdx compared to wild‐type mice. Yet, peak inspiratory pressure generation is remarkably well preserved. Despite profound diaphragm weakness and lower muscle activation during maximum non‐ventilatory efforts, inspiratory pressure‐generating capacity is preserved in young adult mdx mice, revealing compensation in support of respiratory system performance that is adequate, at least early in dystrophic disease. Abstract Diaphragm dysfunction is recognized in the mdx mouse model of muscular dystrophy; however, there is a paucity of information concerning the neural control of dystrophic respiratory muscles. In young adult (8 weeks of age) male wild‐type and mdx mice, we assessed ventilatory capacity, neural activation of the diaphragm and external intercostal (EIC) muscles and inspiratory pressure‐generating capacity during ventilatory and non‐ventilatory behaviours. We hypothesized that respiratory muscle weakness is associated with impaired peak inspiratory pressure‐generating capacity in mdx mice. Ventilatory responsiveness to hypercapnic hypoxia was determined in conscious mice by whole‐body plethysmography. Diaphragm isometric and isotonic contractile properties were determined ex vivo. In anaesthetized mice, thoracic oesophageal pressure, and diaphragm and EIC electromyogram (EMG) activities were recorded during baseline conditions and sustained tracheal occlusion for 30–40s. Despite substantial diaphragm weakness, mdx mice retain the capacity to enhance ventilation during hypercapnic hypoxia. Peak volume‐ and flow‐related measures were also maintained in anaesthetized, vagotomized mdx mice. Peak inspiratory pressure was remarkably well preserved during chemoactivated breathing, augmented breaths and maximal sustained efforts during airway obstruction in mdx mice. Diaphragm and EIC EMG activities were lower during airway obstruction in mdx compared to wild‐type mice. We conclude that ventilatory capacity is preserved in young mdx mice. Despite profound respiratory muscle weakness and lower diaphragm and EIC EMG activities during high demand in mdx mice, peak inspiratory pressure is preserved, revealing adequate compensation in support of respiratory system performance, at least early in dystrophic disease. We suggest that a progressive loss of compensation during advancing disease, combined with diaphragm dysfunction, underpins the development of respiratory system morb...

BackgroundCarotid body (peripheral oxygen sensor) sensitisation is pivotal in the development of chronic intermittent hypoxia (CIH)-induced hypertension. We sought to determine if exposure to CIH, modelling human sleep apnoea, adversely affects cardiorespiratory control in guinea-pigs, a species with hypoxia-insensitive carotid bodies. We reasoned that CIH-induced disruption of gut microbiota would evoke cardiorespiratory morbidity.MethodsAdult male guinea-pigs were exposed to CIH (6.5% O2 at nadir, 6 cycles.hour−1) for 8 h.day−1 for 12 consecutive days.FindingsCIH-exposed animals established reduced faecal microbiota species richness, with increased relative abundance of Bacteroidetes and reduced relative abundance of Firmicutes bacteria. Urinary corticosterone and noradrenaline levels were unchanged in CIH-exposed animals, but brainstem noradrenaline concentrations were lower compared with sham. Baseline ventilation was equivalent in CIH-exposed and sham animals; however, respiratory timing variability, sigh frequency and ventilation during hypoxic breathing were all lower in CIH-exposed animals. Baseline arterial blood pressure was unaffected by exposure to CIH, but β-adrenoceptor-dependent tachycardia and blunted bradycardia during phenylephrine-induced pressor responses was evident compared with sham controls.InterpretationIncreased carotid body chemo-afferent signalling appears obligatory for the development of CIH-induced hypertension and elevated chemoreflex control of breathing commonly reported in mammals, with hypoxia-sensitive carotid bodies. However, we reveal that exposure to modest CIH alters gut microbiota richness and composition, brainstem neurochemistry, and autonomic control of heart rate, independent of carotid body sensitisation, suggesting modulation of breathing and autonomic homeostasis via the microbiota-gut-brainstem axis. The findings have relevance to human sleep-disordered breathing.FundingThe Department of Physiology, and APC Microbiome Ireland, UCC.

Key pointsr Respiratory failure is a leading cause of mortality in Duchenne muscular dystrophy (DMD), but little is known about the control of breathing in DMD and animal models.r We show that young (8 weeks of age) mdx mice hypoventilate during basal breathing due to reduced tidal volume. Basal CO 2 production is equivalent in wild-type and mdx mice.r We show that carotid bodies from mdx mice have blunted responses to hyperoxia, revealing hypoactivity in normoxia. However, carotid body, ventilatory and metabolic responses to hypoxia are equivalent in wild-type and mdx mice.r Our study revealed profound muscle weakness and muscle fibre remodelling in young mdx diaphragm, suggesting severe mechanical disadvantage in mdx mice at an early age.r Our novel finding of potentiated neural motor drive to breathe in mdx mice during maximal chemoactivation suggests compensatory neuroplasticity enhancing respiratory motor output to the diaphragm and probably other accessory muscles.Abstract Patients with Duchenne muscular dystrophy (DMD) hypoventilate with consequential arterial blood gas derangement relevant to disease progression. Whereas deficits in DMD diaphragm are recognized, there is a paucity of knowledge in respect of the neural control of breathing in dystrophinopathies. We sought to perform an analysis of respiratory control in a model of DMD, the mdx mouse. In 8-week-old male wild-type and mdx mice, ventilation and metabolism, carotid body afferent activity, diaphragm muscle force-generating capacity, and muscle fibre size, distribution and centronucleation were determined. Diaphragm EMG activity and responsiveness to chemostimulation was determined. During normoxia, mdx mice hypoventilated, owing to a reduction in tidal volume. Basal CO 2 production was not different between wild-type and mdx mice. Carotid sinus nerve responses to hyperoxia were blunted in mdx, suggesting hypoactivity. However, carotid body, ventilatory and metabolic responses to hypoxia were equivalent in wild-type and mdx mice. Diaphragm force was severely depressed in mdx mice, with evidence of fibre remodelling and damage. Diaphragm EMG responses to chemoactivation were enhanced in mdx mice. We conclude that there is evidence of chronic hypoventilation in young mdx mice. Diaphragm dysfunction confers mechanical deficiency in mdx resulting in impaired capacity to generate normal tidal volume at rest and decreased absolute ventilation during chemoactivation. Enhanced mdx diaphragm EMG responsiveness suggests compensatory neuroplasticity facilitating respiratory motor output, which may extend to accessory muscles of breathing. Our results may have relevance to emerging treatments for human DMD aiming to preserve ventilatory capacity.

Background It is increasingly evident that perturbations to the diversity and composition of the gut microbiota have significant consequences for the regulation of integrative physiological systems. There is growing interest in the potential contribution of microbiota-gut-brain signalling to cardiorespiratory control in health and disease. Methods In adult male rats, we sought to determine the cardiorespiratory effects of manipulation of the gut microbiota following a 4-week administration of a cocktail of antibiotics. We subsequently explored the effects of administration of faecal microbiota from pooled control (vehicle) rat faeces, given by gavage to vehicle- and antibiotic-treated rats. Findings Antibiotic intervention depressed the ventilatory response to hypercapnic stress in conscious animals, owing to a reduction in the respiratory frequency response to carbon dioxide. Baseline frequency, respiratory timing variability, and the expression of apnoeas and sighs were normal. Microbiota-depleted rats had decreased systolic blood pressure. Faecal microbiota transfer to vehicle- and antibiotic-treated animals also disrupted the gut microbiota composition, associated with depressed ventilatory responsiveness to hypercapnia. Chronic antibiotic intervention or faecal microbiota transfer both caused significant disruptions to brainstem monoamine neurochemistry, with increased homovanillic acid:dopamine ratio indicative of increased dopamine turnover, which correlated with the abundance of several bacteria of six different phyla. Interpretation Chronic antibiotic administration and faecal microbiota transfer disrupt gut microbiota, brainstem monoamine concentrations and the ventilatory response to hypercapnia. We suggest that aberrant microbiota-gut-brain axis signalling has a modulatory influence on respiratory behaviour during hypercapnic stress. Fund Department of Physiology and APC Microbiome Ireland, University College Cork, Ireland.

New Findings r What is the central question of this study?Chronic intermittent hypoxia (CIH)-induced hypertension is commonly believed to be a consequence of sympathetic nervous system hyperactivity, but direct recordings of chronic vasoconstriction have never been performed hitherto. We determined whether chronic vasoconstriction contributes to the development of hypertension in CIH-exposed animals. r What is the main finding and its importance?We found no evidence of chronic vasoconstriction in CIH-exposed rats; instead, the development of hypertension was due to an increase in cardiac output. This attempt to increase O 2 flow may lead to the initial development of hypertension. Increased in cardiac output has never been previously reported and could be an important parameter to measure in sleep apnoea patients.Chronic intermittent hypoxia (CIH) in animal models has been shown to result in hypertension and elevation of sympathetic nervous system activity. Sympathetically mediated vasoconstriction is believed to be the primary mechanism underpinning CIH-induced hypertension; however, the potential contribution of the heart is largely overlooked. We sought to determine the contribution of cardiac output (CO) and lumbar sympathetic control of the hindlimb circulation to CIH-induced hypertension. Male Wistar rats (n = 64) were exposed to 2 weeks of CIH [cycles of 90 s hypoxia (5% O 2 nadir) and 210 s normoxia] or normoxia for 8 h day −1 . Under urethane anaesthesia, CIH-treated animals developed hypertension (81.4 ± 2.2 versus 91.6 ± 2.4 mmHg; P < 0.001), tachycardia (397 ± 8 versus 445 ± 7 beats min −1 ; P < 0.001) and an increased haematocrit (42.4 ± 0.4 versus 45.0 ± 0.4%; P < 0.001). Echocardiography revealed that CIH exposure increased the CO [19.3 ± 1.7 versus 25.8 ± 2.6 ml min −1 (100 g) −1 ; P = 0.027] with no change in total peripheral resistance (4.93 ± 0.49 versus 4.17 ± 0.34 mmHg ml −1 min −1 ; P = 0.123). Sympathetic ganglionic blockade revealed that sympathetic control over blood pressure was not different (−27.7 ± 1.6 versus −32.3 ± 2.9 mmHg; P = 0.095), and no chronic vasoconstriction was found in the hindlimb circulation of CIH-treated animals (39.4 ± 2.5 versus 38.0 ± 2.4 μl min −1 mmHg −1 ; P = 0.336). Lumbar sympathetic control over the hindlimb circulation was unchanged in CIH-treated animals (P = 0.761), although hindlimb arterial sympathetic density was increased (P = 0.012) and vascular sensitivity to phenylephrine was blunted (P = 0.049). We conclude that increased CO is sufficient to explain the development of CIH-induced hypertension, which may be an 1313 Development of chronic intermittent hypoxia-induced hypertension early adaptive response to raise O 2 flow. We propose that sustained elevated cardiac work may ultimately lead to heart failure.