Breathing with neuromuscular disease: Does compensatory plasticity in the motor drive to breathe offer a potential therapeutic target in muscular dystrophy?

Duchenne muscular dystrophy is a fatal neuromuscular disease associated with respiratory-related morbidity and mortality. Herein, we review recent work by our group exploring deficits and compensation in the respiratory control network governing respiratory homeostasis in a pre-clinical model of DMD, the mdx mouse. Deficits at multiple sites of the network provide considerable challenges to respiratory control. However, our work has also revealed evidence of compensatory neuroplasticity in the motor drive to breathe enhancing diaphragm muscle activity during increased chemical drive. The finding may explain the preserved capacity for mdx mice to increase ventilation in response to chemoactivation. Given the profound dysfunction in the primary pump muscle of breathing, we argue that activation of accessory muscles of breathing may be especially important in mdx (and perhaps DMD). Notwithstanding the limitations resulting from respiratory muscle dysfunction, it may be possible to further leverage intrinsic physiological mechanisms serving to compensate for weak muscles in attempts to preserve or restore ventilatory capacity. We discuss current knowledge gaps and the need to better appreciate fundamental aspects of respiratory control in pre-clinical models so as to better inform intervention strategies in human DMD.

O'Halloran KD ，Burns DP 《-》

Sensorimotor control of breathing in the mdx mouse model of Duchenne muscular dystrophy.

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. We show that young (8 weeks of age) mdx mice hypoventilate during basal breathing due to reduced tidal volume. Basal CO2 production is equivalent in wild-type and mdx mice. 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. 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. 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. 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 CO2 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.

Burns DP ，Roy A ，Lucking EF ，McDonald FB ，Gray S ，Wilson RJ ，Edge D ，O'Halloran KD ... -  《-》

Inspiratory pressure-generating capacity is preserved during ventilatory and non-ventilatory behaviours in young dystrophic mdx mice despite profound diaphragm muscle weakness.

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. 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 morbidity in dystrophic diseases.

Burns DP ，Murphy KH ，Lucking EF ，O'Halloran KD ... -  《-》

Respiratory performance in Duchenne muscular dystrophy: Clinical manifestations and lessons from animal models.

Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disease. Lack of dystrophin in skeletal muscles leads to intrinsic weakness, injury, subsequent degeneration and fibrosis, decreasing contractile function. Dystropathology eventually presents in all inspiratory and expiratory muscles of breathing, severely curtailing their critical function. In people with DMD, premature death is caused by respiratory or cardiac failure. There is an urgent need to develop therapies that improve quality of life and extend life expectancy in DMD. Surprisingly, there is a dearth of information on respiratory control in animal models of DMD, and respiratory outcome measures are often limited or absent in clinical trials. Characterization of respiratory performance in murine and canine models has revealed extensive remodelling of the diaphragm, the major muscle of inspiration. However, significant compensation by extradiaphragmatic muscles of breathing is evident in early disease, contributing to preservation of peak respiratory system performance. Loss of compensation afforded by accessory muscles in advanced disease is ultimately associated with compromised respiratory performance. A new and potentially more translatable murine model of DMD, the D2.mdx mouse, has recently been developed. Respiratory performance in D2.mdx mice is yet to be characterized fully. However, based on histopathological features, D2.mdx mice might serve as useful preclinical models, facilitating the testing of new therapeutics that rescue respiratory function. This review summarizes the pathophysiological mechanisms associated with DMD both in humans and in animal models, with a focus on breathing. We consider the translational value of each model to human DMD and highlight the urgent need for comprehensive characterization of breathing in representative preclinical models to better inform human trials.

Delaney R ，O'Halloran KD 《-》

Loss of compensation afforded by accessory muscles of breathing leads to respiratory system compromise in the mdx mouse model of Duchenne muscular dystrophy.

O'Halloran KD ，Maxwell MN ，Marullo AL ，Hamilton CP ，Ó Murchú SC ，Burns DP ，Mahony CM ，Slyne AD ，Drummond SE ... -  《-》