Respiratory capacity is maintained despite Duchenne muscular dystrophy‐related diaphragm weakness

Duchenne muscular dystrophy (DMD) is a recessive X-linked genetic disorder characterized by dystrophin deficiency, progressive weakness and atrophy of the musculature, resulting in a complete loss of ambulation and function, usually within the first two decades of life. DMD and its myodegenerative effects are typically present by 3–5 years of age, with a prevalence of approximately one in every 3500 live male births (McDonald et al. 2015). In addition to the extensive loss of skeletal muscle function, individuals with DMD suffer from an inevitable decline in diaphragmatic force generation capacity, which progresses over time. Much of the existing literature on DMD-related respiratory function focuses on dystrophin deficiencies specific to the musculature; however, the presence and expression of dystrophin in neurons may also have a significant influence on chemosensitivity, ventilatory behaviour, motor neuron control and compensation (McDonald et al. 2015). The potential role of neural-related mechanism(s) on ventilation in DMD is less clear. A recent study published in the Journal of Physiology by Burns et al. (2019) attempted to address this gap in the literature by examining diaphragmatic ventilatory and non-ventilatory behaviours in mdx mice, comprising an animal model for DMD. Burns et al. (2019) aimed to investigate how respiratory function and performance, oesophageal pressure and ventilatory muscle EMG are influenced by significant functional diaphragm weakness in 8-week-old mdx mice. Significant diaphragm weakness in 8-week-old mdx mice was confirmed via ex vivo analyses of the diaphragm muscle. Contraction time and twitch/tetanic force showed significant reductions in performance in response to muscle stimulation between 60 and 160 Hz, comprising a range corresponding to a variety of the ventilatory behaviours examined (Burns et al. 2019). To test the hypothesis that respiratory muscle weakness was associated with reduced inspiratory pressure generating capacity in mdx mice, Burns et al. (2019) employed several ventilatory (e.g. O2 and CO2 challenges) and non-ventilatory (e.g. airway obstruction) experimental protocols. To elicit a ventilatory challenge in the mdx mice, Burns et al. (2019) delivered several different gas mixtures containing incremental increases in inspired CO2 (i.e. hypercapnia), as well as a combination of hypercapnia and reduced inspired O2 (i.e. hypoxia). The combination of hypercapnia and hypoxia elicits a ventilatory response mediated via both central and peripheral chemoreceptor pathways, and the resulting respiratory response was measured volumetrically via whole body plethysmography. Substantial diaphragm weakness in the mdx mice was confirmed by Burns et al. (2019) but, surprisingly, it was demonstrated that (i) the ventilatory response to the combined hypercapnic hypoxia challenge was not significantly altered and (ii) there was no reduction in peak inspiratory pressure generation. In support of the former finding, a previous study Mosqueira et al. (2013) found that 6–7-month-old mdx mice displayed normal hypercapnic ventilatory responses after a number of hypercapnic challenges. The study by Burns et al. (2019) also assessed augmented breaths (i.e. ‘sighs’), which are known to involve motor unit recruitment beyond maximal chemo-activation. Remarkably, during the augmented breaths, it was found that peak inspiratory pressure generation was preserved in the mdx mice. Collectively, the primary findings that mdx mice maintain normal respiratory chemosensitivity and inspiratory pressure generation which, despite diaphragm weakness, allows for the retention of ventilatory capacity in the mdx mice similar to that of wild-type mice via maintained neural drive and mechanical compensatory mechanism(s). Burns et al. (2019) also utilized diaphragm and external intercostal muscle EMG to assess motor recruitment. Sustained airway obstruction (non-ventilatory) challenges demonstrated decreased EMG activity in both the diaphragm and external intercost muscles of the mdx mice compared to wild-type mice indicating that these challenges were beyond their compensatory or neuromuscular capacity. However, during the ventilatory stimuli (i.e. hypercapnia and hypoxia), Burns et al. (2019) found impressive preservation in the diaphragm and external intercostal EMG indicating adequate diaphragmatic reserve compensation. Because of these findings, Burns et al. (2019) suggest that accessory respiratory muscle activation is probably responsible for this preserved ventilatory behaviour. A study by Jensen et al. (2017) assessed the impact of accessory respiratory muscle activity on respiration by recording scalene and trapezius EMG in rats with amyotrophic lateral sclerosis. The inclusion of additional measurements of accessory inspiratory or expiratory muscles should be considered in the future to clarify the mechanism(s) responsible for mechanical compensation. The study by Burns et al. (2019) introduced new and exciting findings related to ventilatory and behaviour compensation; however, the applicability of the aforementioned findings to the human DMD model is debatable. Genetic compensatory mechanism(s) exist within mdx mice that have the potential to mitigate clinical progression and ventilatory capacity deterioration (McGreevy et al. 2015). Because of the tendency for mdx mice to present milder clinical symptoms in this regard, it is necessary to consider the accuracy and appropriate application of the mdx mouse model when assessing mechanisms related to respiratory control. Although mdx mice are dystrophin deficient, a similar structural protein, utrophin, remains intact and may become upregulated over time in response to the lack of dystrophin. The possibility of enhanced utrophin expression remains a relatively unknown area of research, although a number of new DMD-related mouse models are emerging, which may lead to a more humanized animal model for DMD. The mdx:utrophin+/− mouse, for example, is haploinsufficient for utrophin and shows more significant muscle performance deficits compared to wild-type and mdx mice, potentially making it a better representation of human DMD compared to the mdx mouse (McDonald et al. 2015). A double knockout mdx:utrophin−/− mouse also exists, which has complete deficiencies in both dystrophin and utrophin; however, this model has severe muscle deficiencies and an extremely blunted lifespan, which is beyond the characteristics of human DMD. A study by McDonald et al. (2015) reiterates that, although relatively new to the field of DMD research, the mdx:utrophin+/− mouse model of DMD may be an optimal intermediate between both the mdx and double knockout mouse models and should therefore be considered in future DMD research. Reductions in diaphragm function is a central physiological consequence and characterization of DMD, and the disease associated respiratory decline becomes more evident with age. The findings reported by Burns et al. (2019) are certainly invaluable; however, the transferability and long-term consequences of these ventilatory defects remains unclear. The majority of diaphragm weakness is already established by 8 weeks in mdx mice, which is the age of the mice that Burns et al. (2019) utilized. However, assessing the longitudinal effects of DMD using similar experimental protocols as Burns et al. (2019) should be considered for future research to fully characterize a time-frame of the observed respiratory compensatory mechanism(s). Future research should also consider repeating a similar series of experiments in different DMD animal models such as the mdx:utrophin+/− mouse model because this may allow researchers to uncover a more well-rounded illustration of respiratory function over the course of DMD in a way that could be more accurately applied to human clinical manifestations of the disease. Burns et al. (2019) demonstrated admirable use of physiological markers and techniques to analyse ventilatory function and capacity in the mdx mouse, which should also be employed in similar research efforts. The implications of the study by Burns et al. (2019) could fuel future endeavours that aim to improve the understanding and management of DMD disease, as well as applicability between humans and animal models. Although DMD is a complex disease, research undertakings similar to Burns et al. (2019) improves our current understanding of the mechanism(s), complications, and therapeutic management of DMD-related respiratory decline. No competing interests declared. All persons listed as authors qualify for authorship, and all those who qualify for authorship are listed as authors. No funding was received.

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