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

Abstract

Despite profound diaphragm weakness, peak inspiratory pressure‐generating capacity is preserved in young mdx mice revealing adequate compensation by extra‐diaphragmatic muscles of breathing in early dystrophic disease. We hypothesised that loss of compensation gives rise to respiratory system compromise in advanced dystrophic disease. Studies were performed in male wild‐type (n = 196) and dystrophin‐deficient mdx mice (n = 188) at 1, 4, 8, 12 and 16 months of age. In anaesthetised mice, inspiratory pressure and obligatory and accessory respiratory EMG activities were recorded during baseline and sustained tracheal occlusion for up to 30–40 s to evoke peak system activation to task failure. Obligatory inspiratory EMG activities were lower in mdx mice across the ventilatory range to peak activity, emerging in early dystrophic disease. Early compensation protecting peak inspiratory pressure‐generating capacity in mdx mice, which appears to relate to transforming growth factor‐β1‐dependent fibrotic remodelling of the diaphragm and preserved accessory muscle function, was lost at 12 and 16 months of age. Denervation and surgical lesion of muscles of breathing in 4‐month‐old mice revealed a greater dependency on diaphragm for peak inspiratory performance in wild‐type mice, whereas mdx mice were heavily dependent upon accessory muscles (including abdominal muscles) for peak performance. Accessory EMG activities were generally preserved or enhanced in young mdx mice, but peak EMG activities were lower than wild‐type by 12 months of age. In general, ventilation was reasonably well protected in mdx mice until 16 months of age. Despite the early emergence of impairments in the principal obligatory muscles of breathing, peak inspiratory performance is compensated in early dystrophic disease due to diaphragm remodelling and facilitated contribution by accessory muscles of breathing. Loss of compensation afforded by accessory muscles underpins the emergence of respiratory system morbidity in advanced dystrophic disease. imageKey points Despite diaphragm weakness, peak inspiratory performance is preserved in young dystrophin‐deficient mdx mice revealing adequate compensation by extra‐diaphragmatic muscles. Peak obligatory muscle (diaphragm, external intercostal, and parasternal intercostal) EMG activities are lower in mdx mice, emerging early in dystrophic disease, before the temporal decline in peak performance. Peak EMG activities of some accessory muscles are lower, whereas others are preserved. There is greater recruitment of the trapezius muscle in mdx mice during peak system activation. In phrenicotomised mice with confirmed diaphragm paralysis, there is a greater contribution made by extra‐diaphragmatic muscles to peak inspiratory pressure in mdx compared with wild‐type mice. Surgical lesion of accessory (including abdominal) muscles adversely affects peak pressure generation in mdx mice. Diaphragm remodelling leading to stiffening provides a mechanical advantage to peak pressure generation via the facilitated action of extra‐diaphragmatic muscles in early dystrophic disease. Peak accessory EMG activities are lower in 12‐month‐old mdx compared to wild‐type mice. Peak inspiratory pressure declines in mdx mice with advanced disease. We conclude that compensation afforded by accessory muscles of breathing declines in advanced dystrophic disease precipitating the emergence of respiratory system dysfunction.

BREATHE DMD: boosting respiratory efficacy after therapeutic hypoxic episodes in Duchenne muscular dystrophy

“…Reduced respiratory frequency and tidal volume in mdx mice at 3 and 6 months (Huang et al., 2011) has also been reported, while at 7 months a reduction in respiratory frequency and minute ventilation compared to wild‐type has been demonstrated (Markham et al., 2015). Moreover, mdx mice show blunted ventilatory responses to hypercapnia (Gayraud et al., 2007) and hyperoxia and hypoxia at 8 weeks of age (Burns et al., 2017, 2018), although these changes maybe heterogeneous in their expression, as the same research group has reported no change in basal breathing or ventilatory responses to hypercapnic hypoxia in mdx mice over a considerable portion of the natural history of the disease (Burns et al., 2019; O'Halloran et al., 2023). In the golden retriever canine model of DMD, ventilatory insufficiency is also evident (Mead et al., 2014).…”

“…Respiratory control in the mdx model of DMD has been comprehensively studied by our group (Burns et al., 2017, 2019; O'Halloran et al., 2023). Despite profound diaphragm weakness and decreased diaphragm electromyogram (EMG) activity, peak‐inspiratory pressure generating capacity is preserved for up to 12 months of age revealing that compensatory mechanisms offset the substantive dysfunction of the obligatory muscles of breathing in mdx mice.…”

“…Further investigations have revealed that accessory muscle EMG activities are preserved in early dystrophic disease (O'Halloran et al., 2023). Whereas the magnitude of neural recruitment of the cleidomastoid, sternohyoid and scalene muscles was equivalent in wild‐type and mdx mice at 4 months of age, there was a small but significant increase in the maximal levels of trapezius muscle activity in mdx (O'Halloran et al., 2023), suggesting a capacity for plasticity.…”

“…Whereas the magnitude of neural recruitment of the cleidomastoid, sternohyoid and scalene muscles was equivalent in wild‐type and mdx mice at 4 months of age, there was a small but significant increase in the maximal levels of trapezius muscle activity in mdx (O'Halloran et al., 2023), suggesting a capacity for plasticity. Whereas, in general, plasticity in the motor control of accessory muscles of breathing (by way of enhancement of muscle electrical activity) does not manifest in mdx mice (O'Halloran et al., 2023), accessory muscle activation in early dystrophic disease is maintained, serving to support breathing in the presence of reduced electrical activation and inherent weakness of the obligatory respiratory muscles. Indeed, it appears it is the loss of compensation provided by accessory muscles that gives rise to ventilatory insufficiency in mdx mice, and perhaps human DMD (O'Halloran et al., 2023).…”

“…Whereas, in general, plasticity in the motor control of accessory muscles of breathing (by way of enhancement of muscle electrical activity) does not manifest in mdx mice (O'Halloran et al., 2023), accessory muscle activation in early dystrophic disease is maintained, serving to support breathing in the presence of reduced electrical activation and inherent weakness of the obligatory respiratory muscles. Indeed, it appears it is the loss of compensation provided by accessory muscles that gives rise to ventilatory insufficiency in mdx mice, and perhaps human DMD (O'Halloran et al., 2023).…”