Breathing in Duchenne muscular dystrophy: translation to therapy

Mhandire, Doreen; Burns, David P.; Roger, Angela L.; O’Halloran, Ken D.; ElMallah, Mai K.

doi:10.1113/jp281671

Cited by 22 publications

(18 citation statements)

References 162 publications

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“…DMD causes progressive fat deposition and fibrosis of skeletal muscles resulting in loss of ambulation and progressive respiratory insufficiency and failure in the second decade of life. [5][6][7][8] A less common condition is spinal muscular atrophy (SMA), an autosomal recessive disease caused by mutations in the survival motor neuron 1 (SMN1) gene, with a prevalence of 1:10,000−1:11,000 among live births. 9,10 SMA was previously known as the most common genetic cause of death in infancy, but thanks to the introduction of SMA in the newborn screening programs across most of the United States and other developed countries, as well as the Food and Drug Administration (FDA) approval of three disease modifying therapies, the phenotype and outcomes of patients with SMA is rapidly evolving and improving.…”

Section: Introductionmentioning

confidence: 99%

ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease

Leon‐Astudillo

Okorie

McCown

et al. 2023

Pediatric Pulmonology

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The American Thoracic Society Core Curriculum updates clinicians annually in pediatric pulmonary disease. This is a concise review of the Pediatric Pulmonary Medicine Core Curriculum presented at the 2022 American Thoracic Society International Conference. Neuromuscular diseases (NMD) comprise a variety of conditions that commonly affect the respiratory system and cause significant morbidity including dysphagia, chronic respiratory failure, and sleep disordered breathing. Respiratory failure is the most common cause of mortality in this population. Substantial progress has been made in diagnosis, monitoring and treatment for NMD over the last decade. Pulmonary function testing (PFT) is utilized to objectively measure respiratory pump function and PFT milestones are utilized in NMD‐specific pulmonary care guidelines. New disease modifying therapies are approved for the treatment of patients with Duchenne muscular dystrophy and spinal muscular atrophy (SMA), including the first ever approved systemic gene therapy, in the case of SMA. Despite extraordinary progress in the medical management of NMD, little is known regarding the respiratory implications and long‐term outcomes for patients in the era of advanced therapeutics and precision medicine. The combination of technological and biomedical advancements has increased the complexity of the medical decision‐making process for patients and families, thus emphasizing the importance of balancing respect for autonomy with the other foundational principles of medical ethics. This review features an overview of PFT, noninvasive ventilation strategies, novel and developing therapies, as well as the ethical considerations specific to the management of patients with pediatric NMD.

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Section: Introductionmentioning

confidence: 99%

ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease

Leon‐Astudillo

Okorie

McCown

et al. 2023

Pediatric Pulmonology

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“…In DMD, there is a progressive decline in respiratory muscle strength and pulmonary function culminating in ventilatory insufficiency leading to cardiorespiratory failure (De Bruin et al., 1997; Hukins & Hillman, 2000; Khirani et al., 2014; Smith et al., 1989). Studies characterising respiratory control in DMD are limited, but deficits and compensations in respiratory control are described in the mdx mouse (Mhandire et al., 2022; O'Halloran & Burns, 2019), which are important to delineate in the context of interventional therapies for human dystrophinopathies.…”

Section: Introductionmentioning

confidence: 99%

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,

Maxwell,

Marullo

et al. 2023

The Journal of Physiology

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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.

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“…Such considerations also potentially widen the relevance of this important work to other muscle-wasting disorders. Mhandire et al (2022) describe the features of respiratory insufficiency in people with DMD and preclinical models of dystrophic disease. Respiratory failure is the leading cause of premature death in severe muscular dystrophy.…”

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confidence: 99%

“…The Physiological Society‐sponsored symposium ‘ Breathing with neuromuscular disease: translation to therapy ’ was held at the Experimental Biology Meeting in 2021, a virtual event in the light of the coronavirus disease 2019 pandemic. The cut and thrust of the discussion concerning DMD are developed further in two Topical Review articles recently published in The Journal (Mhandire et al., 2022; Petrof, 2022). The articles highlight advances in the understanding of dystrophic disease arising from studies using the mdx mouse model, revealing the phenomenon of trained immunity driving muscle pathology in muscular dystrophy (Petrof, 2022) and a widening of the vista of respiratory deficits and compensations in preclinical models of DMD with consideration of gene therapy strategies.…”

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confidence: 99%