{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T08:18:34Z","timestamp":1772007514677,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["SFI 19\/FFP\/6628 INSPIRE DMD"],"award-info":[{"award-number":["SFI 19\/FFP\/6628 INSPIRE DMD"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Despite profound diaphragm weakness, peak inspiratory pressure\u2010generating capacity is preserved in young <jats:italic>mdx<\/jats:italic> mice revealing adequate compensation by extra\u2010diaphragmatic 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\u2010type (<jats:italic>n<\/jats:italic>\u00a0=\u00a0196) and dystrophin\u2010deficient <jats:italic>mdx<\/jats:italic> mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a0188) at 1, 4, 8, 12 and 16\u00a0months 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\u201340\u00a0s to evoke peak system activation to task failure. Obligatory inspiratory EMG activities were lower in <jats:italic>mdx<\/jats:italic> mice across the ventilatory range to peak activity, emerging in early dystrophic disease. Early compensation protecting peak inspiratory pressure\u2010generating capacity in <jats:italic>mdx<\/jats:italic> mice, which appears to relate to transforming growth factor\u2010\u03b21\u2010dependent fibrotic remodelling of the diaphragm and preserved accessory muscle function, was lost at 12 and 16\u00a0months of age. Denervation and surgical lesion of muscles of breathing in 4\u2010month\u2010old mice revealed a greater dependency on diaphragm for peak inspiratory performance in wild\u2010type mice, whereas <jats:italic>mdx<\/jats:italic> mice were heavily dependent upon accessory muscles (including abdominal muscles) for peak performance. Accessory EMG activities were generally preserved or enhanced in young <jats:italic>mdx<\/jats:italic> mice, but peak EMG activities were lower than wild\u2010type by 12\u00a0months of age. In general, ventilation was reasonably well protected in <jats:italic>mdx<\/jats:italic> mice until 16\u00a0months 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.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15718-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Despite diaphragm weakness, peak inspiratory performance is preserved in young dystrophin\u2010deficient <jats:italic>mdx<\/jats:italic> mice revealing adequate compensation by extra\u2010diaphragmatic muscles.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Peak obligatory muscle (diaphragm, external intercostal, and parasternal intercostal) EMG activities are lower in <jats:italic>mdx<\/jats:italic> 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 <jats:italic>mdx<\/jats:italic> mice during peak system activation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In phrenicotomised mice with confirmed diaphragm paralysis, there is a greater contribution made by extra\u2010diaphragmatic muscles to peak inspiratory pressure in <jats:italic>mdx<\/jats:italic> compared with wild\u2010type mice. Surgical lesion of accessory (including abdominal) muscles adversely affects peak pressure generation in <jats:italic>mdx<\/jats:italic> mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Diaphragm remodelling leading to stiffening provides a mechanical advantage to peak pressure generation via the facilitated action of extra\u2010diaphragmatic muscles in early dystrophic disease. Peak accessory EMG activities are lower in 12\u2010month\u2010old <jats:italic>mdx<\/jats:italic> compared to wild\u2010type mice. Peak inspiratory pressure declines in <jats:italic>mdx<\/jats:italic> mice with advanced disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conclude that compensation afforded by accessory muscles of breathing declines in advanced dystrophic disease precipitating the emergence of respiratory system dysfunction.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp285203","type":"journal-article","created":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T06:02:56Z","timestamp":1694239376000},"page":"4441-4467","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Loss of compensation afforded by accessory muscles of breathing leads to respiratory system compromise in the <i>mdx<\/i> mouse model of Duchenne muscular dystrophy"],"prefix":"10.1113","volume":"601","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8832-1153","authenticated-orcid":false,"given":"Ken 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Health University College Cork  Cork Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Se\u00e1n C.","family":"\u00d3 Murch\u00fa","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine and Health University College Cork  Cork Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7221-3628","authenticated-orcid":false,"given":"David P.","family":"Burns","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine and Health University College Cork  Cork Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conor M.","family":"Mahony","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine and Health University College Cork  Cork Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aoife 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