{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:55:42Z","timestamp":1792047342428,"version":"4.4.0"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T00:00:00Z","timestamp":1646524800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Oxidative stress is implicated in the pathophysiology of Duchenne muscular dystrophy (DMD, caused by mutations in the dystrophin gene), which is the most common and severe of the muscular dystrophies. To our knowledge, the distribution of iron, an important modulator of oxidative stress, has not been assessed in DMD. We tested the hypotheses that iron accumulation occurs in mouse models of DMD and that modulation of iron through the diet or chelation could modify disease severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed iron distribution and total elemental iron using LA\u2010ICP\u2010MS on skeletal muscle cross\u2010sections of 8\u2010week\u2010old Bl10 control mice and dystrophic <jats:italic>mdx<\/jats:italic> mice (with moderate dystrophy) and dystrophin\/utrophin\u2010null mice (<jats:italic>dko<\/jats:italic>, with severe dystrophy). In addition, <jats:italic>mdx<\/jats:italic> mice (4\u00a0weeks) were treated with either an iron chelator (deferiprone 150\u00a0mg\/kg\/day) or iron\u2010enriched feed (containing 1% added iron as carbonyl iron). Immunoblotting was used to determine the abundance of iron\u2010 and mitochondria\u2010related proteins. (Immuno)histochemical and mRNA assessments of fibrosis and inflammation were also performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed a significant increase in total elemental iron in hindlimb muscles of <jats:italic>dko<\/jats:italic> mice (+50%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and in the diaphragm of <jats:italic>mdx<\/jats:italic> mice (+80%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), with both tissues exhibiting severe pathology. Iron dyshomeostasis was further evidenced by an increase in the storage protein ferritin (<jats:italic>dko<\/jats:italic>: +39%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and ferroportin compared with Bl10 control mice (<jats:italic>mdx<\/jats:italic>: +152% and <jats:italic>dko<\/jats:italic>: +175%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Despite having features of iron overload, dystrophic muscles had lower protein expression of ALAS\u20101, the rate\u2010limiting enzyme for haem synthesis (<jats:italic>dko<\/jats:italic> \u221244%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), and the haem\u2010containing protein myoglobin (<jats:italic>dko<\/jats:italic> \u221254%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Deferiprone treatment tended to decrease muscle iron levels in <jats:italic>mdx<\/jats:italic> mice (\u221230%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.1), which was associated with lower oxidative stress and fibrosis, but suppressed haem\u2010containing proteins and mitochondrial content. Increasing iron via dietary intervention elevated total muscle iron (+25%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) but did not aggravate the pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Muscles from dystrophic mice have increased iron levels and dysregulated iron\u2010related proteins that are associated with dystrophic pathology. Muscle iron levels were manipulated by iron chelation and iron enriched feed. Iron chelation reduced fibrosis and reactive oxygen species (ROS) but also suppressed haem\u2010containing proteins and mitochondrial activity. Conversely, iron supplementation increased ferritin and haem\u2010containing proteins but did not alter ROS, fibrosis, or mitochondrial activity. Further studies are required to investigate the contribution of impaired ferritin breakdown in the dysregulation of iron homeostasis in DMD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12950","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:39:22Z","timestamp":1646613562000},"page":"1541-1553","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Iron overload and impaired iron handling contribute to the dystrophic pathology in models of Duchenne muscular dystrophy"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9059-3238","authenticated-orcid":false,"given":"Francesca M.","family":"Alves","sequence":"first","affiliation":[{"name":"Centre for Muscle Research, Department of Anatomy and Physiology The University of Melbourne  Melbourne Victoria Australia"},{"name":"Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-2850","authenticated-orcid":false,"given":"Kai","family":"Kysenius","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4447-9020","authenticated-orcid":false,"given":"Marissa K.","family":"Caldow","sequence":"additional","affiliation":[{"name":"Centre for Muscle Research, Department of Anatomy and Physiology The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6469-9592","authenticated-orcid":false,"given":"Justin P.","family":"Hardee","sequence":"additional","affiliation":[{"name":"Centre for Muscle Research, Department of Anatomy and Physiology The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-6436","authenticated-orcid":false,"given":"Jin D.","family":"Chung","sequence":"additional","affiliation":[{"name":"Centre for Muscle Research, Department of Anatomy and Physiology The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0016-0998","authenticated-orcid":false,"given":"Jennifer","family":"Trieu","sequence":"additional","affiliation":[{"name":"Centre for Muscle Research, Department of Anatomy and Physiology The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5922-7643","authenticated-orcid":false,"given":"Dominic J.","family":"Hare","sequence":"additional","affiliation":[{"name":"Monash eResearch Centre Monash University  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7777-4747","authenticated-orcid":false,"given":"Peter J.","family":"Crouch","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3479-2427","authenticated-orcid":false,"given":"Scott","family":"Ayton","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8259-9069","authenticated-orcid":false,"given":"Ashley I.","family":"Bush","sequence":"additional","affiliation":[{"name":"Melbourne Dementia Research Centre, The 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