{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:38:49Z","timestamp":1789018729959,"version":"build-2803163510"},"reference-count":75,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T00:00:00Z","timestamp":1551225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004411","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","award":["S13 SI 0592"],"award-info":[{"award-number":["S13 SI 0592"]}],"id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT 153159"],"award-info":[{"award-number":["PJT 153159"]}],"id":[{"id":"10.13039\/501100000024","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":[[2020,4]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Ninety\u2010eight per cent of patients with Duchenne muscular dystrophy (DMD) develop cardiomyopathy, with 40% developing heart failure.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>While increased propensity for mitochondrial induction of cell death has been observed in left ventricle, it remains unknown whether this is linked to impaired mitochondrial respiratory control and elevated H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> emission prior to the onset of cardiomyopathy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Classic mouse models of DMD demonstrate hyper\u2010regeneration in skeletal muscle which may mask mitochondrial abnormalities. Using a model with less regenerative capacity that is more akin to DMD patients, we observed elevated left ventricular mitochondrial H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> and impaired oxidative phosphorylation in the absence of cardiac remodelling or overt cardiac dysfunction at 4\u00a0weeks.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These impairments were associated with dysfunctions at complex I, governance by ADP and creatine\u2010dependent phosphate shuttling, which results in a less efficient response to energy demands.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Mitochondria may be a therapeutic target for the treatment of cardiomyopathy in DMD.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>In Duchenne muscular dystrophy (DMD), mitochondrial dysfunction is predicted as a response to numerous cellular stressors, yet the contribution of mitochondria to the onset of cardiomyopathy remains unknown. To resolve this uncertainty, we designed <jats:italic>in vitro<\/jats:italic> assessments of mitochondrial bioenergetics to model mitochondrial control parameters that influence cardiac function. Both left ventricular mitochondrial responsiveness to the central bioenergetic controller ADP and the ability of creatine to facilitate mitochondrial\u2013cytoplasmic phosphate shuttling were assessed. These measurements were performed in D2.B10\u2010DMD<jats:italic><jats:sup>mdx<\/jats:sup><\/jats:italic>\/2J mice \u2013 a model that demonstrates skeletal muscle atrophy and weakness due to limited regenerative capacities and cardiomyopathy more akin to people with DMD than classic models. At 4\u00a0weeks of age, there was no evidence of cardiac remodelling or cardiac dysfunction despite impairments in ADP\u2010stimulated respiration and ADP attenuation of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> emission. These impairments were seen at both submaximal and maximal ADP concentrations despite no reductions in mitochondrial content markers. The ability of creatine to enhance ADP's control of mitochondrial bioenergetics was also impaired, suggesting an impairment in mitochondrial creatine kinase\u2010dependent phosphate shuttling. Susceptibly to permeability transition pore opening and the subsequent activation of cell death pathways remained unchanged. Mitochondrial H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> emission was elevated despite no change in markers of irreversible oxidative damage, suggesting alternative redox signalling mechanisms should be explored. These findings demonstrate that selective mitochondrial dysfunction precedes the onset of overt cardiomyopathy in D2<jats:italic>.mdx<\/jats:italic> mice, suggesting that improving mitochondrial bioenergetics by restoring ADP, creatine\u2010dependent phosphate shuttling and complex I should be considered for treating DMD patients.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp277306","type":"journal-article","created":{"date-parts":[[2019,1,24]],"date-time":"2019-01-24T19:11:20Z","timestamp":1548357080000},"page":"1377-1392","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Impairments in left ventricular mitochondrial bioenergetics precede overt cardiac dysfunction and remodelling in Duchenne muscular dystrophy"],"prefix":"10.1113","volume":"598","author":[{"given":"Meghan C.","family":"Hughes","sequence":"first","affiliation":[{"name":"School of Kinesiology and Health Science and the Muscle Health Research Centre York University  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofhia V.","family":"Ramos","sequence":"additional","affiliation":[{"name":"School of Kinesiology and Health Science and the Muscle Health Research Centre York University  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick C.","family":"Turnbull","sequence":"additional","affiliation":[{"name":"School of Kinesiology and Health Science and the Muscle Health Research Centre York University  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8232-0432","authenticated-orcid":false,"given":"Brittany A.","family":"Edgett","sequence":"additional","affiliation":[{"name":"Department of Human Health and Nutritional Sciences and Cardiovascular Research Group University of Guelph  Guelph ON Canada"},{"name":"Department of Pharmacology Dalhousie Medicine New Brunswick  Saint John New Brunswick Canada"},{"name":"IMPART Team Canada Investigator Network  Saint John New Brunswick Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9463-7093","authenticated-orcid":false,"given":"Jason S.","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Human Health and Nutritional Sciences and Cardiovascular Research Group University of Guelph  Guelph ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazari","family":"Polidovitch","sequence":"additional","affiliation":[{"name":"Department of Biology and the Muscle Health Research Centre  York University  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Schlattner","sequence":"additional","affiliation":[{"name":"Laboratory of Fundamental and Applied Bioenergetics (LBFA) and SFR Environmental and Systems Biology (BEeSy) University Grenoble Alpes  Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter H.","family":"Backx","sequence":"additional","affiliation":[{"name":"Department of Biology and the Muscle Health Research Centre  York University  Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4482-547X","authenticated-orcid":false,"given":"Jeremy A.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Human Health and Nutritional Sciences and Cardiovascular Research Group University of Guelph  Guelph ON Canada"},{"name":"IMPART Team Canada Investigator Network  Saint John New Brunswick Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5745-5888","authenticated-orcid":false,"given":"Christopher G. 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