{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:24:05Z","timestamp":1790767445610,"version":"4.1.0"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,12,19]],"date-time":"2021-12-19T00:00:00Z","timestamp":1639872000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004411","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Muscular dystrophy (MD) causes muscle wasting and is often lethal in patients due to a lack of proven therapies. In contrast, mouse models of MD are notoriously mild. We have previously shown severe human\u2010like muscle pathology in <jats:italic>mdx<\/jats:italic> [Duchenne MD (DMD)] and dysferlin\u2010deficient limb\u2010girdle MD type 2B (LGMD2B) mice by inactivating the gene encoding for apolipoprotein E (ApoE), a lipid transporter synthesized by the liver, brain and adipocytes to regulate lipid and fat metabolism. Having recently established that human DMD is a novel type of primary genetic dyslipidaemia with elevated cholesterol, we sought to determine whether cholesterol could exacerbate the muscle wasting process observed in severe rodent MD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Severe <jats:italic>mdx<\/jats:italic> and dysferlin knock\u2010out mice lacking ApoE were treated with ezetimibe (15\u00a0mg\/kg\/day), a clinically approved drug exhibiting few pleiotropic effects. In separate studies, dietary cholesterol was raised (from 0.2% to 2% cholesterol) in combination with experimental micro\u2010injury and direct cholesterol injection assays. Muscles were assessed histologically for changes in collagen and adipocyte infiltration and both transcriptomic and cellular changes by RNA\u2010seq and fluorescence\u2010activated cell sorting analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Treatment of severe DMD and LGMD2B mice with ezetimibe completely prevented clinical signs of ambulatory dysfunction (0% incidence vs. 33% for vehicle treatment; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Histological analyses revealed that ezetimibe\u2010reduced fibro\u2010fatty infiltration up to 84% and 63% in severely affected triceps (<jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.0001) and gastrocnemius (<jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.003) muscles, resulting in a respective 1.9\u2010fold and 2.2\u2010fold retention of healthy myofibre area (<jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.0001). Additionally, raising dietary cholesterol and thus concentrations of plasma low\u2010density lipoprotein\u2010associated cholesterol (by 250%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) reduced overall survivability (by 100%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and worsened muscle damage in the LGMD2B triceps by 767% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.03). Micro\u2010pin\u2010induced mechanical injury in LGMD2B mice fed a high cholesterol diet exacerbated muscle damage by 425% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.03) and increased macrophage recruitment (by 98%; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.03) compared with those injured on a chow diet. Parallel RNA\u2010seq analyses revealed that injury in cholesterol\u2010fed mice also modulated the expression of 3671 transcripts (1953 up\u2010regulated), with fibrogenic, inflammatory and programmed cell death\u2010associated pathways among the most enriched. Mice lacking dysferlin also displayed heightened muscle necrosis (by 123%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) following a direct intramuscular injection of cholesterol compared with control mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Cholesterol exacerbates rodent MD. Specific inhibition of cholesterol absorption with ezetimibe may safely attenuate human MD severity and delay death.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12879","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T06:31:12Z","timestamp":1639981872000},"page":"544-560","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Cholesterol absorption blocker ezetimibe prevents muscle wasting in severe dysferlin\u2010deficient and <i>mdx<\/i> mice"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1734-9896","authenticated-orcid":false,"given":"Zoe","family":"White","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Pharmacology &amp; Therapeutics University of British Columbia (UBC)  Vancouver BC Canada"},{"name":"UBC Centre for Heart Lung Innovation St. Paul's Hospital  Vancouver BC 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Wei\u2010Han","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Pharmacology &amp; Therapeutics University of British Columbia (UBC)  Vancouver BC Canada"},{"name":"UBC Centre for Heart Lung Innovation St. Paul's Hospital  Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin G.","family":"Sirois","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute, Department of Pharmacology and Physiology Universit\u00e9 de Montr\u00e9al  Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0368-2620","authenticated-orcid":false,"given":"Fabio","family":"Rossi","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Department of Medical Genetics University of British Columbia (UBC)  Vancouver BC 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