{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:25:21Z","timestamp":1790429121843,"version":"4.1.0"},"reference-count":69,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,12,17]],"date-time":"2019-12-17T00:00:00Z","timestamp":1576540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011724","name":"Muscular Dystrophy UK","doi-asserted-by":"publisher","award":["RA4\/3015"],"award-info":[{"award-number":["RA4\/3015"]}],"id":[{"id":"10.13039\/100011724","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P003125\/1"],"award-info":[{"award-number":["MR\/P003125\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N024850\/1"],"award-info":[{"award-number":["MR\/N024850\/1"]}],"id":[{"id":"10.13039\/501100000265","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":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Duchenne muscular dystrophy (DMD) is a fatal muscle\u2010wasting disorder caused by genetic loss of dystrophin protein. Extracellular microRNAs (ex\u2010miRNAs) are putative, minimally invasive biomarkers of DMD. Specific ex\u2010miRNAs (e.g. miR\u20101, miR\u2010133a, miR\u2010206, and miR\u2010483) are highly up\u2010regulated in the serum of DMD patients and dystrophic animal models and are restored to wild\u2010type levels following exon skipping\u2010mediated dystrophin rescue in <jats:italic>mdx<\/jats:italic> mice. As such, ex\u2010miRNAs are promising pharmacodynamic biomarkers of exon skipping efficacy. Here, we aimed to determine the degree to which ex\u2010miRNA levels reflect the underlying level of dystrophin protein expression in dystrophic muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Candidate ex\u2010miRNA biomarker levels were investigated in <jats:italic>mdx<\/jats:italic> mice in which dystrophin was restored with peptide\u2010PMO (PPMO) exon skipping conjugates and in <jats:italic>mdx\u2010Xist<\/jats:italic><jats:sup>\u0394hs<\/jats:sup> mice that express variable amounts of dystrophin from birth as a consequence of skewed X\u2010chromosome inactivation. miRNA profiling was performed in <jats:italic>mdx\u2010Xist<\/jats:italic><jats:sup>\u0394hs<\/jats:sup> mice using the FirePlex methodology and key results validated by small RNA TaqMan RT\u2010qPCR. The muscles from each animal model were further characterized by dystrophin western blot and immunofluorescence staining.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The restoration of ex\u2010myomiR abundance observed following PPMO treatment was not recapitulated in the high dystrophin\u2010expressing <jats:italic>mdx\u2010Xist<\/jats:italic><jats:sup>\u0394hs<\/jats:sup> group, despite these animals expressing similar amounts of total dystrophin protein (~37% of wild\u2010type levels). Instead, ex\u2010miRNAs were present at high levels in <jats:italic>mdx\u2010Xist<\/jats:italic><jats:sup>\u0394hs<\/jats:sup> mice regardless of dystrophin expression. PPMO\u2010treated muscles exhibited a uniform pattern of dystrophin localization and were devoid of regenerating fibres, whereas <jats:italic>mdx\u2010Xist<\/jats:italic><jats:sup>\u0394hs<\/jats:sup> muscles showed non\u2010homogeneous dystrophin staining and sporadic regenerating foci.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Uniform dystrophin expression is required to prevent ex\u2010miRNA release, stabilize myofiber turnover, and attenuate pathology in dystrophic muscle.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12506","type":"journal-article","created":{"date-parts":[[2019,12,18]],"date-time":"2019-12-18T06:12:26Z","timestamp":1576649546000},"page":"578-593","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology"],"prefix":"10.1002","volume":"11","author":[{"given":"Tirsa L.E.","family":"van Westering","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  South Parks Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia","family":"Lomonosova","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  South Parks Road Oxford UK"},{"name":"Department of Paediatrics University of Oxford  South Parks Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.L.","family":"Coenen\u2010Stass","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  South Parks Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne A.","family":"Betts","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  South Parks Road Oxford UK"},{"name":"Department of Paediatrics University of Oxford  South Parks Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amarjit","family":"Bhomra","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  South Parks Road Oxford UK"},{"name":"Department of Paediatrics University of Oxford  South Parks Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margriet","family":"Hulsker","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy E.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Paediatrics University of Oxford  South Parks Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"McClorey","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  South Parks Road Oxford UK"},{"name":"Department of Paediatrics University of Oxford  South Parks Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke","family":"Aartsma\u2010Rus","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike","family":"van Putten","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.A.","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  South Parks Road Oxford UK"},{"name":"Department of Paediatrics University of Oxford  South Parks Road Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3313-7631","authenticated-orcid":false,"given":"Thomas C.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  South Parks Road Oxford UK"},{"name":"Department of Paediatrics University of Oxford  South Parks Road Oxford UK"},{"name":"Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90035-W"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.122.4.809"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.8.3710"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.45.4.677"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00180110"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2010.05.010"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00207374"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-13-73"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073810371004"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.014"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3819"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000005680"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr291"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2013-306350"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2007.07.005"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh174"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2016.11.011"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv155"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2014.03.006"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.3233\/JND-150102"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2017.09.002"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200603008"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.35"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.07.066"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804549105"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201100133"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018388"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2012.26"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2018.08.005"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt724"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw237"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds082"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031937"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2012.30"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0089237"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/1480-9222-16-5"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.9.e45"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.21-4-459"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.1.241"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.2144\/03342mt01"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17081334"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880121013"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199003000-00002"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004290050036"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2009.03.003"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.6.581"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2018.10.008"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055281"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.07.021"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080263"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2014.29"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.01.009"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-224170"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/4033"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv381"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90597-7"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/337570a0"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(97)00052-7"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.10.1725"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad5143"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad5177"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14454"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau1549"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2018.06.006"},{"key":"e_1_2_8_66_1","article-title":"Prevalence and long\u2010term monitoring of humoral immunity against adeno\u2010associated virus in Duchenne muscular dystrophy patients","author":"Leborgne C","year":"2018","journal-title":"Cell Immunol"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-016-0316-x"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12015-017-9792-7"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(95)00147-T"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12261"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcsm.12506","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12506","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.12506","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12506","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T08:35:42Z","timestamp":1694075742000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.12506"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,17]]},"references-count":69,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1002\/jcsm.12506"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.12506","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,17]]},"assertion":[{"value":"2019-08-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}