{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:37:22Z","timestamp":1789475842179,"version":"build-2803163510"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K08\u2010NS120812"],"award-info":[{"award-number":["K08\u2010NS120812"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R21NS140497"],"award-info":[{"award-number":["R21NS140497"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD095897"],"award-info":[{"award-number":["R01HD095897"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS092651"],"award-info":[{"award-number":["R01NS092651"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS111275\u201001"],"award-info":[{"award-number":["R21NS111275\u201001"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["BX004419"],"award-info":[{"award-number":["BX004419"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["BX006231"],"award-info":[{"award-number":["BX006231"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL153460"],"award-info":[{"award-number":["R01 HL153460"]}],"id":[{"id":"10.13039\/100000050","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":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Duchenne muscular dystrophy (DMD) is a fatal X\u2010linked recessive disease due to loss\u2010of\u2010function variants in the\n                      <jats:italic>DYSTROPHIN<\/jats:italic>\n                      gene. DMD\u2010related skeletal muscle wasting is typified by an aberrant immune response involving upregulation of the TGF\u03b2 family of cytokines, like TGF\u03b21 and BMP4. We previously demonstrated that bone morphogenetic protein 4 (BMP4) is increased in DMD and BMP4 stimulation induces a 20\u2010fold upregulation of\n                      <jats:italic>Smad8<\/jats:italic>\n                      transcription in muscle cells. However, the role of BMP4 in late\u2010stage DMD skeletal muscle is unknown. We hypothesized that BMP4 signalling is a driver of aberrant gene expression in late\u2010stage human DMD skeletal muscle detectable by a transcriptomic signature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Transcriptomes from skeletal muscle biopsies of late\u2010stage DMD versus non\u2010DMD controls and C2C12 muscle cells with or without BMP4 stimulation were generated using RNA\u2010Seq. We tested transcriptional differences at the single transcript level in skeletal muscle biopsy samples from three patients with DMD and compared them to three non\u2010DMD. They were then analyzed by Ingenuity Pathway Analysis, weighted gene coexpression network analyses (WGCNA) and Gene Set Enrichment Analysis (GSEA). Key hub and high\u2010fold change genes overlapping in the DMD and BMP4 muscle transcriptomes were validated in additional primary and bulk skeletal muscle samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 3048 transcripts in the human muscle and 5291 transcripts in C2C12 muscle cells were differentially expressed. WGCNA identified an overlapping molecular signature of 1027 genes dysregulated in DMD muscle that were induced in BMP4\u2010stimulated C2C12 muscle cells.\n                      <jats:italic>SERPING1<\/jats:italic>\n                      and\n                      <jats:italic>Aff3<\/jats:italic>\n                      were identified as the top hub genes. Highly upregulated DMD muscle transcripts that overlapped with BMP4\u2010stimulated C2C12 muscle cells included\n                      <jats:italic>ADAM12<\/jats:italic>\n                      ,\n                      <jats:italic>SERPING1<\/jats:italic>\n                      ,\n                      <jats:italic>SMAD8<\/jats:italic>\n                      and\n                      <jats:italic>SFRP4<\/jats:italic>\n                      . DMD skeletal muscle analysis showed aberrant upregulation of TGF\u03b2 signalling, extracellular matrix remodelling and collagen biosynthesis pathways, in contrast to inhibited mitochondrial and metabolic pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In summary, the DMD transcriptome was characterized by dysregulation of immune function, ECM remodelling and muscle bioenergetic metabolism. We additionally define a late\u2010stage DMD skeletal muscle transcriptome that overlaps with a BMP4\u2010induced molecular signature in C2C12 muscle cells. This supports BMP4\/Smad8 pathway as a disease\u2010driving regulator of transcriptomic changes in late\u2010stage DMD skeletal muscle. Further exploration of this cross\u2010species transcriptomic signature may expand our understanding of the evolution of dystrophic signalling pathways and the associated gene networks, which could be evaluated for therapeutic development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70005","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T05:29:57Z","timestamp":1752211797000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Late\u2010Stage Skeletal Muscle Transcriptome in Duchenne Muscular Dystrophy Shows a BMP4\u2010Induced Molecular Signature"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7757-1843","authenticated-orcid":false,"given":"Hanna","family":"Sothers","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Genetics, Genomics and Bioinformatics, Graduate School of Biomedical Sciences University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianzhen","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Neurology University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Children's of Alabama  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David\u00a0K.","family":"Crossman","sequence":"additional","affiliation":[{"name":"Department of Genetics, School of Medicine University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7406-5171","authenticated-orcid":false,"given":"Matthew\u00a0S.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Genetics, Genomics and Bioinformatics, Graduate School of Biomedical Sciences University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Department of Pediatrics, Division of Pediatric Neurology University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Children's of Alabama  Birmingham Alabama USA"},{"name":"Department of Genetics, School of Medicine University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Department of Neurology University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2647-9422","authenticated-orcid":false,"given":"Merry\u2010Lynn\u00a0N.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Genetics, Genomics and Bioinformatics, Graduate School of Biomedical Sciences University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Department of Genetics, School of Medicine University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"UAB Civitan International Research Center (CIRC)  Birmingham Alabama USA"},{"name":"UAB Center for Exercise Medicine  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9391-7464","authenticated-orcid":false,"given":"Peter\u00a0H.","family":"King","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Birmingham Veterans Affairs Medical Center  Birmingham Alabama USA"},{"name":"Killion Center for Neurodegeneration and Experimental Therapeutics University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3029-0761","authenticated-orcid":false,"given":"Michael\u00a0A.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Genetics, Genomics and Bioinformatics, Graduate School of Biomedical Sciences University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Department of Pediatrics, Division of Pediatric Neurology University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Children's of Alabama  Birmingham Alabama USA"},{"name":"Department of Genetics, School of Medicine University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"},{"name":"Department of Neurology University of Alabama at Birmingham (UAB)  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(87)90579-4"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa7322"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117417"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000173836.09176.c4"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.135703"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2010.10.003"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.03.004"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23147515"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000032603"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.151.6.1321"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(02)00093-7"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192571199"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7285com"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201402079"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.117"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23137"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt703"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1001057"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210695200"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl023"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0138425"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1256-12.2012"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202216225"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.241372"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg065"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070435"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.133314"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2014.00011"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-004-0941-0"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2007.06.004"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2011.05.011"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.07.008"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.42.25273"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.14.5973-5984.2005"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139520"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106570200"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054362"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70005","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T07:47:41Z","timestamp":1755848861000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.70005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,10]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/jcsm.70005"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.70005","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.04.19.590266","asserted-by":"object"}]},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,10]]},"assertion":[{"value":"2024-05-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70005"}}