{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T12:22:58Z","timestamp":1777724578581,"version":"3.51.4"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T00:00:00Z","timestamp":1703548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82201553"],"award-info":[{"award-number":["82201553"]}],"id":[{"id":"10.13039\/501100001809","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":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>We aimed to analyse genome\u2010wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle\u2010derived genome\u2010wide RNA\u2010sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single\u2010sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA\u2010Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real\u2010time PCR (qRT\u2010PCR) analysis, western blot analysis, and single\u2010nucleus RNA\u2010sequencing (snRNA\u2010seq) were performed in the remaining patients to validate the most correlated gene signature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation\/immune response and extracellular matrix remodelling compared with 29 BMD muscles (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). The ssGSEA\u2010Cor pipeline revealed that the gene set of <jats:italic>CDKN2A<\/jats:italic> and <jats:italic>CDKN2B<\/jats:italic> was the most correlated gene signature for fibrofatty replacement (histological <jats:italic>r<\/jats:italic><jats:sub>s<\/jats:sub>\u00a0=\u00a00.744, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; MRI <jats:italic>r<\/jats:italic><jats:sub>s<\/jats:sub>\u00a0=\u00a00.718, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Muscle qRT\u2010PCR confirmed that <jats:italic>CDKN2A<\/jats:italic> mRNA expression in both 15 DMD (median\u00a0=\u00a025.007, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and 12 BMD (median\u00a0=\u00a05.654, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) patients were significantly higher than that in controls (median\u00a0=\u00a01.101), while no significant difference in <jats:italic>CDKN2B<\/jats:italic> mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle <jats:italic>CDKN2A<\/jats:italic> mRNA expression respectively correlated with muscle MRI (<jats:italic>r<\/jats:italic><jats:sub>s<\/jats:sub>\u00a0=\u00a00.883, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and histological fibrofatty replacement (<jats:italic>r<\/jats:italic><jats:sub>s<\/jats:sub>\u00a0=\u00a00.804, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and disease duration (<jats:italic>r<\/jats:italic><jats:sub>s<\/jats:sub>\u00a0=\u00a00.645, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and North Star Ambulatory Assessment total scores (<jats:italic>r<\/jats:italic><jats:sub>s<\/jats:sub>\u00a0=\u00a0\u22120.698, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Muscle western blot analysis confirmed that both four DMD (median\u00a0=\u00a02.958, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and four BMD (median\u00a0=\u00a01.959, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) patients had a significantly higher level of <jats:italic>CDKN2A<\/jats:italic> protein expression than controls (median\u00a0=\u00a01.068). The snRNA\u2010seq analysis of two DMD muscles revealed that <jats:italic>CDKN2A<\/jats:italic> was mainly expressed in fibro\u2010adipogenic progenitors, satellite cells, and myoblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identify <jats:italic>CDKN2A<\/jats:italic> expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13410","type":"journal-article","created":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T10:39:17Z","timestamp":1703587157000},"page":"98-111","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology 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