{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:03:19Z","timestamp":1784887399547,"version":"3.55.0"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100018952","name":"Birmingham Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018952","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":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Patients with end\u2010stage liver disease (ESLD) often present with sarcopenia, defined as loss of skeletal muscle mass and quality, which is associated with reduced quality of life and increased mortality. However, the molecular mechanisms driving sarcopenia in ESLD are not fully understood and there are currently no therapeutic interventions. This study aimed to identify potential circulating factors contributing to sarcopenia progression in ESLD by assessing their role in driving transcriptomic alterations in skeletal muscle.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Quadriceps muscle tissue, plasma and serum were obtained from ESLD patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200924) and age\/sex\u2010matched healthy controls (HC;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200918) (Clinical Trial ID: NCT04734496, Ethical Approval 18\/WM\/0167). Total RNA from snap\u2010frozen vastus lateralis muscle biopsies underwent RNA sequencing (Illumina). Serum concentrations of 60 cytokines were profiled by Luminex and ELISA, with comparisons made both between ESLD and HC, and across ESLD aetiologies (alcohol\u2010related, NAFLD, viral hepatitis, other). In\u00a0vitro, primary human myotubes (from non\u2010ESLD aged donors, NRES #16\/SS\/0172) were treated with 10% ESLD or HC plasma (24\u2009h,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20096 per group) followed by RNA sequencing (BGI Genomics). Differentially expressed genes (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05, fold\u2010change &gt;\u20091.5) were identified via Qlucore and DESeq2, and pathway analysis performed using Ingenuity (Qiagen). The impact of physiological concentrations of candidate cytokines (IL\u20101\u03b1, GDF\u201015 and HGF) on myotube thickness, differentiation and mitochondrial function was assessed by immunofluorescence microscopy, RT\u2010qPCR and metabolic flux assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In ESLD muscle, 387 and 225 genes were significantly up\u2010 and downregulated compared to HC, respectively, with cellular senescence identified as a top dysregulated function. Upstream regulator analysis predicted activation of hepatocyte growth factor (HGF) and interleukin\u20101 signalling. Subgroup analysis revealed distinct transcriptomic profiles based on disease aetiology. Serum profiling identified 15 cytokines significantly elevated (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and five reduced (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) in ESLD, including increased HGF and reduced interleukin\u20101 receptor antagonist. Stratified analysis also revealed aetiology specific cytokine profiles, with only GDF\u201015 significantly (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) elevated in all groupsTwenty\u2010four\u2010hour ESLD plasma treatment induced 423 differentially expressed genes in human myotubes, which were again associated with significant activation of senescence pathways, with IL\u20101 identified as a key upstream driver. In\u00a0vitro, IL\u20101\u03b1, GDF\u201015, and HGF significantly reduced myotube thickness, nuclear fusion index and perturbed metabolism (increased glycolysis, impaired oxidative phosphorylation).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, these findings suggest that sarcopenia in ESLD is driven by aetiology\u2010specific mechanisms, highlighting the potential for targeted therapies to improve muscle mass and function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70294","type":"journal-article","created":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T22:09:17Z","timestamp":1777241357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic Drivers and Molecular Mechanisms of Sarcopenia in Aetiology\u2010Specific End\u2010Stage Liver Disease"],"prefix":"10.1002","volume":"17","author":[{"given":"Thomas","family":"Nicholson","sequence":"first","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie\u00a0L.","family":"Allen","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"School of Sport, Exercise and Rehabilitation Science University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan\u00a0I.","family":"Quinlan","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"School of Sport, Exercise and Rehabilitation Science University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amritpal","family":"Dhaliwal","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Liver Transplant Unit Queen Elizabeth Hospital  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Macleod","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Price","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Hazeldine","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael\u00a0S.","family":"Sagmeister","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Department of Metabolism and Systems Science, School of Medical Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Ditchfield","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty\u00a0C.","family":"McGee","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicity\u00a0R.","family":"Williams","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"School of Sport, Exercise and Rehabilitation Science University of Birmingham  Birmingham UK"},{"name":"Liver Transplant Unit Queen Elizabeth Hospital  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed\u00a0M.","family":"Elsharkawy","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Liver Transplant Unit Queen Elizabeth Hospital  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew\u00a0J.","family":"Armstrong","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Liver Transplant Unit Queen Elizabeth Hospital  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn\u00a0A.","family":"Greig","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"School of Sport, Exercise and Rehabilitation Science University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet\u00a0M.","family":"Lord","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh","family":"Breen","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"School of Sport, Exercise and Rehabilitation Science University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6785-2310","authenticated-orcid":false,"given":"Simon\u00a0W.","family":"Jones","sequence":"additional","affiliation":[{"name":"National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre  Birmingham UK"},{"name":"Department of Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k2817"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.14309\/ctg.0000000000000584"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1017\/BJN20061943"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2016.10.028"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12411"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.11.006"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29107"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0780613"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00333.2001"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v29.i19.2905"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.21037\/tgh.2018.07.06"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00373.2020"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.7861\/clinmed.2020-0089"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP091157"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.15055.1"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-16-0011"},{"key":"e_1_2_10_18_1","article-title":"Differentiation of the SH\u2010SY5Y Human Neuroblastoma Cell Line","volume":"108","author":"Shipley M. M.","year":"2016","journal-title":"Journal of Visualized Experiments"},{"issue":"23","key":"e_1_2_10_19_1","first-page":"9393","article-title":"Single Nuclei Profiling Identifies Cell Specific Markers of Skeletal Muscle Aging, Frailty, and Senescence","volume":"14","author":"Perez K.","year":"2022","journal-title":"Aging (Albany NY)"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180217"},{"key":"e_1_2_10_21_1","article-title":"The Role of mTORC1 in the Regulation of Skeletal Muscle Mass","volume":"11","author":"Bodine S. C.","year":"2022","journal-title":"F1000Research"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00788"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2023.101636"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-016-0484-y"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2011.00070"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2020.112179"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-024-01287-y"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.851520"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13062"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.74831"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.278.1.C174"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13395"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.18063"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.5009\/gnl16049"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2409515"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-022-00972-z"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.70204"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70294","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.70294","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70294","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T09:18:40Z","timestamp":1784884720000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.70294"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,26]]},"references-count":36,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/jcsm.70294"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.70294","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.08.21.671433","asserted-by":"object"}]},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,26]]},"assertion":[{"value":"2025-07-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70294"}}