{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T17:32:04Z","timestamp":1789061524910,"version":"build-2803163510"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,6]]},"abstract":"ABSTRACT<\/jats:title>Background<\/jats:title>Skeletal muscle is a major target for ethanol\u2010induced perturbations, leading to sarcopenia in alcohol\u2010related liver disease (ALD). The complex interactions and pathways involved in adaptive and maladaptive responses to ethanol in skeletal muscle are not well understood. Unlike hypothesis\u2010driven experiments, an integrated multiomics\u2010experimental validation approach provides a comprehensive view of these interactions.<\/jats:p><\/jats:sec>Methods<\/jats:title>We performed multiomics analyses with experimental validation to identify novel regulatory mechanisms of sarcopenia in ALD. Studies were done in a comprehensive array of models including ethanol\u2010treated (ET) murine and human\u2010induced pluripotent stem cell\u2013derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD) and human patients with alcohol\u2010related cirrhosis and controls. We generated 13 untargeted datasets, including chromatin accessibility (assay for transposase accessible chromatin), RNA sequencing, proteomics, phosphoproteomics, acetylomics and metabolomics, and conducted integrated multiomics analyses using UpSet plots and feature extraction. Key findings were validated using immunoblots, redox measurements (NAD+<\/jats:sup>\/NADH ratio), imaging and senescence\u2010associated molecular phenotype (SAMP) assays. Mechanistic studies included mitochondrial\u2010targeted Lactobacillus brevis<\/jats:italic><\/jats:styled-content> NADH oxidase (MitoLbNOX) to increase redox ratio and MitoTempo as a mitochondrial free radical scavenger.<\/jats:p><\/jats:sec>Results<\/jats:title>Multiomics analyses revealed enrichment in mitochondrial oxidative function, protein synthesis and senescence pathways consistent with the known effects of hypoxia\u2010inducible factor 1\u03b1 (HIF1\u03b1) during normoxia. Across preclinical and clinical models, HIF1\u03b1 targets (n<\/jats:italic>\u2009=\u200932 genes) and signalling genes (n<\/jats:italic>\u2009>\u2009100 genes) (n<\/jats:italic>\u2009=\u20093 ATACseq, n<\/jats:italic>\u2009=\u200965 phosphoproteomics, n<\/jats:italic>\u2009=\u200910 acetylomics, n<\/jats:italic>\u2009=\u20096 C2C12 proteomics, n<\/jats:italic>\u2009=\u2009106 C2C12 RNAseq, n<\/jats:italic>\u2009=\u200964 hiPSC RNAseq, n<\/jats:italic>\u2009=\u200930 hiPSC proteomics, n<\/jats:italic>\u2009=\u20093 mouse proteomics, n<\/jats:italic>\u2009=\u200925 mouse RNAseq, n<\/jats:italic>\u2009=\u20098 human RNAseq, n<\/jats:italic>\u2009=\u20093 human proteomics) were increased. Stabilization of HIF1\u03b1 (C2C12, 6hEtOH 0.24\u2009\u00b1\u20090.09; p<\/jats:italic>\u2009=\u20090.043; mALD 0.32\u2009\u00b1\u20090.074; p<\/jats:italic>\u2009=\u20090.005; data shown as mean difference\u2009\u00b1\u2009standard error mean) was accompanied by enrichment in the early transient and late change clusters, \u2212log(p<\/jats:italic>\u2010value)\u2009=\u20091.5\u20133.8, of the HIF1\u03b1 signalling pathway. Redox ratio was reduced in ET myotubes (C2C12: 15512\u2009\u00b1\u2009872.1, p<\/jats:italic>\u2009<\u20090.001) and mALD muscle, with decreased expression of electron transport chain components (CI\u2013V, p<\/jats:italic>\u2009<\u20090.05) and Sirt3 (C2C12: 0.067\u2009\u00b1\u20090.023, p<\/jats:italic>\u2009=\u20090.025; mALD: 0.41\u2009\u00b1\u20090.12, p<\/jats:italic>\u2009=\u20090.013). Acetylation of mitochondrial proteins was increased in both models (C2C12: 107364\u2009\u00b1\u20094558, p<\/jats:italic>\u2009=\u20090.03; mALD: 40036\u2009\u00b1\u200918\u2009987, p<\/jats:italic>\u2009=\u20090.049). Ethanol\u2010induced SAMP was observed across models (P16: C2C12: 0.2845\u2009\u00b1\u20090.1145, p<\/jats:italic>\u2009<\u20090.05; hiPSCm: 0.2591, p<\/jats:italic>\u2009=\u20090.041). MitoLbNOX treatment reversed redox imbalance, HIF1\u03b1 stabilization, global acetylation and myostatin expression (p<\/jats:italic>\u2009<\u20090.05).<\/jats:p><\/jats:sec>Conclusions<\/jats:title>An integrated multiomics approach, combined with experimental validation, identifies HIF1\u03b1 stabilization and accelerated post\u2010mitotic senescence as novel mechanisms of sarcopenia in ALD. These findings show the complex molecular interactions leading to mitochondrial dysfunction and progressive sarcopenia in ALD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13818","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T05:41:26Z","timestamp":1746078086000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Integrated Multiomics Analyses of the Molecular Landscape of Sarcopenia in Alcohol\u2010Related Liver Disease"],"prefix":"10.1002","volume":"16","author":[{"given":"Nicole","family":"Welch","sequence":"first","affiliation":[{"name":"Departments of Gastroenterology and Hepatology Cleveland Clinic, Lerner Research Institute Cleveland Ohio USA"},{"name":"Departments of Inflammation and Immunity Cleveland Clinic, Lerner Research Institute Cleveland Ohio 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