{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T23:17:20Z","timestamp":1782947840688,"version":"3.54.5"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Backgrounds<\/jats:title>\n                    <jats:p>Peripheral artery disease (PAD) frequently causes to persistent functional impairment in skeletal muscle even after successful revascularization, implicating non-ischemic pathological mechanisms. Sarcopenia, a myopathy characterized by progressive loss of muscle mass, strength, and function\u2014shares these non-ischemic features and affects approximately one-third of PAD patients, yet the molecular basis of their comorbidity remains poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Three transcriptome datasets (GSE120642, GSE181930, and GSE226151) were included in the analysis, covering skeletal muscle samples from peripheral artery disease (PAD) and sarcopenia. Weighted gene co-expression network analysis (WGCNA) was performed independently for each disease cohort, followed by parallel feature selection using three machine learning algorithms (LASSO, Random Forest, and Boruta) to identify shared diagnostic biomarkers. Immune cell infiltration was deconvoluted using CIBERSORT. Drug-gene interaction analysis was conducted via DGIdb. The functional role of the lead candidate S100A9 was validated by untargeted metabolomic profiling of C2C12 myoblasts treated with recombinant S100A9.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seventy-six overlapping disease-associated genes were identified from WGCNA, and five core diagnostic biomarkers\u2014BCKDHB, PIM1, JAML, NFE2, and S100A9 \u2014 were selected through three-way machine learning consensus. Enrichment analyses revealed shared involvement of innate immune activation, granulocyte infiltration, and branched-chain amino acid (BCAA) catabolism. CIBERSORT deconvolution confirmed elevated neutrophil abundance as a convergent immune feature of both diseases. Metabolomic profiling demonstrated that recombinant S100A9 disrupted nucleotide and energy homeostasis, induced mitophagy dysregulation, and promoted oxidative stress in C2C12 myoblasts. DGIdb screening identified Paquinimod, a selective S100A9 inhibitor with Phase II clinical safety data, as a candidate for therapeutic repositioning.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study reveals that upregulation of skeletal muscle inflammation and abnormal branched-chain amino acid metabolism may be common features of PAD and sarcopenia. BCKDHB, PIM1, JAML, NFE2, and S100A9 were identified as common diagnostic biomarkers, and metabolomics further confirmed that S100A9 may be a potential intervention target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1874960","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T22:10:29Z","timestamp":1782943829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["S100A9 as a shared biomarker and mediator of metabolic dysfunction in peripheral artery disease and sarcopenia"],"prefix":"10.3389","volume":"17","author":[{"given":"Yaming","family":"Guo","sequence":"first","affiliation":[{"name":"The Key Laboratory of Geriatrics of NHC, Institute of Geriatric Medicine, Beijing Hospital, National Center for Gerontology, National Clinical Research Center for Gerontology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Geriatrics of NHC, Institute of Geriatric Medicine, Beijing Hospital, National Center for Gerontology, National Clinical Research Center for Gerontology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Li","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Geriatrics of NHC, Institute of Geriatric Medicine, Beijing Hospital, National Center for Gerontology, National Clinical Research Center for Gerontology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Beijing, China"]},{"name":"Medical School, University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/j.apmr.2017.10.017","article-title":"Sarcopenia in peripheral arterial disease: prevalence and effect on functional status","volume":"99","author":"Addison","year":"2018","journal-title":"Archives of Phys. Med. and Rehabilitation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/nrc3829","article-title":"Cancer cachexia: understanding the molecular basis","volume":"14","author":"Argil\u00e9s","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"B5","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1186\/s12967-023-04369-z","article-title":"Mitochondrial dysfunction: roles in skeletal muscle atrophy","volume":"21","author":"Chen","year":"2023","journal-title":"J. Transl. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1002\/jcsm.12596","article-title":"Single\u2010cell deconstruction of post\u2010sepsis skeletal muscle and adipose tissue microenvironments","volume":"11","author":"Cho","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3703","DOI":"10.3390\/nu15173703","article-title":"The role of nutrition in the treatment of sarcopenia in old patients: from restoration of mitochondrial activity to improvement of muscle performance, a systematic review","volume":"15","author":"Cochet","year":"2023","journal-title":"Nutrients"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e42499","DOI":"10.1016\/j.heliyon.2025.e42499","article-title":"Application of CIBERSORTx and BayesPrism to deconvolution of bulk RNA-Seq data from human myocardium and skeletal muscle","volume":"11","author":"Conning-Rowland","year":"2025","journal-title":"Heliyon"},{"key":"B9","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.ejvs.2019.05.006","article-title":"Global vascular guidelines on the management of chronic limb-threatening ischemia","volume":"58","author":"Conte","year":"2019","journal-title":"Eur. J. of Vasc. and Endovascular Surg."},{"key":"B10","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/ageing\/afy169","article-title":"Sarcopenia: revised European consensus on definition and diagnosis","volume":"48","author":"Cruz-Jentoft","year":"2019","journal-title":"Age and Ageing"},{"key":"B11","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1177\/1358863X20945794","article-title":"Skeletal muscle capillary density is related to anaerobic threshold and claudication in peripheral artery disease","volume":"25","author":"Duscha","year":"2020","journal-title":"Vasc. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/s43587-025-00815-3","article-title":"An mTOR paradox in sarcopenia via BCAA catabolism","volume":"5","author":"Feige","year":"2025","journal-title":"Nat. Aging"},{"key":"B13","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.avsg.2022.07.009","article-title":"Inflammation and loss of skeletal muscle mass in chronic limb threatening ischemia","volume":"88","author":"Ferreira","year":"2023","journal-title":"Ann. of Vasc. Surg."},{"key":"B14","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1161\/CIRCULATIONAHA.118.034165","article-title":"Antiangiogenic VEGF165 b regulates macrophage polarization via S100A8\/S100A9 in peripheral artery disease","volume":"139","author":"Ganta","year":"2019","journal-title":"Circulation"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1007\/s00018-015-1866-6","article-title":"Regulation and function of the NFE2 transcription factor in hematopoietic and non-hematopoietic cells","volume":"72","author":"Gasiorek","year":"2015","journal-title":"Cell Mol. Life Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.3390\/nu14061249","article-title":"IGF-1 signaling regulates mitochondrial remodeling during myogenic differentiation","volume":"14","author":"Guan","year":"2022","journal-title":"Nutrients"},{"key":"B17","doi-asserted-by":"publisher","first-page":"663","DOI":"10.3390\/bioengineering11070663","article-title":"Pretreatment sarcopenia and MRI-based radiomics to predict the response of neoadjuvant chemotherapy in triple-negative breast cancer","volume":"11","author":"Guo","year":"2024","journal-title":"Bioeng. (Basel)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/s13075-021-02573-0","article-title":"An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod","volume":"23","author":"Hesselstrand","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1161\/CIRCRESAHA.116.303566","article-title":"Pathogenesis of the limb manifestations and exercise limitations in peripheral artery disease","volume":"116","author":"Hiatt","year":"2015","journal-title":"Circulation Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12986-018-0271-1","article-title":"Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements","volume":"15","author":"Hole\u010dek","year":"2018","journal-title":"Nutr. Metab. (Lond)."},{"key":"B21","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s42003-025-07654-3","article-title":"Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy","volume":"8","author":"Huang","year":"2025","journal-title":"Commun. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"588","DOI":"10.3390\/antiox10040588","article-title":"Mitochondrial dysfunction is a common denominator linking skeletal muscle wasting due to disease, aging, and prolonged inactivity","volume":"10","author":"Hyatt","year":"2021","journal-title":"Antioxidants"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1158\/0008-5472.CAN-12-2730","article-title":"Tasquinimod is an allosteric modulator of HDAC4 survival signaling within the compromised cancer microenvironment","volume":"73","author":"Isaacs","year":"2013","journal-title":"Cancer Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s41232-022-00234-6","article-title":"Mechanisms of cooperative cell-cell interactions in skeletal muscle regeneration","volume":"42","author":"Koike","year":"2022","journal-title":"Inflamm. Regen."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v036.i11","article-title":"Feature selection with the Boruta package","volume":"36","author":"Kursa","year":"2010","journal-title":"J. Stat. Soft"},{"key":"B26","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinforma."},{"key":"B27","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1186\/s12877-024-05144-5","article-title":"Associations between sarcopenia and circulating branched-chain amino acids: a cross-sectional study over 100,000 participants","volume":"24","author":"Liu","year":"2024","journal-title":"BMC Geriatr."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.14336\/AD.2025.0701","article-title":"Advancing single-cell transcriptomic analysis to reveal age-related skeletal muscle changes: a systematic review","volume":"17","author":"Liu","year":"2025","journal-title":"Aging Dis"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1565379","DOI":"10.3389\/fimmu.2025.1565379","article-title":"Shared circulating diagnostic biomarkers and molecular mechanisms in ischemic stroke and systemic lupus erythematosus","volume":"16","author":"Ma","year":"2025","journal-title":"Front. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1161\/CIRCRESAHA.114.303517","article-title":"Lower extremity manifestations of peripheral artery disease: the pathophysiologic and functional implications of leg ischemia","volume":"116","author":"McDermott","year":"2015","journal-title":"Circulation Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.1113\/jphysiol.2008.153551","article-title":"Calprotectin is released from human skeletal muscle tissue during exercise","volume":"586","author":"Mortensen","year":"2008","journal-title":"The J. of Physiology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cmet.2018.10.013","article-title":"Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids","volume":"29","author":"Neinast","year":"2019","journal-title":"Cell Metab."},{"key":"B32","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1146\/annurev-physiol-020518-114455","article-title":"Branched chain amino acids","volume":"81","author":"Neinast","year":"2019","journal-title":"Annu. Rev. Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat. Methods"},{"key":"B34","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/1476-4598-9-107","article-title":"Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors","volume":"9","author":"Olsson","year":"2010","journal-title":"Mol. Cancer"},{"key":"B35","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/nri.2017.105","article-title":"Neutrophil extracellular traps in immunity and disease","volume":"18","author":"Papayannopoulos","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"H867","DOI":"10.1152\/ajpheart.00690.2021","article-title":"Impaired microcirculatory function, mitochondrial respiration, and oxygen utilization in skeletal muscle of claudicating patients with peripheral artery disease","volume":"322","author":"Park","year":"2022","journal-title":"Am. J. of Physiology-Heart and Circulatory Physiology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1002\/jcsm.12587","article-title":"Sarcopenia and peripheral arterial disease: a systematic review","volume":"11","author":"Pizzimenti","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1093\/gerona\/glw017","article-title":"Sarcopenia is associated with lower skeletal muscle capillarization and exercise capacity in older adults","volume":"71","author":"Prior","year":"2016","journal-title":"GERONA"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1007\/s00125-018-4611-5","article-title":"Plasma branched chain\/aromatic amino acids, enriched mediterranean diet and risk of type 2 diabetes: case-cohort study within the PREDIMED trial","volume":"61","author":"Ruiz-Canela","year":"2018","journal-title":"Diabetologia"},{"key":"B40","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.jvssci.2022.03.003","article-title":"S100A8 and S100A9 are elevated in chronically threatened ischemic limb muscle and induce ischemic mitochondrial pathology in mice","volume":"3","author":"Salyers","year":"2022","journal-title":"JVS-Vascular Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/0092-8674(95)90531-6","article-title":"Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoeitin\/MGDF in megakaryocyte development","volume":"81","author":"Shivdasani","year":"1995","journal-title":"Cell"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1200\/JCO.2016.66.9697","article-title":"Randomized, double-blind, placebo-controlled phase III study of tasquinimod in men with metastatic castration-resistant prostate cancer","volume":"34","author":"Sternberg","year":"2016","journal-title":"JCO"},{"key":"B43","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1161\/CIRCULATIONAHA.114.011004","article-title":"Drug-coated balloon Versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial","volume":"131","author":"Tepe","year":"2015","journal-title":"Circulation"},{"key":"B44","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression shrinkage and selection Via the lasso","volume":"58","author":"Tibshirani","year":"1996","journal-title":"J. of the R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2300720","DOI":"10.1002\/mnfr.202300720","article-title":"Bcat2\u2010Mediated branched\u2010chain amino acid catabolism is linked to the aggravated inflammation in Obese with psoriasis mice","volume":"68","author":"Wang","year":"2024","journal-title":"Mol. Nutr. Food Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"176","DOI":"10.61189\/691939hefazb","article-title":"The role and research progress of ferroptosis in myocardial injury in sepsis","volume":"31","author":"Wang","year":"2025","journal-title":"Perioper. Precis. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"108194","DOI":"10.1016\/j.phrs.2026.108194","article-title":"Metabolic control of immunity and inflammation: mitochondrial dynamics, pharmacological targets, and therapeutic opportunities","volume":"227","author":"Wang","year":"2026","journal-title":"Pharmacol. Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function","volume":"38","author":"Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"12609","DOI":"10.1038\/s41598-024-63626-3","article-title":"Skeletal muscle desmin alterations following revascularization in peripheral artery disease claudicants","volume":"14","author":"Wilburn","year":"2024","journal-title":"Sci. Rep."},{"key":"B50","doi-asserted-by":"publisher","first-page":"155533","DOI":"10.1016\/j.metabol.2023.155533","article-title":"Epidemiology of sarcopenia: prevalence, risk factors, and consequences","volume":"144","author":"Yuan","year":"2023","journal-title":"Metabolism"},{"key":"B51","doi-asserted-by":"publisher","first-page":"240859","DOI":"10.5713\/ab.24.0859","article-title":"Transcriptome analysis of injured muscle identifies new candidate genes for satellite cell growth and myofiber formation during early muscle regeneration","volume":"39","author":"Yuan","year":"2026","journal-title":"Anim. Biosci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"584582","DOI":"10.2147\/JIR.S584582","article-title":"ATP-P2X7R-NLRP3 axis as a unifying mechanism of ATP-induced cell death in degenerative bone and cardiovascular diseases","volume":"19","author":"Zhang","year":"2026","journal-title":"J. Inflamm. Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/s43587-024-00797-8","article-title":"Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target","volume":"5","author":"Zuo","year":"2025","journal-title":"Nat. Aging"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1874960\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T22:10:30Z","timestamp":1782943830000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1874960\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":53,"alternative-id":["10.3389\/fgene.2026.1874960"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1874960","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]},"article-number":"1874960"}}