{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:29:14Z","timestamp":1792517354607,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR070178"],"award-info":[{"award-number":["R01AR070178"]}],"id":[{"id":"10.13039\/100000002","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":[[2025,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Functional iron deficiency affects a large proportion of patients with chronic diseases and is increasingly observed in older adults. Clinical evidence links iron deficiency to sarcopenia, yet the mechanistic relationship between iron status and muscle regeneration remains poorly defined. This study investigates how iron depletion alters muscle stem cell (MuSC) proliferation and skeletal muscle regeneration, focusing on HIF\u20102\u03b1 signalling.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Male and female\n C57BL\/6\u2009J<\/jats:italic>\n mice (4\u2009week old,\n n<\/jats:italic>\n \u2009>\u200920 per group in total) were fed iron\u2010sufficient (IS) or iron\u2010deficient (ID) chow for 4\u2009weeks before cardiotoxin\u2010induced tibialis anterior (TA) muscle injury. Muscle mass, MuSC proliferation and histological changes in regenerating TA muscles were evaluated at 10 and 30\u2009days after injury (dpi). Pharmacological HIF\u20102\u03b1 inhibition (PT2385) was used to determine causal mechanisms. Data were analyzed by\n t<\/jats:italic>\n tests and one\u2010way ANOVA.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Iron deficiency significantly reduced MuSC proliferation (\u221210.2% Ki67\n +<\/jats:sup>\n MuSC at 10 dpi,\n p<\/jats:italic>\n \u2009<\u20090.01,\n n<\/jats:italic>\n \u2009=\u20095) and myoblast EdU incorporation (\u221218.1%,\n p<\/jats:italic>\n \u2009<\u20090.001), leading to smaller regenerating myofibres (\u221222.7% median cross\u2010sectional area at 30 dpi,\n p<\/jats:italic>\n \u2009<\u20090.01,\n n<\/jats:italic>\n \u2009=\u20093) and impaired muscle mass recovery (males: \u221213.9%\n p<\/jats:italic>\n \u2009<\u20090.001, females: \u22129.4%\n p<\/jats:italic>\n \u2009<\u20090.05,\n n<\/jats:italic>\n \u2009=\u20096). HIF\u20102\u03b1 inhibition with PT2385 in ID mice increased MuSC proliferation (+7.1% Ki67\n +<\/jats:sup>\n MuSC at 10 dpi,\n p<\/jats:italic>\n \u2009<\u20090.01,\n n<\/jats:italic>\n \u2009=\u20095) and restored muscle mass (males: +10.3%\n p<\/jats:italic>\n \u2009<\u20090.001, females: +5.5%\n p<\/jats:italic>\n \u2009<\u20090.05,\n n<\/jats:italic>\n \u2009=\u20096). Mechanistically, iron deficiency stabilized HIF\u20102\u03b1 in proliferating MuSC, which upregulated retinoblastoma protein (Rb1), repressed E2F target RNA levels and induced G0\/G1 cell cycle arrest. This impaired myoblast expansion and delayed muscle regeneration in\u00a0vitro and in\u00a0vivo. In ID mice, PT2385 restored MuSC proliferation, accelerated myofibre maturation and enhanced muscle mass recovery without compromising MuSC self\u2010renewal. Chromatin immunoprecipitation demonstrated HIF\u20102\u03b1 binding at the\n Rb1<\/jats:italic>\n promoter, increasing Rb transcription and reducing H3K27 acetylation at E2F target loci.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Iron deficiency impairs skeletal muscle regeneration by stabilizing HIF\u20102\u03b1 in MuSC, inducing Rb1 RNA expression, and repressing E2F\u2010dependent proliferation. Transient HIF\u20102\u03b1 inhibition rescues MuSC proliferation and muscle repair under iron\u2010deficient conditions, highlighting HIF\u20102\u03b1 as a potential therapeutic target to counteract sarcopenia in aging and chronic diseases.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70124","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T07:32:46Z","timestamp":1764142366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Iron Deficiency Impairs Muscle Stem Cell Proliferation and Skeletal Muscle Regeneration via HIF\u20102\u03b1 Stabilization"],"prefix":"10.1002","volume":"16","author":[{"given":"Wenyan","family":"Fu","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine The University of Georgia Athens Georgia USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine The University of Georgia Athens Georgia USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Yin","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine The University of Georgia Athens Georgia USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Xie","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine The University of Georgia Athens Georgia USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9621-0138","authenticated-orcid":false,"given":"Hang","family":"Yin","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine The University of Georgia Athens Georgia USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia Athens Georgia 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