{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T16:20:36Z","timestamp":1784737236211,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"Barunsesang Hospital","doi-asserted-by":"publisher","award":["2021R1F1A1055815"],"award-info":[{"award-number":["2021R1F1A1055815"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Muscle atrophy is defined as the progressive degeneration or shrinkage of myocytes and is triggered by factors such as aging, cancer, injury, inflammation, and immobilization. Considering the total amount of body iron stores and its crucial role in skeletal muscle, myocytes may have their own iron regulation mechanism. Although the detrimental effects of iron overload or iron deficiency on muscle function have been studied, the molecular mechanism of iron-dependent muscle atrophy has not been elucidated. Using human muscle tissues and in the mouse rotator cuff tear model, we confirmed an association between injury-induced iron depletion in myocytes and muscle atrophy. In differentiated C2C12 myotubes, the effects of iron deficiency on myocytes and the molecular mechanism of muscle atrophy by iron deficiency were evaluated. Our study revealed that the lower iron concentration in injured muscle was associated with the upregulation of ferroportin, an iron exporter that transports iron out of cells. Ferroportin expression was increased by hypoxia-inducible factor 1\u03b1 (HIF1\u03b1), which is activated by muscle injury, and its expression is controlled by HIF1 inhibitor treatment. Iron deprivation caused myocyte loss and a marked depletion of mitochondrial membrane potential leading to muscle atrophy, together with increased levels of myostatin, the upstream regulator of atrogin1 and muscle RING-finger protein-1 (MuRF1). Myostatin expression under iron deficiency was mediated by an orphan nuclear receptor, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome (DAX1).<\/jats:p>","DOI":"10.3390\/cells11182853","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T21:06:52Z","timestamp":1663103212000},"page":"2853","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Novel Muscle Atrophy Mechanism: Myocyte Degeneration Due to Intracellular Iron Deprivation"],"prefix":"10.3390","volume":"11","author":[{"given":"Dae Keun","family":"Suh","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Korea University Anam Hospital, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won-Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Hand and Foot Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo Jin","family":"Yeo","sequence":"additional","affiliation":[{"name":"Joint Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bong Soo","family":"Kyung","sequence":"additional","affiliation":[{"name":"Joint Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koo Whang","family":"Jung","sequence":"additional","affiliation":[{"name":"Joint Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Kyung","family":"Seo","sequence":"additional","affiliation":[{"name":"Research Center for Cartilage Regeneration, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6449-8341","authenticated-orcid":false,"given":"Yong-Soo","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Center for Cartilage Regeneration, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Won","family":"Suh","sequence":"additional","affiliation":[{"name":"Joint Center, Barunsesang Hospital, #75-5, Yatap-ro, Seongnam-si 13497, Gyeonggi-do, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s13539-012-0074-6","article-title":"Molecular and cellular mechanisms of skeletal muscle atrophy: An update","volume":"3","author":"Fanzani","year":"2012","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1097\/MCO.0b013e32833862df","article-title":"Signaling pathways perturbing muscle mass","volume":"13","author":"Glass","year":"2010","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S2213-8587(14)70034-8","article-title":"Age-related and disease-related muscle loss: The effect of diabetes, obesity, and other diseases","volume":"2","author":"Kalyani","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1016\/j.biocel.2011.05.007","article-title":"Mechanotransduction and the regulation of mtorc1 signaling in skeletal muscle","volume":"43","author":"Hornberger","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_5","first-page":"E668","article-title":"Glucocorticoids activate the atp-ubiquitin-dependent proteolytic system in skeletal muscle during fasting","volume":"264","author":"Wing","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1242\/dmm.010389","article-title":"Cellular and molecular mechanisms of muscle atrophy","volume":"6","author":"Bonaldo","year":"2013","journal-title":"Dis. Model Mech."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12576-020-00768-9","article-title":"The ubiquitin-proteasome system in regulation of the skeletal muscle homeostasis and atrophy: From basic science to disorders","volume":"70","author":"Kitajima","year":"2020","journal-title":"J. Physiol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1152\/physrev.00027.2001","article-title":"The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction","volume":"82","author":"Glickman","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E469","DOI":"10.1152\/ajpendo.00204.2014","article-title":"Skeletal muscle atrophy and the e3 ubiquitin ligases murf1 and mafbx\/atrogin-1","volume":"307","author":"Bodine","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1126\/science.1065874","article-title":"Identification of ubiquitin ligases required for skeletal muscle atrophy","volume":"294","author":"Bodine","year":"2001","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0092-8674(04)00343-5","article-title":"Balancing acts: Molecular control of mammalian iron metabolism","volume":"117","author":"Hentze","year":"2004","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2016.12.034","article-title":"A red carpet for iron metabolism","volume":"168","author":"Muckenthaler","year":"2017","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-981-13-9589-5_2","article-title":"Cellular iron metabolism and regulation","volume":"1173","author":"Gao","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1126\/science.1104742","article-title":"Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization","volume":"306","author":"Nemeth","year":"2004","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1242\/jeb.01172","article-title":"Myoglobin: An essential hemoprotein in striated muscle","volume":"207","author":"Ordway","year":"2004","journal-title":"J. Exp. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1002\/jcsm.12314","article-title":"Iron deficiency as energetic insult to skeletal muscle in chronic diseases","volume":"9","author":"Dziegala","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1161\/CIRCULATIONAHA.119.040134","article-title":"Mitochondrial function, skeletal muscle metabolism, and iron deficiency in heart failure","volume":"139","author":"Melenovsky","year":"2019","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6703","DOI":"10.1096\/fj.201901815R","article-title":"Iron deficiency-induced loss of skeletal muscle mitochondrial proteins and respiratory capacity; the role of mitophagy and secretion of mitochondria-containing vesicles","volume":"34","author":"Leermakers","year":"2020","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.exger.2008.02.007","article-title":"Increased iron content and rna oxidative damage in skeletal muscle with aging and disuse atrophy","volume":"43","author":"Hofer","year":"2008","journal-title":"Exp. Gerontol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jtemb.2016.01.011","article-title":"Iron-induced skeletal muscle atrophy involves an akt-forkhead box o3-e3 ubiquitin ligase-dependent pathway","volume":"35","author":"Ikeda","year":"2016","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3389\/fnins.2019.00165","article-title":"Iron metabolism of the skeletal muscle and neurodegeneration","volume":"13","author":"Borkowska","year":"2019","journal-title":"Front Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/jcsm.12203","article-title":"Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in mice","volume":"8","author":"Lee","year":"2017","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"407","DOI":"10.4049\/jimmunol.1103779","article-title":"Myeloid hypoxia-inducible factor-1alpha is essential for skeletal muscle regeneration in mice","volume":"191","author":"Scheerer","year":"2013","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.cell.2010.08.004","article-title":"Reversing cachexia","volume":"142","author":"Tisdale","year":"2010","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1172\/JCI31370","article-title":"Regulation of iron homeostasis by the hypoxia-inducible transcription factors (hifs)","volume":"117","author":"Peyssonnaux","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1053\/j.gastro.2011.03.007","article-title":"Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice","volume":"140","author":"Taylor","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.cell.2010.06.028","article-title":"Two to tango: Regulation of mammalian iron metabolism","volume":"142","author":"Hentze","year":"2010","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.bcmd.2010.07.002","article-title":"Iron metabolism gene expression in human skeletal muscle","volume":"45","author":"Polonifi","year":"2010","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6319","DOI":"10.1182\/blood-2010-12-327957","article-title":"Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis","volume":"117","author":"Chen","year":"2011","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.4049\/jimmunol.1501417","article-title":"The repair of skeletal muscle requires iron recycling through macrophage ferroportin","volume":"197","author":"Corna","year":"2016","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.281.5381.1309","article-title":"Mitochondria and apoptosis","volume":"281","author":"Green","year":"1998","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s13539-011-0035-5","article-title":"The role of myostatin in muscle wasting: An overview","volume":"2","author":"Elkina","year":"2011","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/iub.1392","article-title":"Myostatin: Expanding horizons","volume":"67","author":"Sharma","year":"2015","journal-title":"IUBMB Life"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ymgme.2005.07.019","article-title":"Dax1 origin, function, and novel role","volume":"86","author":"Niakan","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.1210\/en.2005-1651","article-title":"Dax-1 expression is regulated during mammary epithelial cell differentiation","volume":"147","author":"Helguero","year":"2006","journal-title":"Endocrinology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1002\/stem.78","article-title":"Dax-1 knockdown in mouse embryonic stem cells induces loss of pluripotency and multilineage differentiation","volume":"27","author":"Khalfallah","year":"2009","journal-title":"Stem Cells"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1517\/14728220903531454","article-title":"Targeting dax-1 in embryonic stem cells and cancer","volume":"14","author":"Lalli","year":"2010","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1002\/ejhf.467","article-title":"The influence of iron deficiency on the functioning of skeletal muscles: Experimental evidence and clinical implications","volume":"18","author":"Stugiewicz","year":"2016","journal-title":"Eur. J. Heart Fail"},{"key":"ref_39","first-page":"2678","article-title":"Iron limitation promotes the atrophy of skeletal myocytes, whereas iron supplementation prevents this process in the hypoxic conditions","volume":"41","author":"Kobak","year":"2018","journal-title":"Int. J. Mol. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/18\/2853\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:30:18Z","timestamp":1760142618000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/18\/2853"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,13]]},"references-count":39,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["cells11182853"],"URL":"https:\/\/doi.org\/10.3390\/cells11182853","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,13]]}}}