{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:13:58Z","timestamp":1791231238228,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T00:00:00Z","timestamp":1707436800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1R01AR070178"],"award-info":[{"award-number":["1R01AR070178"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006370","name":"Small Business Innovation Research","doi-asserted-by":"publisher","award":["1R41OD030519"],"award-info":[{"award-number":["1R41OD030519"]}],"id":[{"id":"10.13039\/100006370","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":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio\u2010pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Experimental mice were exposed to prolonged normobaric hypoxic air (15%\n                      <jats:italic>p<\/jats:italic>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      , 1\u00a0atm, 2\u00a0weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia\u2010inducible factors HIF\u20101\u03b1 and HIF\u20102\u03b1 in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin\u2010induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC\u2010specific HIF\u20102\u03b1 knockout mice, and mice treated with HIF\u20102\u03b1 inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia\u2010 and HIF\u20102\u03b1\u2010dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann\u2013Whitney\n                      <jats:italic>U<\/jats:italic>\n                      tests.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Chronic hypoxia led to limb muscle atrophy (EDL: 17.7%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001; Soleus: 11.5% reduction in weight,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001) and weakness (10.0% reduction in peak\u2010isometric torque,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001), along with impaired muscle regeneration characterized by diminished myofibre cross\u2010sectional areas, increased fibrosis (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001), and incomplete strength recovery (92.3% of pre\u2010injury levels,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05). HIF\u20102\u03b1 stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01). HIF\u20102\u03b1 ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01), while HIF\u20101\u03b1 ablation did not have the same effect. HIF\u20102\u03b1 stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF\u20102\u03b1. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05), suggesting their therapeutic potential for alleviating chronic hypoxia\u2010associated muscle atrophy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Chronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF\u20102\u03b1 in MuSC and thereby diminishing MuSC proliferation. HIF\u20102\u03b1 increases local ACE levels in skeletal muscle, contributing to hypoxia\u2010induced regenerative deficits. Administration of HIF\u20102\u03b1 or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia\u2010associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13436","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T04:00:23Z","timestamp":1707451223000},"page":"631-645","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Chronic hypoxia impairs skeletal muscle repair via HIF\u20102\u03b1 stabilization"],"prefix":"10.1002","volume":"15","author":[{"given":"Amelia","family":"Yin","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine The University of Georgia  Athens GA USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia  Athens GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Fu","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine The University of Georgia  Athens GA USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia  Athens GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Elengickal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology The University of Georgia  Athens GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joonhee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology The University of Georgia  Athens GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine The University of Georgia  Athens GA USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia  Athens GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Bigot","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm, Institut de Myologie Centre de Recherche en Myologie  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Mamchaoui","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm, Institut de Myologie Centre de Recherche en Myologie  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarrod A.","family":"Call","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology The University of Georgia  Athens GA 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 GA USA"},{"name":"Department of Biochemistry and Molecular Biology The University of Georgia  Athens GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.350"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2004.037531"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12034"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12685"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-020-00553-8"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12600"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13619-022-00108-9"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00043.2011"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13103"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30073"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12390"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2021-0351OC"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039124"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1336-7"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI96208"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-23698-5"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00494"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.2196\/12866"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/147.5.1151"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200407-855OC"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00492.2011"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S124750"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000194594"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.09.010"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2014.12.004"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.688671"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25852"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12636"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12178"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110884"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200271"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.10.027"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.310535"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1881410"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39506"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1602978113"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118698"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.449074"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/15412555.2018.1432034"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)12892-9"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.13436","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.13436","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T04:32:55Z","timestamp":1718685175000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.13436"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,9]]},"references-count":40,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1002\/jcsm.13436"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.13436","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.22541\/au.169627962.29216722\/v1","asserted-by":"object"}]},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,9]]},"assertion":[{"value":"2023-08-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}