{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:03:36Z","timestamp":1789506216363,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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":["K08 AA028794"],"award-info":[{"award-number":["K08 AA028794"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DK113196"],"award-info":[{"award-number":["R01 DK113196"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 AA024333"],"award-info":[{"award-number":["P50 AA024333"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AA021890"],"award-info":[{"award-number":["R01 AA021890"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01AA026976"],"award-info":[{"award-number":["U01AA026976"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R56HL141744"],"award-info":[{"award-number":["R56HL141744"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01DK061732"],"award-info":[{"award-number":["U01DK061732"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01DK062470"],"award-info":[{"award-number":["U01DK062470"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AR071046"],"award-info":[{"award-number":["R21AR071046"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03AA032324"],"award-info":[{"award-number":["R03AA032324"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K12HL141952"],"award-info":[{"award-number":["K12HL141952"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AA032534"],"award-info":[{"award-number":["R01 AA032534"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Skeletal muscle experiences large fluctuations in ATP demand and redox state during contraction, ischaemia and chronic disease, requiring rapid adaptations in substrate selection, mitochondrial workload, vascular coupling, regeneration and protein homeostasis. Hypoxia\u2010inducible factor\u20101a (HIF1a) is classically viewed as an oxygen\u2010responsive transcription factor that mediates rapid adaptation to hypoxia. Accumulating evidence across tissues, including skeletal muscle, indicates that HIF1a is also responsive to physiological and pathological inputs, such as exercise, circadian timing, redox perturbations and endogenous\/exogenous cytotoxins, even when tissue hypoxia is not detectable. During hypoxia, including transient mismatches between oxygen demand and supply during muscle contraction, HIF1a activation shifts metabolism from oxidative to non\u2010oxidative energy production, suppresses non\u2010essential energy\u2010consuming processes, including protein homeostasis, and promotes vascular responses that improve oxygen delivery. Under normoxic conditions, persistent HIF1a activation promotes maladaptive responses, including impaired mitochondrial remodelling, reduced anabolic responsiveness, defective regeneration, fibrosis, and atrophy\u2010 and senescence\u2010associated reprogramming. Current evidence shows that this shift from adaptive to maladaptive signalling is determined in part by post\u2010translational mechanisms that regulate signalling duration and target gene engagement, as well as by fibre type, circadian state and the nature of the upstream stressor. Unlike the robust responses in muscle tissue observed in preclinical models, human muscle biopsies often show modest or transient HIF1a accumulation, yet transcriptional responses indicate meaningful pathway activation, suggesting that biologically relevant signalling occurs even when total protein levels appear low. Genetic models, multiomics, and human studies support HIF1a as a context\u2010dependent regulator of metabolic reprogramming that balances short\u2010term adaptation with long\u2010term energetic cost.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70803-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1113\/jp291159","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T07:17:11Z","timestamp":1789024631000},"page":"7539-7558","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia\u2010inducible factor\u20101a (HIF1a) as a context\u2010dependent integrator of metabolic stress in skeletal muscle"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4655-5146","authenticated-orcid":false,"given":"Nicole","family":"Welch","sequence":"first","affiliation":[{"name":"Department of Inflammation and Immunity Cleveland Clinic  Cleveland Ohio USA"},{"name":"Gastroenterology and Hepatology Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2993-4838","authenticated-orcid":false,"given":"Pugazhendhi","family":"Kannan","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8906-5243","authenticated-orcid":false,"given":"Seshu Vardhan","family":"Pothabathula","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Bellar","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3382-188X","authenticated-orcid":false,"given":"Abhishek A.","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Cancer Sciences Cleveland Clinic  Cleveland Ohio USA"},{"name":"Case Comprehensive Cancer Center  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8776-9597","authenticated-orcid":false,"given":"Srinivasan","family":"Dasarathy","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity Cleveland Clinic  Cleveland Ohio USA"},{"name":"Gastroenterology and Hepatology Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"e_1_2_2_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00499.2015"},{"key":"e_1_2_2_3_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2304fje"},{"key":"e_1_2_2_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00297.2025"},{"key":"e_1_2_2_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01324.2007"},{"key":"e_1_2_2_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP283700"},{"key":"e_1_2_2_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002443107"},{"key":"e_1_2_2_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2009.07.013"},{"key":"e_1_2_2_9_1","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2004.019"},{"key":"e_1_2_2_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2005.06.005"},{"key":"e_1_2_2_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.70031"},{"key":"e_1_2_2_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2004.04.010"},{"key":"e_1_2_2_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-021-01915-1"},{"key":"e_1_2_2_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2424046122"},{"key":"e_1_2_2_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909131106"},{"key":"e_1_2_2_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2504080122"},{"key":"e_1_2_2_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00507-4"},{"key":"e_1_2_2_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(86)83715-8"},{"key":"e_1_2_2_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.895710"},{"key":"e_1_2_2_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.400697"},{"key":"e_1_2_2_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.276.2.H679"},{"key":"e_1_2_2_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200273200"},{"key":"e_1_2_2_23_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.24.9361-9374.2003"},{"key":"e_1_2_2_24_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.23010"},{"key":"e_1_2_2_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.023"},{"key":"e_1_2_2_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00036.2013"},{"key":"e_1_2_2_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-009-0146-8"},{"key":"e_1_2_2_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0020288"},{"key":"e_1_2_2_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00335.2007"},{"key":"e_1_2_2_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1144"},{"key":"e_1_2_2_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/life14010020"},{"key":"e_1_2_2_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22137220"},{"key":"e_1_2_2_33_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00310.2021"},{"key":"e_1_2_2_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808801106"},{"key":"e_1_2_2_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.70411"},{"key":"e_1_2_2_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/function\/zqad013"},{"key":"e_1_2_2_37_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.102327"},{"key":"e_1_2_2_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.03.013"},{"key":"e_1_2_2_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2007.06.002"},{"key":"e_1_2_2_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-020-00553-8"},{"key":"e_1_2_2_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.91.1.173"},{"key":"e_1_2_2_42_1","doi-asserted-by":"publisher","DOI":"10.2478\/hukin-2022-0101"},{"key":"e_1_2_2_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.12.5510"},{"key":"e_1_2_2_44_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI161638"},{"key":"e_1_2_2_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13818"},{"key":"e_1_2_2_46_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP285339"},{"key":"e_1_2_2_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101023"},{"key":"e_1_2_2_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.105325"},{"key":"e_1_2_2_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1117773108"},{"key":"e_1_2_2_50_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI96208"},{"key":"e_1_2_2_51_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.756312"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP291159","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP291159","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP291159","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T20:07:54Z","timestamp":1789502874000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP291159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":50,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1113\/JP291159"],"URL":"https:\/\/doi.org\/10.1113\/jp291159","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-04-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}