{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:08:14Z","timestamp":1790690894404,"version":"4.1.0"},"reference-count":67,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"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":["R25GM060655"],"award-info":[{"award-number":["R25GM060655"]}],"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":["P30AG013319"],"award-info":[{"award-number":["P30AG013319"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CBET\u20132144438"],"award-info":[{"award-number":["CBET\u20132144438"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Orthopaedic Research"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Ischemia\u2010reperfusion injury (IRI) induces skeletal muscle damage through oxidative stress, impaired autophagy, and satellite cell (SC) dysfunction, ultimately compromising regenerative capacity and functional recovery. We investigated whether the naturally occurring autophagy\u2010stimulating compound 2\u2010\n                    <jats:italic>n<\/jats:italic>\n                    \u2010hexyl lanthionine ketenamine phosphonate (2\u2010\n                    <jats:italic>n<\/jats:italic>\n                    \u2010hexyl LKE\u2010P) enhances SC resilience and promotes early regenerative responses following IRI. Primary SCs isolated from Sprague Dawley rats (96% Pax\u20107+ purity) were treated with 2\u2010\n                    <jats:italic>n<\/jats:italic>\n                    \u2010hexyl LKE\u2010P or rapamycin. Autophagic flux was assessed using CYTO\u2010ID flow cytometry and Western blot analysis of LC3\u2010I and LC3\u2010II, and viability was assessed under baseline and hydrogen peroxide (H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    )\u2010induced oxidative stress conditions. In parallel, a proof\u2010of\u2010concept hindlimb IRI model (3\u2010h tourniquet) evaluated early functional recovery and transcriptional changes. In vitro, 2\u2010\n                    <jats:italic>n<\/jats:italic>\n                    \u2010hexyl LKE\u2010P significantly increased autophagy flux and enhanced SC viability across concentrations and treatment durations, whereas rapamycin reduced proliferation. Under 500\u2009\u00b5M H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    , which decreased viability by ~63%, 2\u2010\n                    <jats:italic>n<\/jats:italic>\n                    \u2010hexyl LKE\u2010P restored cell survival toward control levels, demonstrating robust protection against oxidative stress. In vivo, treated animals demonstrated improved grip strength recovery between days 2 and 7 post\u2010injury compared to PBS\u2010treated controls. Molecular analyzes revealed significant upregulation of autophagy regulators (Beclin\u20101, ULK\u20101) and antioxidant marker SOD\u20101, with coordinated upward trends in additional autophagy (ATG\u20107, LC3, p62) and myogenic genes (MyoG, MHC). Collectively, these findings suggest that 2\u2010\n                    <jats:italic>n<\/jats:italic>\n                    \u2010hexyl LKE\u2010P enhances SC survival by modulating autophagy and reinforcing antioxidant defenses, resulting in improved early functional recovery following IRI. These results identify 2\u2010\n                    <jats:italic>n<\/jats:italic>\n                    \u2010hexyl LKE\u2010P modulation of autophagy and oxidative stress as a promising therapeutic strategy for limiting IRI\u2010induced skeletal muscle damage.\n                  <\/jats:p>","DOI":"10.1002\/jor.70269","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:35:13Z","timestamp":1787733313000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lanthionine Ketenamine Derivative Enhances Early Functional Recovery Following Skeletal Muscle Ischemia\u2010Reperfusion Injury Through Modulation of Autophagy and Oxidative Stress"],"prefix":"10.1002","volume":"44","author":[{"given":"Valentina","family":"Barrera","sequence":"first","affiliation":[{"name":"Department of Biomedical and Chemical Engineering UT San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Jose H.","family":"Trevi\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Chemical Engineering UT San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1222-2538","authenticated-orcid":false,"given":"Travis T.","family":"Denton","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences Washington State University Health Sciences Spokane Spokane Washington State USA"},{"name":"Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine Washington State University Health Sciences Spokane Spokane Washington State USA"},{"name":"Steve Gleason Institute for Neuroscience Washington State University Health Sciences Spokane Spokane Washington State USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7854-5375","authenticated-orcid":false,"given":"Blake B.","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology, Long School of Medicine UT San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Rathbone","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Chemical Engineering UT San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulieth","family":"Soto","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Chemical Engineering UT San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6594-8802","authenticated-orcid":false,"given":"Maria A. Gonzalez","family":"Porras","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Chemical Engineering UT San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3147-209X","authenticated-orcid":false,"given":"Hugo","family":"Giambini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Chemical Engineering UT San Antonio San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/096721099300100404"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0967-2109(02)00070-4"},{"key":"e_1_2_10_4_1","first-page":"65","article-title":"Prevention of Oxidative Stress Due to Tourniquet Application. Analysis of the Effects of Local Hypothermia and Systemic Allopurinol Administration","volume":"199","author":"Erdogan D.","year":"1999","journal-title":"Acta Orthopaedica Belgica"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2006.05.036"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2011.05.061"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2013.12.026"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00408.2005"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00032.2003"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0185(200012)260:4<350::AID-AR30>3.0.CO;2-6"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.293167.116"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00421-2"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1123\/jsr.2016-0107"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.91.2.534"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.08.021"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.50"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10758"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3014"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.10.008"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1115172"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.146506"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.1.3.2017"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.70"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16187"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells1030325"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.4.14392"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00237"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.041814"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi061888s"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5247-09.2010"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2014.10.581"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3182a74372"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1789209"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules15085581"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-29437-8"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.03.007"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0091-679x(08)60378-7"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.TEA.2020.0138"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2008.08.003"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16187"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-237388"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-014-1984-8"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2018.01.052"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60676-7"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-91701-w"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/85.2.377"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2247"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-237388"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-014-1984-8"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-394309-5.00006-7"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2019.7743"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020712-163918"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21093289"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370215581306"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.048"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.260631"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20170021"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-010-9855-x"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101760"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16336"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2024.1502326"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.03.182"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1753000"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13000"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1060104"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.173920"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-022-01786-1"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1080\/00015385.2021.2024701"}],"container-title":["Journal of Orthopaedic Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jor.70269","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jor.70269","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jor.70269","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:41:27Z","timestamp":1790689287000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jor.70269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":67,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/jor.70269"],"URL":"https:\/\/doi.org\/10.1002\/jor.70269","archive":["Portico"],"relation":{},"ISSN":["0736-0266","1554-527X"],"issn-type":[{"value":"0736-0266","type":"print"},{"value":"1554-527X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"assertion":[{"value":"2026-02-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70269"}}