{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:38:08Z","timestamp":1785407888418,"version":"3.56.0"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T00:00:00Z","timestamp":1629763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004080","name":"Korea Drug Development Fund","doi-asserted-by":"publisher","award":["HN21C0447"],"award-info":[{"award-number":["HN21C0447"]}],"id":[{"id":"10.13039\/501100004080","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["2021R1A2B5B02001462"],"award-info":[{"award-number":["2021R1A2B5B02001462"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["2020R1C1C1003652"],"award-info":[{"award-number":["2020R1C1C1003652"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["2020R1A2C2004761"],"award-info":[{"award-number":["2020R1A2C2004761"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["2017R1A5A2015061"],"award-info":[{"award-number":["2017R1A5A2015061"]}],"id":[{"id":"10.13039\/501100001321","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":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Skeletal muscle regeneration is an adaptive response to injury that is crucial to the maintenance of muscle mass and function. A p21\u2010activated kinase 4 (PAK4) serine\/threonine kinase is critical to the regulation of cytoskeletal changes, cell proliferation, and growth. However, PAK4's role in myoblast differentiation and regenerative myogenesis remains to be determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a mouse model of myotoxin (notexin)\u2010induced muscle regeneration. <jats:italic>In vitro<\/jats:italic> myogenesis was performed in the C2C12 myoblast cell line, primary myoblasts, and primary satellite cells. <jats:italic>In vivo<\/jats:italic> overexpression of PAK4 or kinase\u2010inactive mutant PAK4<jats:sup>S474A<\/jats:sup> was conducted in skeletal muscle to examine PAK4's kinase\u2010dependent effect on muscle regeneration. The regeneration process was evaluated by determining the number and size of multinucleated myofibres and expression patterns of myogenin and eMyHC. To explore whether PAK4 inhibition improves muscle regeneration, mice were injected intramuscularly with siRNA that targeted PAK4 or orally administered with a chemical inhibitor of PAK4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>p21\u2010activated kinase 4 was highly expressed during the myoblast stage, but expression gradually and substantially decreased as myoblasts differentiated into myotubes. PAK4 overexpression, but not kinase\u2010inactive mutant PAK4<jats:sup>S474A<\/jats:sup> overexpression, significantly impeded myoblast fusion and MyHC\u2010positive myotube formation in C2C12 cells, primary myoblasts, and satellite cells (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Conversely, PAK4 silencing led to an 8.7% and a 20.3% increase in the number of multinucleated larger myotubes in C2C12 cells and primary myoblasts. Further, <jats:italic>in vivo<\/jats:italic> overexpression of PAK4 by adenovirus injection to mice prior to and after myotoxin\u2010induced injury led to a 52.6% decrease in the number of eMyHC\u2010positive myofibres on Day 5 in tibialis anterior muscles as compared with those injected with control adenoviruses (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), while Ad\u2010PAK4<jats:sup>S474A<\/jats:sup> showed comparable muscle regeneration parameters. PAK4\u2010induced repression of muscle regeneration coincided with an increase in phosphatase and tensin homologue (PTEN) expression and a decrease in phosphoinositide 3\u2010kinase\u2010Akt signalling. In contrast, PAK4 silencing reduced PTEN expression in mice. Consistent with these findings, prodrug of PAK4 inhibitor CZh\u2010226 (30\u00a0mg\/kg) orally administered to mice repressed PTEN expression and accelerated myotube formation. Subsequent mechanistic studies revealed that PAK4 directly phosphorylates PPAR\u03b3 at S273 to increase its transcription activity, thereby up\u2010regulating PTEN expression. Importantly, an analysis of the Genotype\u2010Tissue Expression database showed a positive correlation between PAK4 and PTEN in human skeletal muscle tissues (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>p1\u2010activated kinase 4 is a new member of PPAR\u03b3 kinase, and PAK4 inhibition may have a therapeutic role as an accelerant of muscle regeneration.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12774","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T02:03:50Z","timestamp":1629857030000},"page":"1776-1788","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["p21\u2010activated kinase 4 phosphorylates peroxisome proliferator\u2010activated receptor \u03a5 and suppresses skeletal muscle regeneration"],"prefix":"10.1002","volume":"12","author":[{"given":"Yuancheng","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Yeob","family":"Han","sequence":"additional","affiliation":[{"name":"School of Pharmacy Jeonbuk National University  Jeonju Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In Hyuk","family":"Bang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Ju","family":"Bae","sequence":"additional","affiliation":[{"name":"School of Pharmacy Jeonbuk National University  Jeonju Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3768-4285","authenticated-orcid":false,"given":"Byung\u2010Hyun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12416"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.01130"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI40373"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/82_2010_78"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00336.2017"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13255"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C600315200"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.11.002"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2016.12.014"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-01600-9"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.255"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2013.03.002"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111878"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12303"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00222-16"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03093-6"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.04.022"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3656"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2016.00091"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-002-0647-0"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09291"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5295.2100"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10383"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13887"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.08.016"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M700253200"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14328"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.015230"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.261"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.09.050"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867327666200716113136"}],"container-title":["Journal 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