{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T07:08:09Z","timestamp":1783840089775,"version":"3.55.0"},"reference-count":52,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MedComm"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    We recently identified that AMP\u2010activated protein kinase (AMPK) \u03b12 phosphorylation at S491 is mediated by p21\u2010activated kinase 4 (PAK4), leading to muscular and systemic insulin resistance. This study examined how muscle PAK4 deletion affects atrophy in male mice and its link to human sarcopenia. Dexamethasone treatment increased the mRNA and protein levels of PAK4, which was partially the result of glucocorticoid response elements activation in the promoter of the\n                    <jats:italic>Pak4<\/jats:italic>\n                    gene. Muscle\u2010specific\n                    <jats:italic>Pak4<\/jats:italic>\n                    knockout mice were protected from both dexamethasone\u2010 and denervation\u2010induced muscle atrophy. Likewise, treatment with a proteolysis\u2010targeting chimera (PROTAC) targeting PAK4 also mitigated muscle atrophy. PAK4 inhibition alleviated mitochondrial dysfunction and enhanced the expression of biogenesis\u2010related genes via AMPK activation with reduced AMPK\u03b12\u2010S491 phosphorylation. Notably, muscle overexpression of phospho\u2010deficient AMPK\u03b12\n                    <jats:sup>S491A<\/jats:sup>\n                    mutant preserved mass in dexamethasone\u2010treated mice, whereas constitutively phosphorylated AMPK\u03b12\n                    <jats:sup>S491D<\/jats:sup>\n                    mutant abolished PAK4 PROTAC's antiatrophy effect. In humans, sarcopenic muscle exhibited higher levels of PAK4 protein and AMPK\u03b12\u2010S491 phosphorylation compared with non\u2010sarcopenia controls, with an inverse correlation to sarcopenic index and grip strength. These findings reveal a novel AMPK phosphorylation\u2010dependent mechanism by which PAK4 regulates mitochondrial function and muscle mass, offering new therapeutic avenues for combating muscle atrophy in chronic disease and aging.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Clinical trial registration<\/jats:bold>\n                    : Not applicable.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70508","type":"journal-article","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T06:53:35Z","timestamp":1764485615000},"source":"Crossref","is-referenced-by-count":1,"title":["Negative Impact of p21\u2010Activated Kinase 4\u2010Mediated AMP\u2010Activated Protein Kinase Inhibition on Sarcopenia in Mice and Humans"],"prefix":"10.1002","volume":"6","author":[{"given":"Jiacheng","family":"Du","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwang Chan","family":"Yu","sequence":"additional","affiliation":[{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Jae","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Jeonbuk National University Medical School  Jeonju Republic of Korea"},{"name":"Department of Orthopedic Surgery Jeonbuk National University Hospital  Jeonju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun\u2010Jung","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Jeonbuk National University Hospital  Jeonju Republic of 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