{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:46:58Z","timestamp":1782708418627,"version":"3.54.5"},"reference-count":53,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Sarcopenia is associated with metabolic dysregulation, yet the molecular mediators remain poorly defined. This study aimed to identify relevant regulators of muscle mass and to elucidate the role and underlying mechanism of progranulin in skeletal muscle protein synthesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We combined transcriptomic profiling of muscles from high\u2010fat diet\u2010fed mice with human genetic data from the HugeAMP Type 2 Diabetes Knowledge Portal to identify potential regulators. Clinically, 172 participants were stratified into low muscle mass (LMM) and normal muscle mass (NMM) groups according to the Asian Working Group for Sarcopenia criteria, and serum progranulin was measured. In\u00a0vitro, recombinant progranulin was applied to L6 myoblasts to assess proliferation and differentiation and to differentiated L6 myotubes to evaluate protein synthesis and mTOR\/S6K\/S6 signaling. We performed shRNA\u2010mediated knockdown of Ephrin type\u2010A receptor 2 (EphA2), a functional progranulin receptor, to determine its impact on progranulin\u2010induced effects\u00a0in L6 myotubes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Transcriptomics identified\n                      <jats:italic>Grn<\/jats:italic>\n                      as a top downregulated gene in metabolically stressed muscle. Clinically, serum progranulin levels were significantly lower in the LMM group than the NMM group (280.71\u2009\u00b1\u2009148.09 vs. 378.96\u2009\u00b1\u2009139.65\u2009ng\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). In\u00a0vitro, progranulin did not affect the proliferation or differentiation of L6 myoblasts. However, it dose\u2010dependently enhanced protein synthesis and increased phosphorylation of mTOR, S6K, and S6 in L6 myotubes. Furthermore, EphA2 knockdown attenuated progranulin\u2010induced protein synthesis and phosphorylation of mTOR, S6K, and S6.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Progranulin acts as a novel regulator of skeletal muscle metabolism, which enhances protein synthesis through EphA2\u2010mediated activation of the mTOR signaling cascade.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70182","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T16:49:17Z","timestamp":1773852557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Progranulin Regulates Protein Synthesis in Myocytes Through an Ephrin Type A Receptor 2\u2010Dependent Pathway"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4522-5863","authenticated-orcid":false,"given":"Ka Chon","family":"Chan","sequence":"first","affiliation":[{"name":"Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiong\u2010Ping","family":"Hii","sequence":"additional","affiliation":[{"name":"Department of Nursing Min\u2010Hwei Junior College of Health Care Management  Tainan Taiwan"},{"name":"Department of Cardiovascular Surgery Chi\u2010Mei Medical Center  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin\u2010Yu","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung\u2010Teng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine School of Medicine, College of Medicine, National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai\u2010Pi","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horng\u2010Yih","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University  Tainan Taiwan"},{"name":"Department of Internal Medicine School of Medicine, College of Medicine, National Cheng Kung University  Tainan Taiwan"},{"name":"Tong\u2010Yuan Diabetes Center, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung\u2010Tsung","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine School of Medicine, College of Medicine, National Cheng Kung University  Tainan Taiwan"},{"name":"Tong\u2010Yuan Diabetes Center, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2020.tb00136.x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/07853890600888413"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223-014-9915-y"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/84.3.475"},{"issue":"4","key":"e_1_2_10_6_1","first-page":"31","article-title":"Maintenance of the Musculoskeletal Mass by Control of Protein Turnover: The Concept of Anabolic Resistance and Its Relevance to the Transplant Recipient","volume":"10","author":"Rennie M. 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