{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:29:23Z","timestamp":1790692163376,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["RS\u20102025\u201002216753"],"award-info":[{"award-number":["RS\u20102025\u201002216753"]}],"id":[{"id":"10.13039\/501100014188","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":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Type 2 diabetes mellitus (T2D) arises from the interplay between peripheral insulin resistance and pancreatic \u03b2\u2010cell dysfunction, ultimately leading to impaired glucose utilization and chronic hyperglycemia. Despite therapeutic advances, the multifactorial nature of T2D continues to demand the development of novel treatment strategies. Progesterone receptor membrane component 1 (PGRMC1) has emerged as a potential modulator of metabolic function, though its role in T2D pathogenesis has not been fully elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To investigate the role of PGRMC1 in T2D, we generated skeletal muscle\u2010specific\n                      <jats:italic>Pgrmc1<\/jats:italic>\n                      knockout (PKO) mice (\n                      <jats:italic>ACTA<\/jats:italic>\n                      <jats:sup>cre<\/jats:sup>\n                      \u2010\n                      <jats:italic>Pgrmc1<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      ). T2D was induced via a high\u2010fat diet combined with streptozotocin (HFD\u2010STZ) or using genetically diabetic (\n                      <jats:italic>lepr<\/jats:italic>\n                      <jats:sup>db<\/jats:sup>\n                      \/\n                      <jats:italic>lepr<\/jats:italic>\n                      <jats:sup>db<\/jats:sup>\n                      ;\n                      <jats:italic>db\/db<\/jats:italic>\n                      ) mice. A small\u2010molecule screen of 330 compounds identified 11\u03b1\u2010hydroxyprogesterone (11\u03b1\u2010OHP) as a PGRMC1\u2010modulating candidate. The antidiabetic efficacy of 11\u03b1\u2010OHP was assessed in\u00a0vitro and across multiple in\u00a0vivo diabetic models. Whole\u2010body PKO mice were used to evaluate the systemic consequences of global Pgrmc1 deletion. Glucose tolerance test (GTT), insulin tolerance test (ITT) and modified homeostatic model assessment for insulin resistance (HOMA\u2010IR, 5\u2010h fasting) were used to evaluate glucose metabolism. Real\u2010time cell metabolism analyser (Seahorse analysis) was used for measuring cellular glycolysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Skeletal muscle PKO improved glucose clearance in GTT (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and insulin sensitivity in ITT (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). Skeletal muscle PKO mice under T2D suppressed insulin resistance according to reduced modified HOMA\u2010IR (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and promoted muscle development (quadriceps femoris, gastrocnemius, tibialis anterior muscle and extensor digitorum longus;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Mechanistically, PGRMC1 interacted with PPP2R5D, a PP2A regulatory subunit, which dephosphorylates RSK1. PGRMC1 loss suppressed PP2A activity, increasing RSK1 phosphorylation and activating AKT signalling, thereby enhancing myoblast proliferation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), differentiation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and glycolysis (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). 11\u03b1\u2010OHP facilitated proteasomal degradation of PGRMC1, elevated pAKT levels and improved glucose clearance in GTT (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and insulin sensitivity in ITT (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) in wild\u2010type mice but not in PKO mice. Notably, 11\u03b1\u2010OHP restored glucose clearance in GTT (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and insulin sensitivity in ITT (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) and increased muscle mass in both HFD\u2010STZ and\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice, but its effects were abolished in skeletal muscle PKO mice. Whole\u2010body PKO mice still increased muscle development and metabolic activation, suggesting minimal interference by systemic PKO.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings identify skeletal muscle\n                      <jats:italic>PGRMC1<\/jats:italic>\n                      as a pivotal regulator of glucose metabolism and highlight its inhibition as a promising muscle\u2010targeted therapeutic approach for T2D management.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70121","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T09:19:19Z","timestamp":1762766359000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting Progesterone Receptor Membrane Component 1 to Improve Muscle Development and Glucose Homeostasis"],"prefix":"10.1002","volume":"16","author":[{"given":"Sang\u00a0R.","family":"Lee","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Chungnam National University  Daejeon Republic of Korea"},{"name":"Department of Physiology Dong\u2010A University College of Medicine  Busan Republic of Korea"},{"name":"Department of Translational Biomedical Sciences, Graduate School of Dong\u2010A University  Busan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moeka","family":"Mukae","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Chungnam National University  Daejeon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Globinna","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Cell and Genetic Engineering University of Ulsan College of Medicine, Asan Medical Center  Seoul Republic of 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