{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:02:05Z","timestamp":1792612925483,"version":"4.5.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","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":[[2025,8]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Sarcopenia is defined by the age\u2010related loss of muscle mass and function, with an impaired regenerative capacity of satellite cells (SCs). Despite their recognized importance in muscle regeneration, human model\u2010based studies on SCs in sarcopenia are still lacking, limiting our understanding of their role in age\u2010related muscle loss. Here, we aimed to develop a sarcopenia model using human pluripotent stem cells (hPSCs)\u2010derived skeletal muscle organoids (hSkMOs) and prevent the sarcopenia progression by testosterone treatment.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n The 3D hSkMOs were generated from hPSC and exhibited structurally and functionally mature muscle fibres and spinal\u2010derived neurons including motor neurons and interneurons. The proportion of muscle and the diameter of muscle fibres were assessed. To investigate the acute pro\u2010inflammatory response and intrinsic regenerative capacity of hSkMOs, we induced sarcopenia\u2010like conditions by TNF\u2010\u03b1 treatment for 2\u2009days and analysed. To model aging\u2010induced sarcopenia and investigate the preventive effect of testosterone, chronic TNF\u2010\u03b1 treatment was applied, followed by testosterone administration. Histological, biochemical, molecular and electrophysiological analyses were conducted in various experiments.<\/jats:p>\n <\/jats:sec>\n \n Result<\/jats:title>\n \n We employed a stepwise differentiation protocol from 2D paraxial mesodermal induction to 3D myogenic specification, concluding with a maturation culture system. We observed that the majority of cells were T\/BRA\u2010 and TBX6\u2010positive (\n +<\/jats:sup>\n ) paraxial mesodermal progenitors (T\/BRA\n +<\/jats:sup>\n , 82.04%; TBX6\n +<\/jats:sup>\n , 78.18%), whereas the neuromesodermal progenitors demonstrated a relatively low proportion (T\/BRA\n +<\/jats:sup>\n \/SOX2\n +<\/jats:sup>\n , 15.91%; TBX6\n +<\/jats:sup>\n \/SOX2\n +<\/jats:sup>\n , 11.45%). Single\u2010nucleus RNA\u2010sequencing and extensive immunohistochemistry confirmed the presence of the myogenic lineage cell types (myogenic progenitors\/SCs, myocytes, muscle fibres) and the neural lineage cell types (spinal\u2010derived interneurons, motor neurons, glial cells, Schwann cells). Additionally, the growth of MyHC\n +<\/jats:sup>\n muscle fibres reached twice the thickness on Day 100 compared to that on Day 50 (\n p<\/jats:italic>\n \u2009<\u20090.0001). We subjected them to TNF\u2010\u03b1 treatment and analysed. Western blot analysis confirmed that TNF\u2010\u03b1\/NF\u2010\n \u03ba<\/jats:italic>\n B pathway associated factors such as NF\u2010\n \u03ba<\/jats:italic>\n B p65, I\n \u03ba<\/jats:italic>\n B\u2010\u03b1 and AKT were highly phosphorylated (\n p<\/jats:italic>\n \u2009<\u20090.05,\n p<\/jats:italic>\n \u2009<\u20090.001). The administration of testosterone increased the proportion of activated SCs (PAX7\n +<\/jats:sup>\n \/MYOD\n +<\/jats:sup>\n , 7.97%; PAX7\n +<\/jats:sup>\n \/Ki67\n +<\/jats:sup>\n , 7.03%) compared to the TNF\u2010\u03b1 group (PAX7\n +<\/jats:sup>\n \/MYOD\n +<\/jats:sup>\n , 2.29%; PAX7\n +<\/jats:sup>\n \/Ki67\n +<\/jats:sup>\n , 2.07%,\n p<\/jats:italic>\n \u2009<\u20090.001). The administration of testosterone increased the Cross\u2010Sectional\u2010Area (987.1\u2009\u03bcm\n 2<\/jats:sup>\n ) compared to the TNF\u2010\u03b1 group (644.7\u2009\u03bcm\n 2<\/jats:sup>\n ,\n p<\/jats:italic>\n \u2009<\u20090.01).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n We successfully developed a hSkMOs to demonstrate the structural maturity of the skeletal muscle and its functional interaction with spinal\u2010derived interneurons and motor neurons. Furthermore, we demonstrated that our hSkMOs are useful for modelling aging\u2010induced sarcopenia and providing a valuable platform for testing therapeutic interventions.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70045","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T11:50:22Z","timestamp":1755172222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Human Pluripotent Stem Cell\u2010Derived Skeletal Muscle Organoid Model of Aging\u2010Induced Sarcopenia"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7643-7148","authenticated-orcid":false,"given":"Seongjun","family":"Park","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, College of Biological Science CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Kyoung","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"},{"name":"Center for Convergence Research of Neurological Disorders Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u00a0Seok","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, College of Biological Science CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin\u00a0Yi","family":"Yeo","sequence":"additional","affiliation":[{"name":"Department of Psychological Medicine, Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"Department of Medical Science, College of Medicine CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeo\u00a0Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Neural Circuit Research Group Korea Brain Research Institute Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junaid","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"},{"name":"BK21 R&E Initiative for Advanced Precision Medicine, Department of Biomedical Sciences Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minju","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"},{"name":"BK21 R&E Initiative for Advanced Precision Medicine, Department of Biomedical Sciences Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seongeun","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"},{"name":"BK21 R&E Initiative for Advanced Precision Medicine, Department of Biomedical Sciences Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeoung\u00a0Eun","family":"Lee","sequence":"additional","affiliation":[{"name":"CHA R&D Institute, CHA Bundang Medical Center CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, College of Biological Science CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su\u00a0Bin","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"},{"name":"BK21 R&E Initiative for Advanced Precision Medicine, Department of Biomedical Sciences Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u00a0Young","family":"Mun","sequence":"additional","affiliation":[{"name":"Neural Circuit Research Group Korea Brain Research Institute Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangyong","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Medical Science, College of Medicine CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"},{"name":"CHA R&D Institute, CHA Bundang Medical Center CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u00a0Ryul","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, College of Biological Science CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"},{"name":"CHA R&D Institute, CHA Bundang Medical Center CHA University Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"},{"name":"Department of Biochemistry CHA University School of Medicine Seongnam\u2010si Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8439-4155","authenticated-orcid":false,"given":"Junghyun","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"},{"name":"Center for Convergence Research of Neurological Disorders Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"},{"name":"BK21 R&E Initiative for Advanced Precision Medicine, Department of Biomedical Sciences Ajou University School of Medicine Suwon Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/127.5.990S"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31138-9"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3918"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11739-023-03339-z"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00061.2017"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25116166"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.12.007"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.87081"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13094"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23095108"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/rr67"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.17.1.311"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-0482-1"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.01.040"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.07.005"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26166"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.22.1.389"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.151035"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00043.2011"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41536-022-00204-z"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2015"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01365-6"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2010.11.005"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1121513"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5488.2363"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13381"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40279-013-0081-6"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03654825"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232315039"},{"key":"e_1_2_7_31_1","first-page":"97","article-title":"Unraveling the Paradoxical Action of Androgens on Muscle Stem Cells","volume":"42","author":"Seo J. Y.","year":"2019","journal-title":"Molecules and Cells"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.05976"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77204"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2023.1037200"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00502.2001"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10522-015-9621-9"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0224162"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70045","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T07:46:52Z","timestamp":1755848812000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.70045"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/jcsm.70045"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.70045","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"2025-01-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70045"}}