{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:31:30Z","timestamp":1788546690979,"version":"build-2803163510"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"JSPS KAKENHI","award":["17H06179"],"award-info":[{"award-number":["17H06179"]}]},{"name":"JSPS KAKENHI","award":["17K19693"],"award-info":[{"award-number":["17K19693"]}]},{"name":"JSPS KAKENHI","award":["15H05978"],"award-info":[{"award-number":["15H05978"]}]}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Post\u2013intensive care syndrome (PICS) is a serious condition involving physical weakness, depression, and cognitive impairment that develop during or after an ICU stay, often resulting in long-term declines in quality of life. Patients with acute respiratory distress syndrome and severe coronavirus disease (COVID-19) are at particularly high risk, yet the molecular mechanisms underlying PICS remain poorly understood. Here, we identify impaired Apelin-APJ signaling as a potential contributor to PICS pathogenesis through the disruption of interorgan homeostasis. Using a mouse model combining acute lung injury and hindlimb immobilization, we observed PICS-like features, including muscle atrophy, lung inflammation, and neurobehavioral abnormalities such as anxiety-like behavior and special working memory. Single-cell RNA sequencing in brain revealed upregulation of gene programs associated with Alzheimer\u2019s disease, depression, and neuroinflammation, particularly in endothelial cells and microglia. Concurrently, Apelin-APJ signaling was downregulated in skeletal muscle. These changes were exacerbated in Apelin-deficient mice and attenuated by muscle-specific Apelin overexpression, which also reduced systemic IL-6 and restored circulating Apelin levels. In survivors of ARDS who had severe COVID-19, ICU-acquired weakness was associated with reduced plasma Apelin and elevated IL-6 levels. Transcriptomic profiling of peripheral blood mononuclear cells from patients with ICU-acquired weakness showed gene expression signatures linked to depression and neurodegeneration, mirroring murine findings. These data suggest that impaired Apelin-APJ signaling may play a role in PICS pathophysiology. Although skeletal muscle appears to contribute to systemic Apelin levels, further studies are needed to clarify tissue-specific roles. Modulating this pathway could offer a therapeutic strategy to mitigate long-term outcomes in ICU survivors.<\/jats:p>","DOI":"10.1165\/rcmb.2025-0028oc","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T19:15:07Z","timestamp":1757358907000},"page":"241-256","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":1,"title":["Protective Role of Apelin in a Mouse Model of Post\u2013Intensive Care Syndrome"],"prefix":"10.1093","volume":"74","author":[{"given":"Yumiko","family":"Imai","sequence":"first","affiliation":[{"name":"Department of Medical Infection System, Research Institute , Nozaki Tokushukai Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuha","family":"Kinugasa","sequence":"additional","affiliation":[{"name":"Department of Medical Infection System, Research Institute , Nozaki Tokushukai Hospital, Osaka, 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Computational Biology and Medical Sciences, The University of Tokyo , Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Fujino","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka University , Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Kubodera","sequence":"additional","affiliation":[{"name":"Rehabilitation Center and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9504-0061","authenticated-orcid":false,"given":"Toru","family":"Kotani","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, Showa Medical University , Tokyo, 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