Protective Role of Apelin in a Mouse Model of Post–Intensive Care Syndrome

Post-intensive 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's 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.