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

Summary

In a murine model combining lung injury and immobilization, impaired Apelin–APJ signaling drove multisystem PICS-like phenotypes that were reversed by muscle-specific Apelin overexpression and worsened by Apelin deficiency. Human ARDS survivors with ICU-acquired weakness had lower plasma Apelin, higher IL-6, and PBMC transcriptomic signatures paralleling murine neuroinflammatory programs.

Key Findings

• A combined acute lung injury plus immobilization mouse model recapitulated PICS-like muscle atrophy, lung inflammation, and neurobehavioral deficits.
• Brain single-cell RNA-seq showed upregulated Alzheimer’s disease, depression, and neuroinflammation programs in endothelial cells and microglia.
• Skeletal muscle Apelin–APJ signaling was downregulated; Apelin deficiency worsened, and muscle-specific Apelin overexpression attenuated PICS-like changes and reduced systemic IL-6.
• In ARDS survivors with severe COVID-19, ICU-acquired weakness was associated with lower plasma Apelin, higher IL-6, and PBMC signatures linked to depression/neurodegeneration.

Clinical Implications

Apelin could serve as a biomarker and therapeutic target for ICU survivors at risk of PICS. Measuring plasma Apelin/IL-6 and developing tissue-specific modulators of Apelin–APJ signaling may enable risk stratification and intervention trials.

Limitations

• Animal model generalizability to human PICS is uncertain; causality in humans remains unproven
• Tissue-specific contributions beyond skeletal muscle require clarification; sample sizes for human cohorts not specified in abstract

Future Directions

Prospective human studies to validate Apelin as a predictive biomarker and interventional trials testing Apelin–APJ pathway modulators (e.g., agonists or gene therapy) with organ-specific targeting.