The Muscle-Liver Immunometabolic Axis in Liver Transplantation: A Decisive Role in Outcomes and Mechanisms.

Liver transplantation has transformed survival for end-stage liver disease, shifting clinical attention from acute rejection to longer-term vulnerability driven by metabolic dysfunction and loss of skeletal-muscle reserve. In this Review, we examine liver transplantation through the muscle-liver immunometabolic axis across the waitlist, perioperative and follow-up phases. Clinical evidence consistently links sarcopenia, frailty, myosteatosis and sarcopenic obesity with infection, prolonged hospitalization and excess mortality after transplantation, while muscle quantity, quality and function often diverge, exposing the limitations of weight-based assessment alone. Mechanistically, nutrient sensing, inflammatory signaling and immune competence converge through pathways involving AMPK, mTOR, PGC-1α, myokines, hyperammonemia and immunosuppressant exposure. These interactions help explain why indispensable immunosuppression may simultaneously protect the graft and impair metabolic recovery. We highlight muscle-directed strategies - including structured prehabilitation and rehabilitation, protein and branched-chain amino acid support, ammonia-aware interpretation and selected anabolic approaches - as pragmatic entry points for improving resilience. However, translation remains limited by heterogeneous definitions, sparse longitudinal phenotyping and a lack of transplant-specific randomized evidence.