Sarcopenia and sepsis fuel a self-perpetuating cycle of immunometabolism decline

Sepsis and sarcopenia are intertwined clinical challenges characterized by profound immunometabolic dysregulation. Traditionally viewed as a passive reservoir, skeletal muscle is now recognized as an active immunometabolic rheostat that dynamically influences systemic inflammation and homeostasis. This review synthesizes recent advances that redefine our understanding of muscle in critical illness, moving beyond simplistic views of catabolism to encompass complex adaptive strategies. This review summarizes recent advances and discusses septic autocannibalism, a process in which muscle proteolysis, driven by a metabolic defense priority, provides key substrates, glutamine for immune function and alanine for hepatic gluconeogenesis. Initially adaptive, sustained activation of this response leads to severe muscle wasting and long-term functional impairment. We analyze the bidirectional relationship between these conditions, focusing on shared risk factors such as immunosenescence and obesity. Key molecular pathways, including the IL-6/JAK/STAT and NF-κB axes, are examined, with particular emphasis on how the temporal release of myokines (e.g., IL-6, IL-15, IGF-1) dictates their shift from adaptive signals to chronic catabolic drivers. Furthermore, we discuss how energy reprogramming, characterized by aerobic glycolysis and mitochondrial failure, disrupts muscle homeostasis. We highlight physical activity as a potent modulator of immunometabolic health through the release of anti-inflammatory myokines and enhanced mitochondrial biogenesis. To propel the field forward, we propose experimental avenues: single-cell spatial transcriptomics to map cellular crosstalk, mitochondrial transplantation to restore energetic capacity, and the identification of "muscle resilience" biomarkers for early intervention. This review underscores the urgent need for integrated immunometabolic approaches to improve outcomes in critically ill patients.