Decoding the mechanistic basis of liver–muscle communication in health and disease

The bidirectional communication between liver and skeletal muscle represents a critical yet underexplored axis in human physiology. Dysfunction in either organ can accelerate pathology in the other, amplifying disease progression. Understanding this interconnected system is essential for developing targeted and effective therapeutic strategies. This comprehensive review elucidates the complex pathophysiological mechanisms underlying liver-muscle crosstalk and identifies novel therapeutic targets for simultaneous intervention in both organs. We analyzed peer-reviewed literature focusing on molecular pathways, biomarkers, and therapeutic interventions targeting the liver-muscle axis, including cardiac muscle interactions. Key parameters examined included inflammatory mediators (TNF-α, IL-6), metabolic regulators (mTOR, AMPK), hepatokines, myokines, cardiokines, and emerging biomarkers such as zonulin. The liver-muscle axis operates through multiple interconnected pathways: (1) inflammatory cascades where TNF-α inhibits muscle mTOR signaling while promoting hepatic stellate cell activation; (2) metabolic disruption through insulin resistance and AMPK pathway dysfunction affecting both organs simultaneously; (3) gut-liver-muscle crosstalk mediated by microbiome-derived metabolites and intestinal permeability markers like zonulin; (4) hepatokine-myokine signaling networks that coordinate metabolic homeostasis; and (5) liver-heart crosstalk involving cardiomyocyte-hepatocyte interactions through FGF21, IL-6/STAT3 signaling, and inflammatory pathways that distinguish cardiac muscle from skeletal muscle responses. Studying the liver-muscle axis helps in understanding metabolic diseases, transforming them from isolated organ pathologies to interconnected systemic disorders. This framework opens new avenues for precision medicine approaches, biomarker development, and therapeutic innovation that simultaneously optimize liver, skeletal muscle, and cardiac health.