Abstract

Background and Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) and sarcopenia frequently coexist, yet their causal relationship and underlying mechanisms remain poorly defined. This study aimed to investigate whether a bidirectional causal link exists between MASLD and sarcopenia and to identify the molecular mediators involved in liver-muscle crosstalk. Methods We applied Mendelian randomization to test the causal effect of sarcopenia-related traits on MASLD risk. To capture distinct clinical features, we established complementary mouse models, including diet-induced and genetic ( ob / ob ) MASLD models, a stelic animal model, and a drug-induced muscle atrophy model. Multi-tissue transcriptomic profiling was performed on liver and muscle to uncover altered pathways. Results Complementing prior genetic evidence establishing MASLD as a causal factor for sarcopenia, our Mendelian randomization analysis revealed that diminished muscle mass and muscle function contribute to an elevated risk of MASLD. In mice with MASLD, we observed loss of muscle mass, reduced strength, and ectopic lipid deposition in skeletal muscle. Conversely, muscle atrophy exacerbated hepatic steatosis, inflammation, and fibrosis in MASLD mice. Transcriptional profiling revealed that sarcopenia impairs hepatic metabolic homeostasis by enhancing fatty acid uptake and impairing oxidative phosphorylation, while MASLD, in turn, promotes muscle dysfunction by exacerbating inflammatory responses and metabolic dysfunction. We further identified C-C motif chemokine ligand 2 as a key myokine that drives MASLD, and adrenomedullin as a key hepatokine that triggers sarcopenia. Conclusions Our findings suggest a potential bidirectional causal relationship between MASLD and sarcopenia, which may be partially mediated by C-C motif chemokine ligand 2 and adrenomedullin.