Bidirectional Regulation between Metabolic Dysfunction-associated Steatotic Liver Disease and Sarcopenia via Liver-muscle Crosstalk
Year: 2026
Type: article
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: ) 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.
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7119010365