Progressive impairment of bioengineered skeletal muscles by MASLD-derived factors: a platform to model liver-induced muscle wasting.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects >30% of the global population and is rising to become the most common liver disorder. MASLD can influence distal organs via secreted mediators, and up to 43% of patients show sarcopenia or related muscle-wasting phenotypes. We developed a modular human three-dimensional bioengineered liver-muscle platform to dissect causal liver-muscle crosstalk. Liver constructs recapitulated steatosis and transition to metabolic dysfunction-associated steatohepatitis (MASH), with inflammatory, apoptotic, immune cell-recruiting and pro-fibrotic signatures. Transferring liver-derived conditioned media to engineered muscles revealed severity-dependent impairment of contractile performance, altered protein balance and myogenic regulation. Contractility declined progressively from steatosis to MASH. Steatotic conditioned media reduced myotube size, whereas MASH conditioned media triggered a compensatory program that partially preserved size despite functional loss. Muscle exposure to MASLD mediators was associated with disrupted autophagic degradation, consistent with impaired flux and accumulation of autophagosomes and lysosomes. This scalable human platform enables systematic investigation of MASLD extrahepatic mechanisms and provides a testbed for perturbations and interventions targeting liver-driven muscle wasting.