Hepatokines lipocalin 2 and osteopontin drive muscle atrophy in MASH.

A bidirectional relationship exists between metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), and sarcopenia, with each worsening the prevalence and prognosis of the other. Hepatokines have recently been shown to affect skeletal muscle metabolism and function, both in the context of MASLD and wasting diseases. We here explored the possibility of targeting hepatokines to counteract MASLD-induced sarcopenia. Integrating mouse and human liver transcriptomics with muscle proteomics from MCD- and GAN-diet induced murine MASH models with sarcopenia, we identified three MASH-induced hepatokines, namely LCN2, LGALS3 and OPN. These hepatokines were elevated in the circulation of mouse MASH models with sarcopenia and in sarcopenic patients with advanced chronic liver disease. C2C12 myotubes treated with liver-secreted proteins as well as recombinant LCN2 and LGALS3 exhibited atrophy. Stable isotope tracing and mitochondrial respiration showed that liver-secreted proteins altered mitochondrial metabolism in C2C12 myotubes, which was recapitulated in primary human myotubes. Human 3D skeletal muscle organoids treated with recombinant proteins exhibited functional impairment. Virus-mediated knockdown of LCN2 in liver of mice with MASH improved muscle function and myotube size, whereas virus-mediated overexpression of LCN2 in the liver aggravated MASH-induced myotube atrophy. Targeting hepatokines may therefore be a feasible future therapeutic strategy against sarcopenia.