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Role of microRNA-21-loaded extracellular vesicles in liver-muscle intercommunication during Metabolic Dysfunction–associated Steatotic Liver Disease
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Orientador(es)
Resumo(s)
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic
liver disease, presenting a wide spectrum of metabolic dysregulation. However, its progression extends
beyond the liver, affecting extrahepatic organs. In skeletal muscle, sarcopenia and myosteatosis are
often associated with advanced MASLD. Previous studies showed that microRNA-21 (miR-21)
continuously increases with MASLD progression in the liver, serum and skeletal muscle, while its
ablation improves outcomes in animal models. In this work, we aimed to evaluate whether liver-derived
extracellular vesicles (EVs) containing miR-21 contribute to skeletal muscle dysfunction in MASLD,
using both a diet-induced MASLD mouse model and an in vitro model of hepatocyte-to-myotube
communication. Mir21 whole-body knockout (WB-KO); Mir21 Alb-Cre KO (Alb-Cre-KO) and wildtype (WT) mice were fed a high-fat diet (HFD), with high fructose/glucose drinking water for 20 weeks
or a standard diet. AML12-derived EVs were incubated with C2C12 myotubes for miR-21 assays and
gene expression was evaluated by RT-qPCR. HFD mice displayed hepatic steatosis without muscle
atrophy or changes in miR-21 levels. However, WB-KO mice showed increased levels of muscle
regeneration factors Pax7 and Myod1, counteracting the decreases observed in WT HFD-fed mice.
Additionally, Alb-Cre-KO HFD-fed mice exhibited reduced expression of atrophy-related gene Fbxo32
compared to WT HFD-fed mice. Hepatocyte miR-21 overexpression led to an increase in miR-21-
loaded EVs, which subsequently elevated miR-21 expression in myotubes. This resulted in increased
levels of genes associated with lipid metabolism, inflammation, muscle regeneration and atrophy, while
decreasing levels of muscle growth inhibitor Myostatin. Notably, miR-21 inhibition in palmitic acidtreated hepatocytes reduced secreted miR-21 in EVs. However, myotube miR-21 expression remained
unchanged after incubation. Overall, these findings suggest that miR-21 ablation promotes skeletal
muscle regeneration and inhibits atrophy. The in vitro model highlighted the role of hepatocytes-derived
miR-21-loaded EVs in inducing myotube dysfunction, closely resembling transcription profiles seen in
MASLD-associated sarcopenia patients.
Descrição
Tese de mestrado, Biologia Evolutiva e do Desenvolvimento, 2025, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Comunicação fígado para músculo MASLD miR-21 Sarcopenia Vesículas extracelulares Teses de mestrado - 2025