Wang Yingqian,Ma Zeqiang,Jiang Lehua,Bojan Nataraj,Sha Yiwen,Huang Boyu,Ming Lianxi,Shen Junnan,Pang Weijun
Background Skeletal muscle lipid deposition is a key manifestation of obesity, often accompanied by decreased exercise capacity and muscle atrophy. Skeletal muscle as the largest organ in the body, makes it challenges for designing targeted drug delivery systems. Lipid nanoparticles (LNPs) are widely used as a safe and efficient delivery carrier, there is limited research on LNPs that specifically target skeletal muscle. Results A LNP designed with five specific receptor complements on its surface, which specifically targets skeletal muscle in vivo in mice, without off-target effects on other tissues and organs. MiR-130a, a regulator of PPARG, which is a key factor in skeletal muscle lipid deposition, was encapsulated with LNP (LNP@miR-130a). In high-fat diet (HFD) mice, LNP@miR-130a effectively reduced skeletal muscle lipid deposition, increased exercise activity and enhanced muscle mass. Interestingly, the myokines in skeletal muscle have also changed which may leading to reduce the adipose tissue weight and liver lipid deposition in HFD mice. Conclusions These results indicated LNP@miR-130a is a promising inhibitor of skeletal muscle lipid deposition and may help alleviate obesity. This study provides new insights for obesity treatment and lays foundation for the development of targeted skeletal muscle therapeutics. Graphical
Xue Li,Hao Liu,Yuan Lv,Wenqian Yu,Xiaomei Liu,Caixia Liu
Aims Congenital diaphragmatic hernia (CDH) is a lethal birth defect characterized by congenital lung malformation, and the severity of pulmonary hypoplasia directly affects the prognosis of infants with CDH. Using a nitrofen-induced CDH rat model, we previously reported that Foxa2 expression was downregulated in CDH lungs by proteomics analysis. Here, we investigate the role of miR-130a-5p/Foxa2 axis in lung development of the nitrofen-induced CDH and evaluate its potential role in vivo prenatal therapy. Main methods Nitrofen was orally administrated on embryonic day (E) 8.5 to establish a rat CDH model, and fetal lungs were collected on E13.5, E15.5, E17.5, E19.5 and E21.5. The binding sites of miR-130a-5p on Foxa2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-130a-5p and Foxa2 were detected using qRT-PCR, ISH, IHC and western blotting. The role of miR-130a-5p/Foxa2 axis in CDH-associated lung development was investigated in ex vivo lung explants. Key findings We found that Foxa2 was downregulated in CDH lung tissues, and Foxa2 upregulating improved CDH branching morphogenesis in ex vivo lung explants. Meanwhile, we also showed that miR-130a-5p was significantly upregulated in CDH lungs and thus inversely correlated with Foxa2. Increasing miR-130a-5p abundance with mimics decreases Foxa2-driven Shh/Gli1 signaling and inhibits branching morphogenesis in ex vivo lung explants. Significance This study was the first to show that the miR-130a-5p/Foxa2 axis played a crucial role in CDH-associated pulmonary hypoplasia. These findings may provide relevant insights into the prenatal diagnosis and prenatal therapy of CDH.
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