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Published on: August 10, 2018
PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and
1Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
Abstract:
Intensive care unit-acquired weakness (ICU-AW) is prevalent in critical care, with limited treatment options. Certain microRNAs, like miR-542, are highly expressed in ICU-AW patients. This study investigates the regulatory role and mechanisms of miR-542 in ICU-AW and explores the clinical potential of miR-542 inhibitors. ICU-AW models were established in C57BL/6 mice through cecal ligation and puncture (CLP) and in mouse C2C12 myoblasts through TNF-α treatment. In vivo experiments demonstrated decreased muscle strength, muscle fiber atrophy, widened intercellular spaces, and increased miR-542-3p/5p expression in ICU-AW mice model. In vitro experiments indicated suppressed ATG5, ATG7 and LC3II/I, elevated MDA and ROS levels, decreased SOD levels, and reduced MMP in the model group. Similar to animal experiments, the expression of miR-542-3p/5p was upregulated. Gel electrophoresis explored the binding of polyethyleneimine/mesoporous silica nanoparticles (PEI/MMNs) to locked nucleic acid (LNA) miR-542 inhibitor (LNA-542). PEI/MMNs@LNA-542 with positive charge (3.03 ± 0.363 mV) and narrow size (206.94 ± 6.19 nm) were characterized. Immunofluorescence indicated significant internalization with no apparent cytotoxicity. Biological activity, examined through intraperitoneal injection, showed that PEI/MMNs@LNA-542 alleviated muscle strength decline, restored fiber damage, and recovered mitochondrial injury in mice. In conclusion, PEI/MMNs nanoparticles effectively delivered LNA-542, targeting ATG5 to inhibit autophagy and alleviate mitochondrial damage, thereby improving ICU-AW.
Insights
This study reveals miR-542's role in intensive care unit-acquired weakness (ICU-AW). Inhibiting miR-542 with nanoparticles improved muscle function and mitochondrial health in ICU-AW models.
Area of Science:
- Biomedical Science
- Molecular Biology
- Critical Care Medicine
Background:
- Intensive care unit-acquired weakness (ICU-AW) is a significant complication in critical care with limited therapeutic options.
- MicroRNAs, specifically miR-542, are upregulated in patients with ICU-AW, suggesting a potential regulatory role.
Purpose of the Study:
- To investigate the regulatory role and underlying mechanisms of miR-542 in the development of ICU-AW.
- To explore the therapeutic potential of miR-542 inhibitors delivered via novel nanoparticle systems for treating ICU-AW.
Main Methods:
- Established ICU-AW mouse models using cecal ligation and puncture (CLP) and in vitro C2C12 myoblasts with TNF-α.
- Utilized polyethyleneimine/mesoporous silica nanoparticles (PEI/MMNs) to deliver locked nucleic acid (LNA) miR-542 inhibitors (LNA-542).
- Characterized nanoparticle-inhibitor complexes and assessed their biological activity, muscle function, and mitochondrial integrity in vivo.
Main Results:
- ICU-AW models exhibited decreased muscle strength, muscle fiber atrophy, and increased miR-542 expression.
- In vitro studies showed suppressed autophagy markers (ATG5, ATG7, LC3II/I) and impaired mitochondrial function (increased ROS, decreased SOD and MMP) with miR-542 upregulation.
- PEI/MMNs@LNA-542 treatment alleviated muscle weakness, restored muscle fiber structure, and improved mitochondrial function in ICU-AW mice.
Conclusions:
- miR-542 plays a critical role in the pathogenesis of ICU-AW by inhibiting autophagy and exacerbating mitochondrial damage.
- PEI/MMNs nanoparticles provide an effective delivery system for LNA-542, demonstrating therapeutic potential for mitigating ICU-AW.
