MicroRNA-139-5p Promotes Functional Recovery and Reduces Pain Hypersensitivity in Mice with Spinal Cord Injury by Target
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ORIGINAL PAPER
MicroRNA‑139‑5p Promotes Functional Recovery and Reduces Pain Hypersensitivity in Mice with Spinal Cord Injury by Targeting Mammalian Sterile 20‑like Kinase 1 Panfeng Wang1,2 · Yuntong Zhang1 · Yan Xia1 · Dayuan Xu1 · Hongrui Wang1 · Dong Liu2 · Shuogui Xu1 · Yongming Sun2 Received: 7 July 2020 / Revised: 13 October 2020 / Accepted: 7 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Currently, there is no cure for spinal cord injury (SCI), a heavy burden on patients physiology and psychology. We found that microRNA-139-5p (miR-139-5p) expression was significantly downregulated in damaged spinal cords in mice. So, we aimed to test the effect of treatment with miR-139-5p on functional recovery and neuropathic pain in mice with SCI and investigate the underlying mechanism. The luciferase reporter assay revealed that miR-139-5p directly targeted mammalian sterile 20-like kinase 1 (Mst1), and miR-139-5p treatment suppressed Mst1 protein expression in damaged spinal cords of mice. Wild-type mice and Mst1(−/−) mice were exposed to SCI and treated with miR-139-5p agomir via intrathecal infusion. Treatment of SCI mice with miR-139-5p accelerated locomotor functional recovery, reduced hypersensitivities to mechanical and thermal stimulations, and promoted neuronal survival in damaged spinal cords. Treatment with miR-139-5p enhanced phosphorylation of adenosine monophosphate-activated protein kinase alpha (AMPKα), improved mitochondrial function, and suppressed NF-κB-related inflammation in damaged spinal cords. Deficiency of Mst1 had similar benefits in mice with SCI. Furthermore, miR-139-5p treatment did not provide further protection in Mst1(−/−) mice against SCI. In conclusion, miR-139-5p treatment enhanced functional recovery and reduced pain hypersensitivity in mice with SCI, possibly through targeting Mst1. Keywords Adenosine monophosphate-activated protein kinase · Inflammation · Mitochondrial function · Allodynia
Introduction Spinal cord injury (SCI) has a rising incidence in China and imposes a great burden on the society [1, 2]. The individuals with SCI typically suffered from severe sensory and locomotor dysfunction and chronic neuropathic pain, and had a Panfeng Wang and Yuntong Zhang have contributed equally to the work. * Shuogui Xu * Yongming Sun [email protected] 1
War and Traumat Emergency Centre, Changhai Hospital, Navy Military Medical University, Changhai Road 168, Shanghai 200433, China
Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Sanxiang Road 1055, Suzhou 215004, China
2
reduced quality of life [3]. Therefore, the development of possible treatment strategies that could accelerate the recovery of motor function and/or mitigate the neuropathic pain is of high priority to individuals with SCI. MicroRNAs (miRNAs) are small (18–22 nucleotides) RNA molecules that do not code for proteins but negatively regulate target gene expression through post-translational repression or promoting mRNA decay [4, 5]. MiR
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