Free radical biology & medicine · 2025
MicroRNA-15b promotes myofascial pain syndrome by targeting NFS1 to regulate mitophagy.
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Han Dawei, Liu Molei, Sheng Mingwei, Jia Lili, Liu Yunxia, Liu Ling, Li Hongxia, Weng Yiqi, Song Xiaofei, Ren Yinghui, Yu Wenli
Аннотация
BACKGROUND AND AIMS: Myofascial pain syndrome (MPS), driven by dysfunction in myofascial trigger points (MTrPs), remains mechanistically unclear. This study aimed to explore miR-15 b's function in MTrP pathogenesis, focusing on its regulation of iron-sulfur (Fe-S) cluster synthesis and mitophagy.
METHODS: A rat MTrP model was established using repetitive mechanical injury and eccentric exercise. Skeletal muscle tissues and primary satellite cells were analysed for miR-15b expression, Fe-S cluster-related proteins (NFS1, NDUFS3, and SDH B), and mitophagy markers (FUN14 structural domain-containing protein 1 (FUNDC1) and LC3-II/I). In vitro, tumour necrosis factor-alpha (TNF-α)-induced inflammation and miR-15b modulation (mimics/sponges) and NFS1 modulation (overexpression/knockdown) were used to assess mitochondrial functions. In vivo, the therapeutic effect on normal and MTrP model rats was evaluated by intramuscular injection of transiently transfected complexes of NFS1 plasmid, miR-15b plasmid or sponge constructs.
RESULTS: MTrP rats exhibited miR-15b, suppressed NFS1, and impaired Fe-S-dependent complexes. Dual luciferase assays verified miR-15b targeting NFS1. Rescue experiments further validated that miR-15b directly inhibits NFS1, increase reactive oxygen species (ROS), lowering mitochondrial membrane potential (MMP), triggering FUNDC1-mediated mitophagy. TNF-α stimulation elevated miR-15b levels, exacerbating mitochondrial dysfunction, whereas miR-15b inhibition restored NFS1 and normalised mitophagy. In normal rats, miR-15b overexpression recapitulated MTrP-like pathology in healthy rats. Moreover, in the MTrP model rats, miR-15b overexpression exacerbated these manifestations, sponge and NFS1 treatment attenuated or even reversed certain pathological changes.
CONCLUSIONS: miR-15b drives MTrP progression by suppressing NFS1, disrupting Fe-S homeostasis, and activating FUNDC1-dependent mitophagy. Targeting miR-15b mitigates mitochondrial dysfunction and pain hypersensitivity, underscoring its therapeutic potential in MPS.
METHODS: A rat MTrP model was established using repetitive mechanical injury and eccentric exercise. Skeletal muscle tissues and primary satellite cells were analysed for miR-15b expression, Fe-S cluster-related proteins (NFS1, NDUFS3, and SDH B), and mitophagy markers (FUN14 structural domain-containing protein 1 (FUNDC1) and LC3-II/I). In vitro, tumour necrosis factor-alpha (TNF-α)-induced inflammation and miR-15b modulation (mimics/sponges) and NFS1 modulation (overexpression/knockdown) were used to assess mitochondrial functions. In vivo, the therapeutic effect on normal and MTrP model rats was evaluated by intramuscular injection of transiently transfected complexes of NFS1 plasmid, miR-15b plasmid or sponge constructs.
RESULTS: MTrP rats exhibited miR-15b, suppressed NFS1, and impaired Fe-S-dependent complexes. Dual luciferase assays verified miR-15b targeting NFS1. Rescue experiments further validated that miR-15b directly inhibits NFS1, increase reactive oxygen species (ROS), lowering mitochondrial membrane potential (MMP), triggering FUNDC1-mediated mitophagy. TNF-α stimulation elevated miR-15b levels, exacerbating mitochondrial dysfunction, whereas miR-15b inhibition restored NFS1 and normalised mitophagy. In normal rats, miR-15b overexpression recapitulated MTrP-like pathology in healthy rats. Moreover, in the MTrP model rats, miR-15b overexpression exacerbated these manifestations, sponge and NFS1 treatment attenuated or even reversed certain pathological changes.
CONCLUSIONS: miR-15b drives MTrP progression by suppressing NFS1, disrupting Fe-S homeostasis, and activating FUNDC1-dependent mitophagy. Targeting miR-15b mitigates mitochondrial dysfunction and pain hypersensitivity, underscoring its therapeutic potential in MPS.