MicroRNA-15b promotes myofascial pain syndrome by targeting NFS1 to regulate mitophagy

  • Free Radic Biol Med. 2025 Aug 27:240:626-640. doi: 10.1016/j.freeradbiomed.2025.08.054.
Dawei Han  1 ,  Molei Liu  2 ,  Mingwei Sheng  3 ,  Lili Jia  4 ,  Yunxia Liu  3 ,  Ling Liu  1 ,  Hongxia Li  3 ,  Yiqi Weng  3 ,  Xiaofei Song  5 ,  Yinghui Ren  6 ,  Wenli Yu  7
Affiliations
  • 1. Department of School of Medicine, Nankai University, Tianjin, 300071, China; Department of College of Life Sciences, Nankai University, Tianjin, 300071, China.
  • 2. Department of School of Medicine, Tianjin Medical University, Tianjin, 300070, China.
  • 3. Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, 300380, China.
  • 4. Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, 300380, China. Electronic address: [email protected].
  • 5. Key Laboratory of Mechanism Theory and Equipment Design of Ministry of Education, School of Mechanical Engineering, Tianjin University, Tianjin, 300354, China.
  • 6. Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, 300380, China. Electronic address: [email protected].
  • 7. Department of School of Medicine, Nankai University, Tianjin, 300071, China; Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, 300380, China. Electronic address: [email protected].
PMID: 40882770 DOI: 10.1016/j.freeradbiomed.2025.08.054
Abstract

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.

Keywords
Iron-sulfur clusters; Mitophagy; Myofascial pain syndrome; NFS1; miR-15b.
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