Swimming exercise alleviates peripheral neuropathic pain by downregulating FTO and promoting m6A methylation of miR-183.

Swimming exercise may alleviate neuropathic pain (NP) in spared nerve injury (SNI) mice by regulating pain-related genes, such as miR-183 and Cacna2d2. However, the related upstream mechanism remains unclear. The demethylase fat-mass and obesity-associated protein (FTO) in the dorsal root ganglia (DRG) participates in NP through m6A modification. However, whether FTO-regulated m6A modification contributes to the analgesic effect of swimming remains unknown. This study aimed to investigate the influence of swimming on FTO expression in the DRG of SNI mice and clarify its role in regulating the m6A modification of miR-183 by inhibiting FTO expression. We established a male SNI mouse model, performed intrathecal injections of adeno-associated viruses to knock down or overexpress FTO, and manipulated the expression of FTO in male and female miR-183 knockout mice. In addition, we subjected the above models to six weeks of swimming training and analyzed the effects on pain behavior, m6A modification levels, and the expression of target gene transcription and protein levels. We observed that swimming exercise downregulated FTO mRNA and protein expressions in the injured L4-L6 DRGs of SNI mice, promoted the m6A modification of miR-183, and showed an association with the increased expression levels of miR-183. These outcomes further reduced the downstream target gene Cacna2d2 and the BDNF/TrkB signaling pathway, which alleviated mechanical and cold allodynia. This study suggested that swimming exercise alleviates NP, potentially by downregulating FTO and promoting m6A methylation of miR-183. FTO-regulated m6A modification plays a key role in the mechanism of exercise-induced analgesia.