Metformin enhances external urethral sphincter integrity and restores continence via AMPK activation in a rat model of stress urinary incontinence

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BACKGROUND: Stress urinary incontinence (SUI) is primarily caused by structural and functional damage to the external urethral sphincter (EUS). In previous studies, metformin, a known AMP-activated protein kinase (AMPK) activator, has shown repair effects after skeletal muscle injury. This study explored its therapeutic effect and molecular mechanisms in SUI associated with EUS injury. METHODS: The SUI model was established by double vaginal dilation. Rats were assigned to sham, vehicle-treated, or metformin-treated (200 mg/kg/day, oral) groups. Urodynamic testing was performed after 7 and 14 days. Subsequently, EUS tissues were isolated for histological (hematoxylin and eosin [H&E], Masson's), apoptotic (TUNEL), ultrastructural (transmission electron microscopy [TEM]), and molecular analyses. Finally, C2C12 myotubes cells were treated with varying concentrations of metformin to evaluate the expression of phosphorylated AMPK (p-AMPK) and MYH1/2, which are markers of skeletal muscle fiber type and regeneration. RESULTS: Abdominal leak point pressure (ALPP) and bladder leak point pressure (BLPP) decreased after double vaginal dilation, suggesting that SUI was established. After treatment for 7 and 14 days, respectively, metformin significantly increased ALPP and BLPP (p < 0.05) without affecting maximum bladder capacity (p > 0.05). Masson's staining and TEM revealed that metformin improved disorganized EUS architecture. Further, Western blot analysis demonstrated that metformin increased the expression of MYH1/2 and p-AMPK in vivo and in vitro. Meanwhile TUNEL assay showed that metformin treatment reduced apoptotic cells in the EUS from SUI rats. CONCLUSIONS: These results indicate that metformin enhances EUS repair to improve SUI via activating the AMPK signaling pathway. These findings provide new insights into therapeutic strategies for SUI.

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