Electrical stimulation activates calpain 2 and subsequently upregulates collagens via the integrin β1/TGF-β1 signaling pathway.

Stress urinary incontinence (SUI) is a public health issue attributed to weakened pelvic supporting tissues. Electrical stimulation (ES) is one of the first-line conservative treatments for SUI. However, the underlying mechanism of ES in the treatment of SUI is not clear. Here, we show that ES suppresses cell apoptosis and upregulates collagen expression by functioning as a cell growth inducer to activate the calpain 2/talin 1/integrin β1/transforming growth factor (TGF)-β1 axis. Specifically, ES promoted Ca2+ to flow into the cytoplasm through the calcium channel, Cav 3.2, thereby activating calpain 2. Then, the activated calpain 2 cleaved talin 1, which induced the activation of integrin β1 and upregulated the TGF-β1-mediated transcription of collagen I and III. Notably, blocking Cav 3.2 suppressed calcium influx and inhibited the activation of downstream proteins. Furthermore, the knockdown of calpain 2 resulted in the reduction of cleaved talin 1, and the shRNA-integrin β1 treatment downregulated the level of activated integrin β1 and the expression of TGF-β1-induced collagen I and III. An association of the ES-modulated collagen I and III upregulation with the therapeutic effect of the ES-Ca2+/calpain 2/talin 1/integrin β1/TGF-β1 axis was demonstrated in mouse fibroblast and mouse SUI models established through vaginal distension (VD). This outcome provides insight into clinical diagnosis and treatment.