Resistance exercise alleviates overactive bladder by attenuating detrusor oxidative stress via peroxynitrite...

Overactive bladder (OAB) remains challenging to treat due to drug intolerance and limited efficacy of behavioral therapies. The mechanistic basis by which exercise improves bladder function is poorly understood. Here, we established a clinically translatable resistance exercise model using graded treadmill loading (5-15% body weight [BW], 10-30 min/day) in a cyclophosphamide (CYP)-induced OAB rat model to identify the optimal therapeutic intensity and delineate redox-related mechanisms. Functional (urodynamics, urine spot test), MRI imaging, histological, immunofluorescence, and untargeted metabolomic analyses were integrated to assess detrusor remodeling and oxidative stress modulation across 11 experimental groups. ModeratSTREe resistance exercise (10% BW, 20 min/day) significantly increased bladder capacity (0.45 ± 0.17 mL-1.28 ± 0.44 mL) and prolonged voiding interval (2.13 ± 0.64 min-6.35 ± 0.93 min; p < 0.001). MRI and histology confirmed reversal of detrusor hypertrophy. Immunofluorescence demonstrated reduced 3-nitrotyrosine accumulation, indicating decreased peroxynitrite (ONOO⁻)-mediated nitrative stress. Metabolomic profiling revealed extensive reprogramming of glutathione metabolism, arginine biosynthesis, and glycine-serine pathways, restoring redox balance and antioxidant capacity. Integration of metabolic and histological data defined a mechanistic framework, "resistance exercise-peroxynitrite reduction-oxidative stress attenuation-detrusor remodeling." In conclusion, our findings identify peroxynitrite reduction and detrusor remodeling as key mechano-redox pathways through which resistance training improves bladder compliance and detrusor relaxation. These results highlight resistance exercise as a clinically feasible, non-pharmacological strategy with translational potential for improving outcomes in patients with OAB.