Overactive bladder (OAB) is a common condition that affects both adults and children, often causing significant discomfort and negatively impacting quality of life. This study aimed to establish a juvenile OAB model induced by short-term high fructose intake and explore the underlying metabolic mechanisms.

Three-week-old female Sprague-Dawley rats were randomly assigned to two groups: a model group fed a 60% fructose diet for one week, and a control group fed a standard diet. Body weight, blood biochemical parameters, urination behavior, and urodynamic function were assessed. Bladder tissue was analyzed using hematoxylin and eosin staining, immunohistochemistry, and immunofluorescence. Molecular and metabolic changes were evaluated via Western blot and metabolomic analysis.

High fructose intake decreased body weight, and no significant differences in blood glucose levels were observed between the model and control groups. Additionally, high fructose intake increased intracellular calcium ion concentrations in bladder tissues. Urodynamic tests showed bladder dysfunction, characterized by increased unstable contractions, shorter contraction intervals, and reduced bladder capacity. Histological analysis revealed alterations in bladder smooth muscle, and metabolic profiling indicated enhanced glycolysis, oxidative stress, and activation of the CaMKK2-AMPK signaling pathway.

These results indicate that OAB symptoms were successfully induced within a short timeframe without the need for prolonged fructose feeding[1].Fructose toxicity, characterized by oxidative stress and mitochondrial dysfunction, is closely associated with cellular damage in various tissues[2].Studies have shown that excessive fructose metabolism leads to the accumulation of F1P, glyceraldehyde(GA), and other metabolites, triggering the production of ROS.Although F1P levels in bladder muscle tissue did not significantly increase, downstream metabolites such as GA and dihydroxyacetone phosphate were markedly elevated, indicating a "fructose escape" phenomenon where unmetabolized fructose spills into peripheral tissues. The significant ROS accumulation and the reduced pyruvate/PEP ratio observed in the Mod group further suggest that hypoxia and oxidative stress are key drivers of OAB.AMPK is traditionally activated by cellular energy deficiency signals[3], but in this study, oxidative stress and calcium ion accumulation emerge as significant contributors to AMPK activation. Additionally, the antagonism of AMPK significantly altered bladder contraction rhythms, reduced unstable contractions, and enhanced contraction amplitude, highlighting the important role of AMPK in regulating bladder function.

Short-term high fructose intake induces OAB-like symptoms in juvenile rats through fructose toxicity, oxidative stress, and Ca2+ accumulation, leading to activation of the CaMKK2-AMPK pathway. This model closely mimics pediatric OAB and provides a valuable tool for studying the role of fructose metabolism in bladder dysfunction, with potential implications for metabolic or antioxidant therapeutic strategies.

Lee WC, Wu KLH, Tain YL, Leu S, Cheng YT, Chan JYH. (2023) Impaired insulin signaling at the bladder mucosa facilitates metabolic syndrome-associated bladder overactivity in rats with maternal and post-weaning fructose exposure. J Formos Med Assoc 122: 258-66.
2.Fang L, Li TS, Zhang JZ, Liu ZH, Yang J, Wang BH, et al. (2021) Fructose drives mitochondrial metabolic reprogramming in podocytes via Hmgcs2-stimulated fatty acid degradation. Signal Transduct Target Ther 6: 253.
3.Dengler F. (2020) Activation of AMPK under Hypoxia: Many Roads Leading to Rome. Int J Mol Sci 21: 2428.