Jaboticaba peel extract combined with physical exercise preserves prostatic epithelium morphology, attenuates the TLR4/NF-κB axis and improves functional musculoskeletal parameters in TRAMP mice

Prostate cancer progression is closely associated with chronic inflammation, in which Toll-like receptor 4 (TLR4) plays a central role by activating NF-κB-dependent signaling. Pre-clinical models, such as the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP), have been used to study this disease due to its well-characterized tumor progression. Physical exercise has been studied as a preventive strategy to reduce the risk of cancer progression, as it seems to modulate the immune system. Furthermore, the jabuticaba (Myrciaria jaboticaba) peel extract (JPE) characterized by our group, which is rich in bioactive polyphenols such as anthocyanins and ellagitannins, has shown chemopreventive potential, reducing the expression of inflammatory markers and oxidative stress in prostatic tissue.However, despite their individual benefits, antioxidant supplementation has been reported to blunt some exercise-induced adaptations. Thus, the aim herein was to evaluate the effects of JPE and physical exercise, alone or combined, on the TLR4/NF-κB inflammatory axis in the prostate of TRAMP mice, as well as their systemic effects on skeletal muscle. For this purpose, 60 TRAMP male mice were divided into four groups: Sedentary TRAMP (SED); Sedentary TRAMP + Jabuticaba (SEDJAB); Exercised TRAMP (EX) and Exercised TRAMP + Jabuticaba (EXJAB). After 8 weeks of treatment and/or treadmill exercise, the animals were euthanized, and samples from the dorsolateral prostate, diaphragm and soleus muscles were harvested and processed for morphological, immunohistochemical and Western Blotting analysis. Grip strength and four-limb hanging tests were also performed. Only the combination of exercise and JPE promoted greater preservation of healthy prostatic epithelium and reduced the incidence of high-grade lesions. In parallel, the EXJAB group showed reduced protein levels and weaker immunostaining of TLR4 in relation to other groups, as well as lower IκBα levels compared to SED, without changes in total or phosphorylated NF-κB. Since IκBα is itself a target gene of NF-κB, these results suggest an attenuation of the NF-κB-dependent inflammatory response, with a weaker negative feedback loop. Functionally, exercise preserved muscle strength and improved muscular endurance, whereas sedentary groups showed a decline in strength, and JPE did not impair these benefits. Likewise, none of the androgenic (AR), growth-related (IGF-1Rα, AKT, p-AKT), inflammatory (TLR4, NF-κB, TNF-α), oxidative (catalase, SOD2), angiogenic (VEGF), myogenic (myogenin) or structural (α-dystroglycan) differed among groups in the soleus or diaphragm, except for diaphragm VEGF, which was lower in EXJAB than in EX, a modest effect that did not translate into functional impairment. Thus, these findings indicate that the bioactive compounds of JPE potentiated the beneficial effects of exercise on the prostate, attenuating the TLR4/NF-κB inflammatory axis without impairing skeletal muscle or exercise functional benefits, supporting this combination as a safe preventive strategy, although further studies are needed to elucidate the underlying mechanisms. Acknowledgments: São Paulo Research Foundation (FAPESP, grant #2024/03822-6).