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Chronic exercise training attenuates prostate cancer-induced molecular remodelling in the testis

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Abstract

Purpose

Prostate cancer is a major cause of cancer-related death in males worldwide and, in addition to impairing prostate function, also causes testicular adaptations. In this study, we aim to investigate the preventive effect of exercise training on PCa-induced testicular dysfunction.

Methods

As a model, we used fifty Wistar Unilever male rats, randomly divided in four experimental groups. Prostate cancer was chemically and hormonally induced in two groups of animals (PCa groups). One control group and one PCa group was submitted to moderate intensity treadmill exercise training. Fifty weeks after the start of the training the animals were sacrificed and sperm, prostate, testis and serum were collected and analyzed. Sperm concentration and morphology, and testosterone serum levels were determined. In addition, histological analyses of the testes were performed, and testis proteomes and metabolomes were characterized.

Results

We found that prostate cancer negatively affected testicular function, manifested as an arrest of spermatogenesis. Oxidative stress-induced DNA damage, arising from reduced testis blood flow, may also contribute to apoptosis of germ cells and consequential spermatogenic impairment. Decreased utilization of the glycolytic pathway, increased metabolism of ketone bodies and the accumulation of branched chain amino acids were also evident in the PCa animals. Conversely, we found that the treadmill training regimen activated DNA repair mechanisms and counteracted several metabolic alterations caused by PCa without impact on oxidative stress.

Conclusions

These findings confirm a negative impact of prostate cancer on testis function and suggest a beneficial role for exercise training in the prevention of prostate cancer-induced testis dysfunction.

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Acknowledgments

We are thankful to the Portuguese Foundation for Science and Technology (FCT), the European Union, QREN, FEDER and COMPETE for funding the Institute of Biomedicine - iBiMED (UID/BIM/04501/2013, POCI-01-0145-FEDER-007628 and UID/BIM/04501/2019), Organic Chemistry, Natural and Agro-food Products - QOPNA (UID/QUI/00062/2013), Aveiro Institute of Materials - CICECO (UID/CTM/50011/2019), Center for the Research and Technology of Agro-Environmental and Biological Sciences - CITAB (UID/AGR/04033/2019) and Research Centre in Physical Activity, Health and Leisure - CIAFEL (UID/DTP/00617/2019) research units, and the research project RUNawayPCa (POCI-01-0145-FEDER-006958 and PTDC/DTP-DES/6077/2014). We also acknowledge the Portuguese National NMR (PTNMR) Network, supported by FCT funds, and the European Union Framework Programme for Research and Innovation HORIZON 2020, under the TEAMING Grant agreement No 739572 - The Discoveries CTR. We are also thankful to Celeste Resende for assistance in sample preparations for histological analyses.

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Authors and Affiliations

Authors

Contributions

BM – study execution, data analysis and discussion, and original draft manuscript preparation; DP –serum and testis biochemical analysis; MCH - serum and testis biochemical analysis and semen analysis; MJF –semen analysis; FS – prostate histological analysis, RV – proteomics data analysis; JAD – testis histological analysis, IFD – metabolomics data analysis and study discussion, JH – data discussion and English editing, PAO – animal protocol implementation and data discussion, RF and MF – study design and data discussion. All authors revised the manuscript and approved the final version.

Corresponding author

Correspondence to Margarida Fardilha.

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Ethical approval

The animal protocol was approved by the animal well-being responsible organ of UTAD and by Direção Geral de Alimentação e Veterinária-DGAV (license n° 021326).

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The authors declare that they have no conflict of interest.

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Electronic supplementary material

Supplementary Table S1

The influence of prostate cancer (PCa) and exercise training (EX) on the incidence of non neoplastic and pre-neoplastic and neoplastic prostate lesions (PDF 120 kb)

Supplementary Table S2

Data from MS/MS analysis extracted from the MaxQuant software, including the identified proteins and the label-free quantification (LFQ) of each sample (XLSX 208 kb)

Supplementary Fig. S1

(a) PCA scores plots of proteomics data, comparing the four experimental groups and differential abundance analysis for (b) CONT+EX vs CONT+SED; (c) PCa + SED vs CONT+SED; and (d) PCa + EX vs CONT+SED (PNG 21 kb)

High resolution image (TIF 121 kb)

Supplementary Fig. S2

(a) PCA scores plot of the metabolomics data comparing the four experimental groups; and PCA and PLS-DA scores plots and respective PLS-DA LV1 loadings plots of 1H NMR spectra for (b) CONT+EX; (c) PCa + SED; (d) PCa + EX, when compared with CONT+SED. Loadings plots are colored as a function of variable importance in projection (VIP) and the assignment of the main signals is indicated (PNG 35 kb)

High resolution image (TIF 196 kb)

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Matos, B., Patrício, D., Henriques, M.C. et al. Chronic exercise training attenuates prostate cancer-induced molecular remodelling in the testis. Cell Oncol. 44, 311–327 (2021). https://doi.org/10.1007/s13402-020-00567-9

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