Swimming Reduces Polyploid Lesions And Modulates Nad + Levels In Mice-induced Colorectal Cancer

INTRODUCTION: Colorectal cancer (CRC) is marked by high prevalence and mortality, attributed to increased demand for oxidized nicotinamide adenine dinucleotide (NAD+). A sedentary lifestyle is a prominent risk factor, and physical exercise has the potential to modulate NAD+, aiding in the reduction and prevention of CRC. PURPOSE: To assess the impact of physical exercise on NAD+ levels and CRC development in male Balb/c mice. METHODOLOGY: Different mice, groups were formed: sedentary (SED), exercise (EX); sedentary induced to CRC (SED/CRC), exercise-induced CRC (EX/CRC) (protocol 020/22 CEUA - UFRJ). Over 16 weeks, mice underwent swimming sessions (30 min, 5 days per week). After 4 weeks, CRC was induced by intraperitoneal administration of Azoxymethane (AOM) at 20 mg/kg and Dextran Sodium Sulfate solution at 2.5% in drinking water (3 cycles of 5 days every 2 weeks). Ten weeks after AOM, in vivo bioluminescence images were obtained using the IVIS™ system to assess CRC progression. Subsequently, the animals were euthanized, and colons were removed for identification and quantification of polypoid lesions. NAD+ levels were assessed by enzymatic assay and gene expression by qPCR. Statistical analysis used the Two-Way ANOVA test (p < 0.05). RESULTS: Bioluminescence images showed a reduction in emission (p/s/cm2/sr) in EX/CRC compared to SED/CRC (1573 vs 3289) p < 0.05. EX/CRC showed a 48,7% (p < 0.05) reduction in polypoid lesions compared to SED/CRC. NAD+ levels increased in EX (1052 ± 183) and SED/CRC (1016.4 ± 131.5), being restored in the EX/CRC condition (721.4 ± 165.8) p < 0.05 to baseline SED levels (609.6 ± 48.5). Next, we assessed changes in mRNA expression of the NAD salvage, de novo synthesis, Preiss-Handler, degradation, and excretion pathways. Among these genes, we found an increase in the expression of the mitochondrially-located NAD-degrading enzyme SIRT5 in the EX/CRC condition compared to SED/CRC (4.1 ± 1.5 vs 1.0 ± 1.2, p < 0.05). This result correlates with increased mitochondrial NAD+ transporter SLC25A51 expression in the EX/CRC condition (2.9 ± 1.9) compared to SED/CRC 1.0 ± 0.5) p > 0.05. CONCLUSION: Physical exercise downmodulates NAD+ levels in the CRC condition, correlating with reduced polypoid lesions and increased Sirt5 expression. Coordination for the Improvement of Higher Education Personnel, Rio de Janeiro State Research Support Foundation