Exercise preconditioning mitigates colon carcinogenesis through targeted epigenetic remodeling and suppression of early preneoplastic lesions

Abstract Exercise reduces colorectal cancer risk, but its protective mechanisms in early carcinogenesis remain unclear. Male C57BL/6 mice (n = 10/group) were used in two experimental designs: (i) an acute molecular and epigenetic study to evaluate early changes 8h and 24h after a single Azoxymethane (AOM) dose; and (ii) a chronic carcinogenic model to assess the biological efficacy of exercise timing on premalignant lesions (Aberrant and mucin-depleted foci) after 6 weeks of AOM exposure. In both, mice underwent a 6-week progressive swimming protocol initiated either before (preconditioning) or concurrent with AOM. We demonstrate that 6-week exercise preconditioning, rather than concurrent training, conferred protection against mucin-depleted foci incidence (P = 0.03). Mechanistically, exercise preconditioning remodeled colon tissue to resist genotoxic stress, evidenced by an accelerated normalization of DNA repair kinetics (Mgmt expression returned to baseline by 24h vs sustained elevation in the AOM non-exercised group, P = 0.002). Exercise preconditioning also induced colon-specific epigenetic reprogramming, including Mgmt promoter hypermethylation (27% increase, P = 0.0043) and 3-fold reduction in expression of the mutagenic deaminase Apobec3 (P < 0.0001). These molecular changes occurred without altering global LINE-1 methylation or body composition, suggesting targeted tissue adaptation rather than systemic effects. These results demonstrate that exercise preconditioning, not concurrent training, provides colon preneoplastic prevention by enhancing DNA repair efficiency and suppressing Apobec3, a key driver of genomic instability and chronic mutational signatures, during the critical window of carcinogen attack.