Exercise training alters circadian clock dynamics in cancer-bearing male mice

Alterations in circadian timing mechanisms are increasingly recognized as contributing to tumor initiation and progression. Moreover, evidence indicates that malignant cells can interfere with the expression and synchronization of core clock genes. Physical exercise is a potent circadian modulator in peripheral tissues, yet its effects on tumor rhythmicity remain unclear. To investigate whether the timing of exercise modulates circadian gene expression and tumor growth in a mouse model of lung cancer. Male C57BL/6J mice bearing Lewis lung carcinoma (LLC) were subjected to treadmill moderate intensity continuous training (55%-65% of maximum speed) at either a fixed (ZT2) or alternating Zeitgeber times (ZTAlt) for 3 weeks. Tumor growth, gene expression of Per1, Per2, Per3, and Rev-Erbα, and TNF-α concentrations were analyzed at six circadian time points. Rhythmic parameters were estimated using Cosinor analysis. Scheduled exercise at ZT2 significantly increased the amplitude of Per2, Per3, and Rev-Erbα expression rhythms in tumor tissue. No rhythmic enhancement was observed in the ZTAlt group. TNF-α acrophase was shifted in the ZT2 group, indicating a temporal immunomodulatory effect. Consistently performing exercise at the same time of day enhances tumor circadian clock genes rhythmicity, supporting chrono-exercise as a potential non-pharmacological adjuvant in cancer treatment.