Cancer cachexia, characterized by severe body weight loss, negatively affects patient quality of life and survival. Although moderate exercise benefits healthy and chronically ill individuals, and the effect of exercise in cachexia generally appears beneficial, conflicting results have been reported in cancer-associated cachexia.

This study examined the effects of moderate aerobic exercise in a rat cancer model, focusing on molecular crosstalk among tumors, serum, and skeletal muscle. Male Sprague-Dawley rats were divided into Non-Cancer, Cancer, and Cancer + Exercise (Ex) groups.

Cancer was induced with an intraperitoneal injection of 7,12-dimethylbenz[a]anthracene (DMBA), and the Cancer + Ex group completed an eight-week treadmill regimen. Tibialis anterior muscle, serum, and tumor tissues were analyzed by RNA sequencing.

DMBA injection produced sarcoma-like tumors, reduced body weight, elevated inflammatory mediators, and activated muscle atrophy genes (Fbxo32). Exercise led to progressive intolerance, further weight loss, lower muscle mass, and larger tumors.

Transcriptomic profiling revealed exacerbated cachexia signatures and suppressed energy metabolism genes in exercised cancer rats. Bioinformatic analysis of serum proteins and tissue transcriptomes identified enhanced chemokine-receptor signaling, including pro-tumorigenic (CXCL6_CXCR2) and pro-cachexia (CCL19_CXCR3, CCL5_CCR3, CXCL11_CXCR3) interactions.

These findings suggest that in a pro-inflammatory cancer context, late-onset moderate exercise may worsen cachexia and stimulate tumor progression. Thus, exercise protocols should be cautiously tailored in cancer settings.