BACKGROUND: Up to 80% of cancer patients suffer from cancer cachexia, an often-fatal wasting syndrome characterized by severe muscle wasting. Due to the lack of diagnostic criteria, most patients progress undetected to late stages of cancer cachexia and become unresponsive to traditional treatment. Exercise can slow the development of cancer-mediated muscle wasting. However, the most beneficial modality of exercise as a protective measure against cancer cachexia and the underlying molecular pathways remain understudied. PURPOSE: To determine if voluntary wheel running can protect against cancer-mediated skeletal muscle wasting and identify affected molecular pathways. METHODS: Male Balb/c mice were randomly separated into four groups, sedentary non-tumor bearing (SED+NT), sedentary tumor bearing (SED+T), wheel run non-tumor bearing (WR+NT), and wheel run tumor bearing groups (WR+T). T groups were implanted with tumor cells (5x105 C26 adenocarcinoma cells in flank), while NT groups remained non-tumor for 4 weeks. During the 4 weeks, WR groups had unlimited access to running wheels while SED mice remained sedentary. Total distance run (km) was measured throughout the activity period. Body weight, grip strength and tumor evaluations were taken at baseline and sacrifice. After 4 weeks, muscle, spleen, and tumor tissue were collected and weighed. To determine underlying molecular pathways, gastrocnemius tissue was analyzed via Western Blotting. RESULTS: Tumor bearing resulted in an 11% decline in body mass (P<0.05), indicating progressive cancer cachexia. WR+T mice did not experience a significant decline in body mass over time. Tumor bearing also resulted in a 15% decrease in grip strength (P<0.05) but was preserved in exercised mice. Exercise-mediated protection of skeletal muscle coincided with lower expression of muscle wasting-associated proteins Atrogin1, MuRF1, GDF15 and GDF8/11 in WR+T compared to SED+T mice. Wheel running resulted in a 48% decrease in tumor mass and a 63% decrease in tumor volume compared to SED tumors (P<0.05). CONCLUSIONS: Data of this study provide evidence of tumor-suppressive and myoprotective effects of wheel running exercise against cancer-mediated skeletal muscle wasting. Exercise seems to protect muscle mass and function, regulate molecular muscle wasting pathways, and stunts tumor growth. These findings are crucial in identifying the significance of exercise as a non-pharmacological, protective measure against cancer cachexia.

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