Voluntary Wheel Running Protects Against Cancer-mediated Skeletal Muscle Wasting And Inhibits Tumor Growth In Male C26 Adenocarcinoma Bearing Mice

Cancer cachexia, a multifactorial wasting syndrome, affects up to 80% of cancer patients. Due to the lack of diagnostic criteria, most patients progress undetected to late stages of cancer cachexia and become unresponsive to treatment. Exercise can slow the development of cancer cachexia. However, the most beneficial modality of exercise to protect against cancer cachexia and the underlying molecular pathways remain unknown. PURPOSE:To determine if voluntary wheel running protects against cancer-mediated skeletal muscle wasting and identify affected molecular pathways. METHODS: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 (WR + T). T groups were implanted with tumor cells (5x105 C26 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. Underlying molecular pathways in gastrocnemius tissue were 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 myoprotection 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). CONCLUSION:Data of this study provide evidence of tumor-suppressive and myoprotective effects of 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.