Physical Activity Protects Against C26 Tumor-mediated Cardiac Dysfunction And Atrophy

There is mounting evidence that cancer cachexia causes cardiac dysfunction which may lead to heart failure. Since cancer cachexia affects up to 80% of cancer patients, it is critical to understand the underlying mechanisms of the disease and to determine possible protective interventions. While physical activity has been shown to be beneficial for cancer survivors, the underlying beneficial mechanisms remain poorly understood. PURPOSE: To determine the protective potential of physical activity on tumor-mediated cardiac dysfunction and atrophy. METHODS: Male Balb/c mice (10 weeks old) were randomly assigned to one of 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 (5x10^5 C26 cells in flank). Animals in WR groups underwent a 4 week physical activity intervention while SED animals remained sedentary. Cardiac function was assessed via echocardiography. RESULTS: Hearts from SED + T were significantly smaller compared to all other groups (P < 0.05). Echocardiography revealed SED + T resulted in significant thinning of left ventricle walls compared to NT groups (P < 0.05) and significantly worse cardiac function compared to all other groups (fractional shortening SED + T: 36%, P < 0.05 vs all other groups). Hearts from SED + T also exhibited significantly elevated levels atrophy proteins MuRF1 and Atrogin1, and inflammatory proteins GDF15 and GDF 8/11 compared to NT groups. These data coincide with physical activity resulting in a 48% decrease in tumor mass (P < 0.05). CONCLUSION: These data demonstrate that tumor bearing can elicit a severe cardiac wasting and dysfunction phenotype driven by inflammation (GDF15, GDF8/11) and atrophy (MuRF1, Atrogin1) signaling. Physical activity concurrent with tumor bearing appears to offer cardioprotection against tumor-mediated cardiac wasting by reducing cardiac inflammation, which may be achieved in part by severely stunting tumor growth. Such data may provide valuable insight into understanding how physical activity and exercise may influence muscle and tumor function and signaling, and the possibility of synergistic effects of anticancer treatments and prescriptive exercise.