Rehabilitative Exercise Protects Against Tumor-mediated Declines In Cardiac And Skeletal Muscle Function In Male Mice

PURPOSE: Tumor-bearing can result in significant loss of lean muscle mass and strength, thus resulting in detrimental functional impairment. Increasing evidence suggests that exercise offers protective benefits for cancer patients; however, the exact mechanism of how exercise attenuates tumor-mediated muscle wasting to preserve muscle function is still unknown. Therefore, the purpose of this study was to 1) determine if rehabilitative exercise (voluntary wheel running) concurrent with tumor-bearing preserves muscle mass and function and 2) determine the underlying protective mechanisms. METHODS: Male mice were randomly assigned to groups: sedentary non-tumor (SED + NT), sedentary tumor (SED + T), wheel running non-tumor (WR + NT), and wheel running tumor (WR + T). On day 1, mice were inoculated with 5x10^5 Lewis lung carcinoma cells in the flank. During the 4-week study, WR mice groups had unlimited access to running wheels. Echocardiograms and grip strength tests were performed on days 0 and 28 to measure heart and skeletal muscle function. Tissues were probed for protective mechanisms. RESULTS: Male tumor-bearing mice (SED + T) displayed the poorest cardiac and skeletal muscle function among all groups. However, rehabilitative exercise (WR + T) protected against tumor-mediated declines in cardiac function (fractional shortening - SED + T: 41% vs WR + T: 53%, P < 0.001) as well as skeletal muscle function (decline in grip strength - SED + T: -26% vs WR + T: -6%, P < 0.01). Moreover, SED + T showed upregulation of MuRF1, Atrogin-1, and Beclin1 protein levels, all of which were downregulated in the WR + T group. In step with this finding, pAKT/AKT protein levels showed the opposite relationship (downregulated in SED + T vs upregulated in WR + T). Since these proteins play critical roles in the balance of muscle synthesis vs degradation, exercise’s ability to regulate these pathways may describe one mechanism by which rehabilitative exercise can preserve muscle and function. CONCLUSION: Rehabilitative exercise was shown to protect cardiac and skeletal muscle function while abrogating muscle wasting during cancer. The identification of cancer-mediated degradative pathways that can be rescued by exercise sheds important light on effective anti-muscle wasting therapies for cancer survivors.