Endurance Exercise Prior To Tumor-bearing Regulates Proteolysis To Protect Against Tumor-mediated Skeletal Muscle Weakness

BACKGROUND: Tumor-bearing is associated with significant skeletal muscle weakness and wasting. While exercise has been shown to be beneficial for cancer survivors, less is known about the most beneficial timing of exercise within the cancer continuum nor the underlying beneficial mechanisms of exercise. Therefore, the purpose of this study was to determine whether exercise prior to tumor bearing (i.e., preconditioning) could offer myoprotection during tumor bearing. METHODS: Male mice were separated into groups: sedentary non-tumor (SED + NT), sedentary tumor (SED + T), treadmill non-tumor (TM + NT), and treadmill tumor (TM + T). Mice underwent an 8-week progressive endurance treadmill intervention (TM) or remained SED. At the end of the preconditioned TM intervention, all groups remained sedentary for 4 weeks. During this 4-week sedentary period, mice were implanted with tumor cells (T group; 5x10^5 LLC cells in flank) or remained non-tumor (NT). Skeletal muscle function was followed throughout the 12-week study and tissues were probed for potential protective mechanisms. RESULTS: Tumor bearing resulted in significant muscle weakness, and endurance exercise initiated prior to tumor-bearing protected against tumor-mediated skeletal muscle weakness and proteolysis. SED + T exhibited significantly worse muscle weakness compared to preconditioned TM + T mice (grip strength - SED + T: 163 g vs TM + T: 174 g; P < 0.05). This coincided with evidence of significant body wasting (decreased body mass and skeletal muscle) in SED + T that was not observed in TM + T. In addition, skeletal muscle proteolytic and metabolic signaling pathways (GDF-8/11, GDF-15, MuRF1, FoxO1) were significantly upregulated in SED + T skeletal muscle compared to TM + T, indicating a protective effect of preconditioning endurance exercise. CONCLUSION: Exercise initiated prior to tumor bearing elicits myoprotective effects - even after exercise has ceased - to protect against tumor-mediated muscle weakness and proteolysis. These data make an important case for the long-term benefits of an active lifestyle that last even after exercise is stopped (i.e., upon cancer diagnosis and treatment). Such information is critical in determining the safe and effective implementation of exercise in the clinical setting.