Exercise Dependent Skeletal Muscle Plasticity and Signaling in Cancer Cachexia

Approximately half of all cancer patients undergo cachexia, a paraneoplastic condition characterized by unintended weight loss, skeletal muscle atrophy, and impaired physical function. Using a pre-clinical mouse model, we compared the effects of high-tension muscle loading (i.e. resistance exercise) and low-tension muscle loading (i.e. aerobic exercise). We hypothesized that high tension exercise would: 1) ameliorate the adverse effects of cachexia on body composition, functional performance, and muscle size to a greater extent than low tension exercise; and 2) induce changes in gene expression profiles and muscle signaling events to favor protein synthesis and suppress protein degradation. Twelve-month old Balb/c mice were initially assigned to control (n=16), low tension exercise (Low Ex, n=16), or high tension exercise (High Ex, n=16). Mice in Low and High Ex groups performed wheel running and weighted ladder climbing, respectively. Wheel running was implemented using a motorized wheel at speeds increased progressively to 7 m/min for 60 min/d, 5 d/wk. To achieve resistance overload, mice were subjected to weighted ladder climbing 3 d/wk. The initial resistance was 50% of body weight with 10% increases bi-weekly. After 8 weeks of training, half of the mice in each initial group were given a subcutaneous injection of colon-26 (C26) tumor cells, followed by an additional 2.5 weeks of training. Overall, 6 groups were studied including: 1) Control (n=8), 2) C26 (n=8), 3) Low Ex (n=8), 4) Low Ex + C26 (n=8), 5) High Ex (n=8), and 6) High Ex + C26 (n=8). Body composition and function were evaluated before and after exercise training while the gastrocnemius and plantaris muscles were excised at sacrifice and analyzed by RT-PCR, western blotting, and histological techniques. Two mice from the High Ex + C26 group (25%) met the endpoints for early euthanasia while all other tumor bearing groups completed the study. For sensorimotor function, significant performance declines occurred in all groups except Low Ex + C26 (Control: -16%, p=0.006; C26: -13%, p=0.001; Low Ex + C26: -1%, p=0.769; High Ex + C26: -23%, p=0.003), with post-training values being greater in Low Ex + C26 compared to C26 (+12%, p=0.08) and High Ex + C26 (+20%, p=0.01). Significant absolute strength declines were observed in all groups (Control: -7%, p=0.021; C26: -23%, p=0.001; Low Ex + C26: -14%, p=0.003; High Ex + C26: -19%, p=0.002), with lower post-values in C26 (-19%, p=0.004) versus Control but not in Low Ex + C26 and High Ex + C26 when compared to Control (p>0.05). When strength was normalized to body mass, significant pre to post reductions were observed in all groups (Control: -7%, p=0.01; C26: -21%, p=0.005; High Ex + C26: -10%, p=0.004) except Low Ex + C26 (p>0.05), with lower post-measurements in C26 (-18%, p=0.02) but not Low Ex + C26 and High Ex + C26 when compared to Control (p>0.05). Gastrocnemius mass was significantly smaller in C26 (-13%, p=0.004), Low Ex + C26 (-14%, p=0.002), and High Ex + C26 (-19%, p<0.001) when compared to Control. There were no differences in gastrocnemius mass amongst the three tumor bearing groups (p>0.05). Similarly, myofiber cross-sectional area of the gastrocnemius was significantly lower (p<0.001) in C26 (1150.77 ± 82.85 µm2; -46%), Low Ex + C26 (1431.20 ± 132.24 µm2; -32%), and High Ex + C26 groups (1266.61 ± 114.86 µm2; -40%) when compared to Control (2118.15 ± 58.79 µm2). No significant differences were noted between the three tumor bearing groups (p>0.05). There was an enlargement of spleen mass in C26 (+195%, p<0.001), Low Ex + C26 (+114%, p<0.001), and High Ex + C26 (+203%, p<0.001) when compared to Control. However, spleen mass in Low Ex + C26 was significantly lower than the other tumor bearing groups including C26 (-27%, p=0.008) and High Ex + C26 (-29%, p=0.008). IGF-IEa mRNA abundance in the plantaris of High Ex + C26 significantly exceeded Control (+79%, p=0.016) while its expression in Low Ex + C26 (+62%, p=0.053) and C26 (+51%, p=0.066) tended to be greater than Control. Regarding the myogenic regulatory factors, transcript levels of myogenin in C26 mice were not different from Control (p>0.05); however, they were significantly greater in High Ex + C26 versus Control (+126%, p=0.036) and C26 (+150%, p=0.018). Overall, these findings refute the hypothesis that resistance loading would provide the greatest degree of protection against cancer cachexia. Given that 25% of High Ex + C26 mice became moribund before the end of the experiment, the possibility exists that high levels of muscle loading may contribute to declines in health. The induction of myogenin by High Ex + C26 only, coupled with increased IGF-I expression provides some degree of support for this notion as it suggests that cachectic muscle exposed to high forces may be activating compensatory mechanisms to cope with the dual stressors imposed by tumor and mechanical loads that ultimately ends up being futile. In contrast, low tension loading preserved physical function and possibly reduced inflammation, suggesting that aerobic exercise performed at a regular weekly frequency may contain therapeutic value for patients with cancer cachexia, albeit in the absence of muscle mass retention.