Effects of low intensity treadmill exercise during cancer cachexia in the male tumor bearing mouse

Cancer cachexia is a complex metabolic wasting syndrome that affects up to 80% of cancer patients and results in death in up to one-third of cancer patients. It is characterized by extreme, progressive skeletal muscle loss, cardiac dysfunction, as well as an abnormal metabolism. While research is growing in this field, there are still no clear diagnostic criteria or treatments for this condition and the mechanisms of cancer cachexia-associated muscle wasting are not well understood. Cancer cachexia remains an untreated condition with irreversible effects, poor prognosis of survival and a significantly reduced quality of life. Therefore, a great need exists to better understand this disease as well as possible treatment interventions. Research has shown that exercise interventions as part of cancer treatment have the potential to attenuate cachexia-associated muscle loss, inhibit tumor growth and improve quality of life. Most aerobic exercise interventions are easily accessible and affordable for cancer patients. Many questions remain regarding the most effective timing, extent, and intensity of exercise as a protective measure against cancer cachexia. Therefore, it is necessary to determine the effectiveness of different types and intensities of exercise to be able to develop a suitable exercise treatment to be used in conjunction with chemotherapy and nutritional interventions. Specifically, the effect of low intensity aerobic exercise as a treatment intervention needs to be assessed, as most cancer patients experience a lack of energy, physical fitness, self-esteem, and reduced quality of life, making it difficult for them to participate in high-intensity exercise. Therefore, the purpose of this study was to determine if low intensity treadmill exercise can act as a protective measure and treatment intervention against cancer cachexia in the male tumor bearing mouse. To test this, 28 male mice were randomly selected and separated into four groups: sedentary non-tumor bearing (SED+NT; n=7), sedentary tumor bearing (SED+T; n=7), low intensity treadmill exercised non-tumor bearing (TM+NT; n=7), and low intensity treadmill exercised tumor bearing (TM+T; n=7). Mice were injected with tumor cells (T group; 5x105 LLC cells in flank) or remained non-tumor bearing (NT) for 4 weeks. During the 4 weeks, mice underwent a low intensity treadmill exercise training protocol (TM) or remained sedentary (SED). To examine the protective effects of exercise, grip strength, echocardiography, and tumor evaluations were taken at baseline and 4-week time points. Gastrocnemius, heart, and tumor tissues were collected 24 hours after the last exercise session of the protocol for further analyses. To better understand the molecular mechanisms and influence of autophagy behind cancer cachexia and exercise, Western Blotting and autophagic flux analyses were performed on these tissues. SED+T mice exhibited the worst skeletal muscle function (grip strength: -23%) and cardiac function (fractional shortening: -8%) compared to all other groups, whereas TM+T mice showed a preservation of grip strength (-15%) and fractional shortening (-5%). Additionally, TM+T mice exhibited significantly smaller tumor masses and volumes (P < 0.05) compared to the SED+T group. Protein expression analysis via Western Blotting as well as autophagic flux analysis indicated potential influence of exercise on regulating autophagy, which is involved in regulating homeostasis between protein synthesis and degradation. The data indicate potential effects of low intensity treadmill exercise on preserving muscle function and stunting tumor growth in cachectic mice. Low intensity exercise may be an effective and accessible treatment intervention for cancer patients. This information is crucial in understanding the significance of exercise in cancer patients and elucidating the importance of timing and intensity of exercise as a protective measure against the detrimental effects of cancer cachexia