Effects Of Tumor-Related Factors And Chemotherapy On Skeletal Muscle And The Protective Effects Of Exercise

Cancer patients often experience cachexia, a form of weight loss consisting mostly of skeletal muscle wasting. Muscle wasting leads to physical disability, poor quality of life, reduced tolerance to treatments and shorter survival. Although the causes of cancer-related muscle atrophy have been studied for decades, the exact mechanisms through which cancer and its treatments promote muscle wasting have yet to be defined. The overall aim of this dissertation is to examine the mediators of muscle wasting in cancer patients during their treatment and examine the modulatory role of exercise to maintain muscle size and function. To address these aims, we studied two different populations of cancer patients to examine the effects of tumor-related factors and chemotherapy to cause muscle atrophy using an in vitro skeletal muscle system. We examined whether tumor cells secrete factors to promote atrophy by evaluating the effects of tumor-conditioned media (CM) from murine and human lung tumor cells (hTCM) on cultured muscle myotubes. We hypothesized that conditioned media from murine and human tumor cells would reduce myotube myosin content a marker for atrophy, decrease mitochondrial content, and increase mitochondrial reactive oxygen species production (ROS), all of which have been reported in model systems using murine tumor cell CM. Cancer patients frequently receive chemotherapy, some of which are known to be myotoxic. Whether these drugs promote muscle wasting, however, is not clear. To address this question, we assessed skeletal muscle structure and protein expression in 13 women diagnosed with breast cancer, who were receiving adjuvant chemotherapy following tumor resection, and 12 non-diseased controls. Furthermore, we evaluated the role of individual chemotherapeutics (doxorubicin and paclitaxel) to cause atrophy, mitochondrial loss and increased reactive oxygen species production in C2C12 cultured muscle myotubes, as well as the modifying effects of a mitochondrial-targeted anti-oxidant. Pre-clinical models show that exercise protects against the deleterious effects of chemotherapy, although the mechanisms underlying these effects are not known. To address this question, we utilized an in vitro model of exercise by treating C2C12 myotubes with doxorubicin (DOX; 0.2 μM for 3 days) with or without daily bouts of electrical field stimulation (STIM). Our results advance the field by showing that the treatments, and not tumor-related factors, promote skeletal muscle atrophy. Moreover, exercise is effective at countering the deleterious effects of chemotherapy and acts via mechanotransductive signaling pathways