Date of Graduation
Doctor of Philosophy in Cell & Molecular Biology (PhD)
Second Committee Member
Third Committee Member
Cancer-induced muscle wasting, otherwise known as cancer-cachexia, is a wasting syndrome that occurs in approximately 80% of cancer patients that is the primary cause of death for 22%-30% of cancer cases. Cancer-cachexia may be metabolically induced; therefore, the central hypothesis of this dissertation is mitochondrial degeneration occurs before cancer-cachexia, and increased oxidative stress because of mitochondrial degeneration in muscle may instigate cancer-cachexia. Lewis Lung Carcinoma cells (LLC) or PBS (control) were injected into the hind-flank of C57Bl6/J mice at 8 wks age, and tumor allowed to develop for 1, 2, 3 or 4 wks. Mitochondrial quality, function, ROS emission, protein synthesis and protein breakdown were assessed. LLC Conditioned Media (LCM) treatment of C2C12 myotubes was used to analyze cancer-cachexia in-vitro. Data were analyzed by one-way (animal experiments) or two-way (cell culture experiments) ANOVA with Student-Newman Kuels post hoc test. Cachectic muscle loss and decreased oxidative capacity was evident only at 4 wks post-tumor implantation. Mitochondrial function decreased by ~25% by 3wks after tumor implantation. Mitochondrial degeneration (MitoTimer) was evident by 2 weeks LLC compared to PBS control. Mitochondrial ROS production was elevated by ~50% to ~100% when compared to PBS at 1-3 wks post-tumor implantation. Mixed FSR Protein synthesis was ~40% lower in 4 wk tumor-bearing mice when compared to PBS controls. Mitochondrial quality control and protein turnover signaling were dysregulated throughout the progression of cancer-cachexia. Ubiquitin content was elevated by ~50% 4wks after tumor implantation. ERK and p38 MAPK phosphorylation was 4 and 3 fold greater than control muscle 4 wks following tumor implantation, respectively. MitoT treatment and inhibition of p38 MAPK ameliorated LCM-induced loss of myotube diameter. These data provide novel insight into mechanisms which may induce cancer-cachexia.
Brown, Jacob Levi, "Cancer-Induced Muscle Wasting" (2018). Theses and Dissertations. 2650.