Date of Graduation

5-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Biological Sciences

Advisor

Nicholas Greene

Committee Member

Sami Dridi

Second Committee Member

Tyrone Washington

Third Committee Member

Jeffrey Wolchok

Keywords

Muscle, Skeletal

Abstract

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.

Available for download on Saturday, April 20, 2019

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