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Thomas A. Blackwell1, Jacob L. Brown1, David E. Lee1, Megan E. Rosa-Caldwell1, Richard A. Perry Jr. 1, Lemuel A. Brown1, Michael P. Wiggs2, Tyrone A. Washington1, & Nicholas P. Greene1 1University of Arkansas, Fayetteville, Arkansas; 2University of Texas at Tyler, Tyler, Texas

Cancer is a major public health problem in the US and the world. In 2013 there were an estimated 1,660,290 new cases of cancer in 2013 alone. Severe weight and muscle loss (cancer-cachexia) is accepted as a common side effect of most cancer, and is estimated to be responsible for 20-40% of cancer-related deaths. The mechanisms that control the development of cancer-cachexia are not well understood. In order for muscle wasting to occur, there must be either a decrease in myogenic factors or an increase in catabolic factors. Most investigations of cancer-cachexia focus on the post-cachectic state and do not examine the progression of the condition. PURPOSE: The purpose of this study is to determine the roles of classical myogenic (MyoD and Myogenin; regulators of myocyte proliferation and differentiation), and catabolic (Atrogin and MuRF; E3 ubiquitin ligases regulating ubiquitin mediated protein degradation) factors in the onset of Cancer-Cachexia. METHODS: Lewis Lung Carcinoma cells (LLC) or Phosphate Buffered Saline (PBS, control) were injected into the hind-flank of normal wildtype C57BL6/J mice at 8 weeks of age, and tumor allowed to develop for 1, 2, 3, or 4 weeks. MyoD, Myogenin, Atrogin, and MuRF were analyzed using RT-PCR for all 5 groups (1, 2, 3, 4 week LLC and PBS). RESULTS: MyoD and Myogenin were significantly lower ~50% in weeks 1 and 2 post-tumor implantation, and returned to baseline for weeks 3 and 4. Atrogin was significantly greater ~3.5-fold in week 4, while MuRF was significantly higher ~2.3-fold in week 3 and ~3.8-fold in week 4 post-tumor implantation. CONCLUSION: Myogenic factors MyoD and Myogenin are significantly repressed only one week following tumor implantation suggesting repressed myogenesis. Whereas classic catabolic factors are not impacted until later in progression of cancer-cachexia. MyoD seems to promote expression of Atrogin and MuRF in cancer-cachexia models.

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