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Kyle L. Rankin1, Wesley S. Haynie1, Megan E. Rosa-Caldwell1, Katarina A. Bejarano1, Seongkyun Lim1, Lemuel A. Brown1, Richard A. Perry1, Nicholas P. Greene1, Tyrone A. Washington1 1University of Arkansas, Fayetteville, Arkansas

Nearly 80% of cancer patients are afflicted with cancer-cachexia, which is associated with wasting of lean body mass and is a prevalent cause of death among cancer patients. The amino acid leucine has been shown to promote muscle growth by augmenting protein synthesis through mTOR activation. Therefore, supplementation of leucine could prove beneficial for mitigating skeletal muscle wasting during cancer cachexia progression. PURPOSE: To determine the effect of leucine supplementation on cancer cachexia in APC Min/+ (APC) mice. METHODS:9 APC and 9 C57BL/6J Wild Type (WT)male litter mates were used in this study. Within each of these two groups, 4 were given water (APC-NL) and 5 were given 1.5% leucine-supplemented water(APC-L), with ad libitum access to food and water. Gastrocnemius(GA)muscle and tibias (TI) were extracted at ~14-21 weeks of age, or when mice became moribund. Tissue was homogenized and analyzed for genetic expression via RT-qPCR. Data were analyzed via Two-Way ANOVA, and following a significant F-test, a Fisher’s LSD post-hoc was run. RESULTS: Body weight for APC-NL mice was ~14% lower than both WT-NL and WT-L(p<0.05).Bodyweight for APC-L mice was ~25% lower than both WT-NL and WT-L (p<0.05).Gastrocnemius mass for APC mice was ~33% lower than both WT-NL and WT-L(p<0.05). There were no differences in GA mass/TI length for either WT-NL or WT-L. APC-NL GA mass/TI length was ~25%lower than both WT-NL and WT-L, and GAmass/TI length for APC-L was ~20% lower than the APC-NL group(p<0.05). There was no difference in expression of MuRF-1across all groups.IL-6expressionin the APC-NL group was~1-fold greater compared to both WT-NL and WT-L(p<0.05).IL-6expression in APC-L was ~1-fold greater than the APC-NL group(p<0.05).There was no statistical difference between WT-NL, WT-Land APC-NL for Atrogin-1expression, but there was a ~6-fold increase in Atrogin-1expression in APC-L compared to both WT-NL and WT-L(p<0.05).CONCLUSION: Cancer cachexia has previously shown marked increases in skeletal muscle atrophy, commonly through atrophy-related genes such as Atrogin-1and MuRF-1, as well as IL-6. Our results indicate leucine supplementation may exacerbate skeletal muscle wasting and increase these atrophic genes and atrophic signaling in conjunction with an already cachectic environment during cancer cachexia.

ACKNOWLEDGEMENTS: This study was funded by the Arkansas Biological Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, and by the National Institutes of Health, Award number: R15 AR069913/AR/NIAMS.

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