This is a revised application to our parent grant "Beta-catenin regulation of skeletal muscle hypertrophy" being submitted in response to RFA-AR-13-003, NIAMS Building Interdisciplinary Research Team (BIRT) Revision Awards. We have established an interdisciplinary research team with Dr. Dasarathy, a transplant hepatologist with a joint appointment in the Department of Pathobiology at the Lerner Research Institute in the Cleveland Clinic. In addition to his clinical duties, Dr. Dasarathy heads an active research program investigating the molecular and metabolic mechanisms underlying skeletal muscle sarcopenia induced by cirrhosis. This work has found that hyperammonemia caused by cirrhosis leads to sarcopenia as the result of increased myostatin expression and decreased protein synthesis. Preliminary data in C2C12 myotubes showed that over- expression of ?-catenin was able to block the increase in myostatin expression in response to ammonium. Based on this preliminary data, we propose in this revision to test the hypothesis that over-expression of ?-catenin will prevent the deleterious effects (decreased protein synthesis, loss of muscle mass) caused by hyperammonemia-induced myostatin expression. To test this hypothesis, the following aim will be pursued: Determine if over-expression of ?-catenin is able to protect skeletal muscle against hyperammonemia. Both in vitro and in vivo experiments will be performed to determine if over-expression of ?-catenin is capable of mitigating the deleterious effects of myostatin expression induced by ammonium. The proposed in vitro and in vivo studies are expected to demonstrate that over-expression of ?-catenin is capable of rescuing the sarcopenic phenotype by repressing myostatin expression. These proposed experiments extend the scope of the original proposal beyond the regulation of ribosome biogenesis by ?-catenin to examine the ability of ?-catenin to prevent cirrhosis-induced sarcopenia. The notion that ?-catenin may provide a mechanism for rescuing the loss of muscle mass associated with cirrhosis has significant clinical implication given the recent identification of small molecules capable of activating ?-catenin signaling. In addition, the data generated under this award are expected to serve as the basis for an R01 grant application in response to PA-12-208 "Functions of Skeletal Muscle beyond Contractions" which seeks to promote research that "leads to novel strategies to protect or treat common diseases and conditions".
The loss of skeletal muscle mass (sarcopenia) associated with cirrhosis has an adverse affect on the survival, quality of life and outcome success following liver transplantation. The purpose of this revision is to test the hypothesis that over-expression of ?-catenin can prevent cirrhotic sarcopenia.