Beta Catenin Regulation of Skeletal Muscle Hypertrophy

描述（由申请人提供）：这是我们根据RFA-AR-13-003， NIAMS建设跨学科研究团队（BIRT）修订奖提交的母基金“β -catenin调控骨骼肌肥大”的修订申请。我们与Dasarathy博士建立了一个跨学科的研究团队，他是克利夫兰诊所勒纳研究所病理生物学部门的移植肝病学家。除了他的临床职责，Dasarathy博士领导一个积极的研究项目，调查由肝硬化引起的骨骼肌肌肉减少症的分子和代谢机制。这项工作发现肝硬化引起的高氨血症导致肌肉生成抑制素表达增加和蛋白质合成减少。在C2C12肌管中的初步数据显示，过表达¿-catenin能够阻断氨胁迫下肌生长抑制素表达的增加。基于这一初步数据，我们提出在本次修订中验证一个假设，即过度表达¿-catenin可以防止高氨诱导的肌肉生长抑制素表达引起的有害影响（蛋白质合成减少，肌肉质量损失）。为了验证这一假设，将追求以下目标：确定过度表达¿-catenin是否能够保护骨骼肌免受高氨血症的影响。体外和体内实验都将进行，以确定过度表达¿-catenin是否能够减轻铵诱导的肌肉生长抑制素表达的有害影响。在体外和体内的研究有望证明过度表达¿-catenin能够通过抑制肌肉生长抑制素的表达来挽救肌肉减少表型。这些拟议的实验扩展了最初提议的范围，超出了通过-catenin调节核糖体生物发生的范围，以检查-catenin预防肝硬化诱导的肌肉减少症的能力。鉴于最近的鉴定，¿-catenin可能提供了一种挽救肝硬化相关肌肉质量损失的机制，这一概念具有重要的临床意义

DESCRIPTION (provided by applicant): 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".