Androgen-Mediated Reversal of Muscle Wasting

描述（由申请人提供）：肌肉萎缩是一种普遍的医疗保健问题，在成年人群中发病率较高，并导致肌肉力量丧失、福尔斯脆弱性增加、医疗保健利用增加和生活质量降低。为了开发新的疗法，将实现肌肉萎缩的最佳逆转，重要的是要了解细胞和分子的变化，肌肉纤维在分解代谢和合成代谢过程。已证明替吉奥（和可能的选择性雄激素受体调节剂或SARM）诱导卫星细胞活化作为肌纤维肥大/新纤维形成的第一步，但机制尚不清楚。对卫星细胞激活的更全面的了解将对我们开发逆转肌肉萎缩的新策略的长期目标做出重大贡献。拟议研究的目标是：（1）比较和对比雄激素剥夺和随后的睾酮或SARM补充对肌肉的细胞和分子效应，对雄激素具有不同的反应性;（2）检查雄激素通过NOS/HGF途径介导卫星细胞活化的假设作用。方法包括评估肌纤维数量和蛋白质合成变化的肌纤维测定;参与卫星细胞活化的特定因子的蛋白质测定;以及确定与雄激素和卫星细胞活化相关的因子表达的RNA信息变化的分子测定。了解雄激素对肌肉卫星细胞的信号传导和随后的激活是对肌肉萎缩状况进行可预测管理的重要里程碑。导致卫星细胞活化的途径可能是复杂的，并且可能根据特定的刺激而变化。拟议研究的意义将是探索一种已知的刺激，雄激素，并确定一种对开发新的治疗干预措施有价值的途径。肌肉萎缩是一种普遍的健康护理问题，导致肌肉力量损失、福尔斯机会增加、医疗保健使用增加和生活质量降低。睾酮治疗可以逆转肌肉萎缩，但有许多副作用。为了开发新的治疗方法，将扭转肌肉萎缩，重要的是要了解细胞和分子的变化，肌肉纤维在萎缩和肥大。这项拟议的研究将探索一种已知的刺激，睾酮或睾酮样化合物（SARM），以确定作用途径，并允许开发新的肌肉萎缩治疗方法。

DESCRIPTION (provided by applicant): Muscle wasting is a prevalent health care problem that has a high morbidity in the adult population and causes a loss of muscle strength, increased vulnerability to falls, increased health care utilization and a reduced quality of life. In order to develop novel therapies that will achieve optimal reversal of muscle wasting, it is important to understand cellular and molecular changes to the muscle fiber during both catabolic and anabolic processes. Testosterone (and presumably selective androgen receptor modulators or SARMs) has been shown to induce satellite cell activation as a first step in muscle fiber hypertrophy/new fiber formation, but the mechanism is unknown. A more complete understanding of satellite cell activation would be a significant contribution towards our long term goal of developing novel strategies for reversal of muscle wasting. The goals of the proposed studies are: (1) to compare and contrast the cellular and molecular effects of androgen deprivation and subsequent testosterone or SARM supplementation on muscles with varying responsiveness to androgens; and (2) to examine the hypothesized role of androgens in mediating satellite cell activation through a NOS/HGF pathway. Methods include muscle fiber assays to evaluate the changes in myonuclear number and protein synthesis; protein assays of specific factors involved in satellite cell activation; and molecular assays to determine changes in RNA message for expression of factors related to androgens and satellite cell activation. Understanding the signaling and subsequent activation of muscle satellite cells by androgen is an important milestone towards the predictable management of muscle wasting conditions. Pathways leading to satellite cell activation are likely to be complex and may vary according to a particular stimulus. The significance of the proposed research will be to explore a known stimulus, androgen, and identify a pathway that can be valuable for the development of novel therapeutic interventions. Muscle wasting is a widespread health care problem causing a loss of muscle strength, increased chance of falls, increased health care use and a reduced quality of life. Testosterone treatment reverses muscle wasting but has many side effects. In order to develop new treatments that will reverse muscle wasting, it is important to understand cellular and molecular changes to the muscle fiber during both wasting and hypertrophy. The proposed research will explore a known stimulus, testosterone or testosterone-like compound (SARM), to identify the pathway of action and allow for the development of new treatments for muscle wasting.