Androgen-Mediated Reversal of Muscle Wasting

描述(申请人提供)：肌肉萎缩是一种普遍存在的保健问题，在成年人中发病率很高，会导致肌肉力量丧失，更容易摔倒，卫生保健利用率增加，生活质量下降。为了开发新的治疗方法，以实现肌肉萎缩的最佳逆转，重要的是了解肌肉纤维在分解代谢和合成代谢过程中的细胞和分子变化。睾酮(以及可能的选择性雄激素受体调节剂或SARM)已被证明诱导卫星细胞激活是肌肉纤维肥大/新纤维形成的第一步，但其机制尚不清楚。对卫星细胞激活的更全面的了解将对我们开发扭转肌肉萎缩的新策略的长期目标做出重大贡献。这项研究的目标是：(1)比较和对比雄激素剥夺和随后补充睾酮或SARM对对雄激素反应不同的肌肉的细胞和分子效应；(2)检验雄激素通过NOS/HGF途径介导卫星细胞激活的假设作用。方法包括：肌纤维分析以评估肌核数量和蛋白质合成的变化；参与卫星细胞激活的特定因素的蛋白质分析；以及确定与雄激素和卫星细胞激活相关的因子表达的RNA信息的变化的分子分析。了解雄激素对肌肉卫星细胞的信号和随后的激活是迈向可预测的肌肉萎缩状况管理的重要里程碑。导致卫星细胞激活的途径可能是复杂的，可能会根据特定的刺激而变化。这项拟议的研究的意义将是探索一种已知的刺激因素--雄激素，并确定一种可能对开发新的治疗干预措施有价值的途径。肌肉萎缩是一个普遍的医疗保健问题，导致肌肉力量丧失、摔倒的几率增加、医疗保健使用量增加和生活质量下降。睾丸素治疗可以逆转肌肉萎缩，但有许多副作用。为了开发逆转肌肉萎缩的新疗法，了解肌肉纤维在萎缩和肥大过程中的细胞和分子变化是很重要的。这项拟议的研究将探索一种已知的刺激因素，即睾酮或类似睾酮的化合物(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.