Androgen-Mediated Reversal of Muscle Wasting

雄激素介导的肌肉萎缩逆转

基本信息

批准号：
7238439
负责人：
CHARLES G. WIDMER
金额：
$ 21.98万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7238439
关键词：
Adult Adverse effects Aging Androgen Receptor Androgens Animals Anterior Binding Biological Assay Biological Availability Castration Chronic Obstructive Airway Disease Complex Condition Data Development Disease Exposure to Fiber Flutamide Goals Growth Factor HIV Healthcare Hepatic Hormones Hypertrophy Kidney Limb structure Malignant neoplasm of prostate Masseter Muscle Mediating Methods Modeling Molecular Morbidity - disease rate Muscle Muscle Fibers Muscle satellite cell Muscular Dystrophies Myosin Heavy Chains NG-Nitroarginine Methyl Ester Nitric Oxide Nitric Oxide Synthase Numbers Oral Pathway interactions Personal Satisfaction Phenotype Population Process Production Prostate Protein Biosynthesis Proteins Quality of life RNA Recovery Research Risk Role Seminal Vesicles Signal Transduction Skeletal Muscle Speed Stimulus Stretching Supplementation Testing Testosterone Therapeutic Intervention Tissues base bone cross reactivity deprivation falls health care service utilization in vitro Model in vivo levator ani muscle male muscle hypertrophy muscle strength neutralizing antibody novel novel strategies novel therapeutics numb protein receptor receptor binding response sarcopenia satellite cell selective androgen receptor modulator size wasting

项目摘要

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.

描述（由申请人提供）：肌肉浪费是一个普遍的医疗保健问题，在成年人口中发病率很高，会导致肌肉力量丧失，增加跌倒的脆弱性，增加医疗保健利用率和生活质量降低。为了开发新的疗法，可以实现肌肉浪费的最佳逆转，在分解代谢过程和合成代谢过程中了解细胞和分子的变化非常重要。已证明睾丸激素（可能是选择性雄激素受体调节剂或SARMS）可以诱导卫星细胞激活，这是肌肉纤维肥大/新纤维形成的第一步，但该机制尚不清楚。对卫星细胞激活的更全面了解将是我们为制定逆转肌肉浪费的新型策略的长期目标做出的重要贡献。拟议的研究的目标是：（1）比较和对比雄激素剥夺以及随后睾丸激素或SARM补充对肌肉的细胞和分子作用，对雄激素有不同的反应；（2）检查雄激素在通过NOS/HGF途径中介导卫星细胞激活中的假设作用。方法包括肌肉纤维测定，以评估肌核数和蛋白质合成的变化；涉及卫星细胞激活的特定因素的蛋白质测定；和分子测定，以确定RNA信息的变化，以表达与雄激素和卫星细胞激活有关的因素。了解雄激素对肌肉卫星细胞的信号传导和随后的激活是朝着肌肉浪费条件进行可预测管理的重要里程碑。导致卫星细胞激活的途径可能很复杂，并且可能会根据特定的刺激而变化。拟议的研究的意义将是探索已知的刺激，雄激素，并确定一种对新型治疗干预措施的发展有价值的途径。肌肉浪费是一个普遍的医疗保健问题，导致肌肉力量丧失，跌倒的机会增加，医疗保健使用增加以及生活质量的降低。睾丸激素治疗逆转肌肉浪费，但副作用很多。为了开发将逆转肌肉浪费的新治疗方法，重要的是要在浪费和肥大期间了解细胞和分子的变化。拟议的研究将探索已知的刺激，睾丸激素或类似睾丸激素的化合物（SARM），以识别作用途径并允许开发新的肌肉浪费治疗方法。