HORMONAL REGULATORS OF MUSCLE AND METABOLISM IN AGING

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。摘要：老年人的骨骼肌质量、肌肉力量和日常生活功能逐渐丧失。衰老还与性腺功能丧失和生长激素(GH)/IGF-1轴的完整性有关。然而，这些激素轴的缺乏与衰老过程中肌肉减少症和功能损伤的关系尚不清楚，也不清楚这两种激素系统在维持正常骨骼肌质量和身体功能方面是否存在相互作用。我们假设这两种激素系统通过不同的互补机制调节肌肉骨骼蛋白质量和收缩纤维，并且睾酮和生长激素的最佳水平对于维持骨骼肌质量、肌肉力量和力量以及在衰老过程中日常生活的完整功能活动是必要的。该建议已被修订，并需要进行一项为期16周的对照研究，以评估这两种合成代谢激素系统在65-90岁的社区老年男性中的独立作用和相互作用，这些老年男性是低促生长激素（IGF-1水平较低）和低性腺状态（总睾酮水平为250-550 ng/dL）。该研究将采用两层随机化的因子设计（2X3），其中108名研究对象将首先使用一种新的Leydig细胞钳夹方法（GnRH激动剂加局部睾酮补充剂）随机分配到低或高水平的睾丸激素水平，以达到目标睾酮水平。每天服用5克外用睾酮可维持低性腺状态（250-550纳克/分升），而每天服用10克外用睾酮可达到高性腺状态（650-950纳克/分升）。在这两组中，受试者将以双盲方式随机接受安慰剂或两种剂量的rhGH治疗（0、3.0、5.0马克杯/公斤/天）中的一种。研究干预措施的直接影响将通过测量混合和收缩（肌动蛋白和肌球蛋白重链[MHC]）骨骼肌蛋白的分数合成率和骨骼肌（泛素和蛋白酶体亚基）的降解以及通过分析骨骼肌合成的局部调节因子（例如IGF- I， IGFBP4，肌生长抑制素）来评估。研究干预的临床效果将通过测量骨骼肌力量、肌肉质量、力量和疲劳（耐力）、身体表现和安全标志的变化来评估。这项研究的结果将导致对雄激素缺乏和生长功能低下在老年人或因肌肉质量和力量减少而有虚弱风险的老年人中的相对作用的重要机制理解。研究结果也应该为未来测试新的、新颖的治疗策略提供有价值的信息，这些治疗策略比肠外治疗对年龄相关性肌肉减少症更耐受、更方便。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT: Elderly persons experience progressive loss of skeletal muscle mass, muscle strength, and functional capacity for activities of daily living. Aging is also associated with a loss of gonadal function and integrity of the growth hormone (GH)/IGF-1 axis. However, the relationship of deficiencies in these hormonal axes to sarcopenia and functional impairment in aging has not been established or whether there is an interaction of these two hormone systems in maintaining normal skeletal muscle mass and physical function. We hypothesize that both hormone systems regulate musculoskeletal protein mass and contractile fibers by different and complimentary mechanisms and that optimal levels of both testosterone and GH are necessary to maintain skeletal muscle mass, muscular strength and power, and full functional activities of daily living during the aging process. This proposal has been revised and entails a controlled, 16 week study to evaluate the independent effects and interaction of these two anabolic hormone systems in community dwelling elderly men 65-90 years of age who are hyposomatotropic (IGF-1 in lower tertile) with low eugonadal status (total testosterone of 250-550 ng/dL). The study will utilize a factorial design (2X3) with a two tiered randomization in which 108 study subjects will first be randomized to either the low or high eugonadal level of testosterone using a novel Leydig cell clamp method (GnRH agonist plus topical testosterone supplementation) to achieve target levels of testosterone. Low gonadal status (250-550 ng/dL) will be maintained with 5 g daily doses of topical testosterone, whereas high gonadal status (650-950 ng/dL) will be achieved with 10 g daily doses. Within these two groups, subjects will be randomized to receive placebo or one of two doses of rhGH therapy (0, 3.0, 5.0 mug/kg/day) in a double blinded fashion. The direct effects of study interventions will be assessed by measuring the fractional synthetic rates of mixed and contractile (actin and myosin heavy chain [MHC]) skeletal muscle proteins and degradation of skeletal muscle (ubiquitin, and proteasome sub-units) and by analyzing local regulators of skeletal muscle synthesis (e.g. IGF- I, IGFBP4, myostatin). The clinical effects resulting from the study interventions will be assessed by measuring change in skeletal muscle strength, muscle mass, power and fatigability (endurance), physical performance, and markers of safety. The findings of this study should result in important mechanistic understanding of the relative contributions of androgen deficiency and hyposomatotrophism in elderly persons with or who are at risk for frailty due to decreased muscle mass and strength. The results should also provide valuable information for future testing of new, novel treatment strategies, which are more tolerable and convenient than parenteral therapies for age associated sarcopenia.