HORMONAL REGULATORS OF MUSCLE AND METABOLISM IN AGING

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 老年人经历骨骼肌质量、肌肉力量和日常生活活动的功能能力的进行性损失。衰老还与性腺功能和生长激素（GH）/IGF-1轴的完整性的丧失有关。然而，在这些激素轴的不足，肌肉减少症和功能障碍的关系，在老龄化尚未建立或是否有这两个激素系统在维持正常的骨骼肌质量和身体功能的相互作用。我们假设，这两个激素系统调节肌肉骨骼蛋白质质量和收缩纤维的不同和互补的机制和睾酮和生长激素的最佳水平是必要的，以维持骨骼肌质量，肌肉力量和权力，以及在衰老过程中的日常生活的全部功能活动。该提案已被修订，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岁的社区居住老年男性中的独立作用和相互作用，这些老年男性具有低促性腺激素（IGF-1在下三分位数）和低正常性腺状态（总睾酮为250-550 ng/dL）。本研究将采用析因设计（2X 3）和两层随机化，其中108例研究受试者将首先使用新型Leydig细胞钳夹法（GnRH激动剂加外用睾酮补充剂）随机分配至低或高真性腺睾酮水平，以达到目标睾酮水平。低性腺状态（250-550 ng/dL）将通过5 g每日剂量的局部睾酮维持，而高性腺状态（650-950 ng/dL）将通过10 g每日剂量实现。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治疗之一（0、3.0、5.0 μ g/kg/天）。将通过测量混合和收缩（肌动蛋白和肌球蛋白重链[MHC]）骨骼肌蛋白的部分合成率和骨骼肌降解（泛素和蛋白酶体亚单位）以及通过分析骨骼肌合成的局部调节因子（例如IGF-1、IGFBP 4、肌肉生长抑制素）来评估研究干预的直接影响。将通过测量骨骼肌强度、肌肉质量、力量和疲劳性（耐力）、体能和安全性标志物的变化来评估研究干预措施产生的临床效应。这项研究的结果应导致重要的机制的理解，雄激素缺乏症和hyposomatotrophism在老年人或谁是脆弱的风险，由于肌肉质量和力量下降的相对贡献。这些结果也为将来测试新的、新颖的治疗策略提供了有价值的信息，这些治疗策略比年龄相关性肌肉减少症的胃肠外治疗更耐受和方便。

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. 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.