HORMONAL REGULATORS OF MUSCLE AND METABOLISM IN AGING

描述：(申请人提供)长者体验进步性 骨骼肌质量、肌力和功能能力的丧失 日常生活活动。衰老也与性腺的丧失有关。 生长激素(GH)/IGF-1轴的功能和完整性。然而， 这些激素轴缺陷与骨质疏松症和 衰老中的功能损害尚未确定，或者是否存在 这两种激素系统在维持正常骨骼肌中的相互作用 质量和物理功能。我们假设两种荷尔蒙系统都调节 肌肉骨骼蛋白质量和收缩纤维的不同和 补充机制与睾酮和生长激素最佳水平 是维持骨骼肌群、肌肉力量和力量所必需的， 以及衰老过程中日常生活的全功能活动。这 提案已修改，需要进行16周的受控研究以进行评估 这两种合成激素系统的独立作用和相互作用 在社区居住中，65-90岁的老年男性发育不良 (低四分位数为IGF-1)有低性腺状态(总睾酮 250-550 ng/dL)。研究将采用析因设计(2X3)，其中 分级随机化，其中108名研究对象将首先随机到 使用新莱迪格的睾丸素的低水平或高水平 细胞钳方法(促性腺激素释放激素激动剂加局部补充睾酮) 达到睾丸激素的目标水平。性腺状态低下(250-550 ng/dL)将 维持每天5克的外用睾丸素，而高剂量 每天服用10g剂量，性腺状态(650-950 ng/dL)就会达到。在 这两组受试者将随机接受安慰剂或两组中的一组 RhGH剂量(0、3.0、5.0µg/kg/d)双盲给药。这个 研究干预的直接效果将通过测量 混合和收缩(肌动蛋白和肌球蛋白重)的合成比率 链[MHC])骨骼肌蛋白质与骨骼肌的降解 (泛素和蛋白酶体亚单位)，并通过分析 骨骼肌合成(如IGF-I、IGFBP4、Myostatin)。临床部 研究干预措施产生的效果将通过测量来评估 骨骼肌力量、肌肉质量、力量和疲劳性的变化 (耐力)、身体表现和安全标志。这项研究的发现 研究应该导致对相对的重要的机械性的理解 老年人雄激素缺乏和促性腺激素减退的作用 有或有因肌肉质量和力量减少而有虚弱风险的。 这些结果还应该为未来测试新的、 新的治疗策略，比 老年相关骨质疏松症的肠外治疗。

DESCRIPTION: (provided by applicant) 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 hyposomatotropism 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.