HORMONAL REGULATORS OF MUSCLE AND METABOLISM IN AGING

衰老过程中肌肉和新陈代谢的激素调节剂

• 批准号: 7953905
• 负责人: E TODD SCHROEDER
• 金额: $ 0.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953905
• 关键词: Actins; Activities of Daily Living; Age; Age-Years; Aging; Aging-Related Process; Agonist; Androgens; Communities; Computer Retrieval of Information on Scientific Projects Database; Dose; Double-Blind Method; Elderly; Elderly man; Fiber; Funding; Future; Grant; Hormonal; Hormones; IGFBP4 gene; Institution; Insulin-Like Growth Factor I; Intervention Studies; Mass Spectrum Analysis; Measures; Methods; Muscle; Muscle Proteins; Musculoskeletal; Myosin Heavy Chains; Performance; Persons; Physical Endurance; Physical Function; Placebos; Proteins; Randomized; Relative (related person); Research; Research Personnel; Resources; Risk; Safety; Skeletal Muscle; Somatotropin; Source; Study Subject; Supplementation; System; Testing; Testosterone; Ubiquitin; United States National Institutes of Health; biomedical resource; clinical effect; design; experience; frailty; functional disability; gonad function; leydig interstitial cell; multicatalytic endopeptidase complex; muscle form; muscle metabolism; muscle strength; myostatin; novel; protein degradation; r-hGH-M; sarcopenia; treatment strategy

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 老年人的骨骼肌群、肌力和日常生活活动的功能能力逐渐丧失。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，这些激素轴的缺陷与骨质疏松症和衰老功能损害的关系尚未确定，也没有确定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和互补的机制来调节肌肉骨骼蛋白质量和收缩纤维，并且在衰老过程中，维持骨骼肌质量、肌肉力量和力量以及日常生活的充分功能活动所必需的最佳睾酮和生长激素水平是必需的。这项建议已被修订，并进行了一项为期16周的对照研究，以评估这两种合成激素系统在65-90岁的社区老年男性中的独立效果和相互作用，这些老年男性是发育不良(下四分位数为IGF-1)、优生素水平低(总睾酮为250-550 ng/dL)的老年男性。这项研究将利用因子设计(2X3)，采用两层随机设计，其中108名研究对象将首先被随机分成两组，使用一种新的Leydig细胞钳制方法(GnRH激动剂加局部补充睾酮)，随机选择低水平或高水平的睾酮，以达到目标水平的睾酮。每日外用5克睾酮可维持低性腺状态(250-550 ng/dL)，而每日10 g剂量可维持较高性腺状态(650-950 ng/dL)。在这两组中，受试者将随机接受安慰剂或两种剂量(0，3.0，5.0ug/kg/天)中的一种，以双盲方式接受治疗。研究干预措施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链[MHC])骨骼肌蛋白质的合成比率和骨骼肌(泛素和蛋白酶体亚单位)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、肌肉生长抑制素)来评估。研究干预措施产生的临床效果将通过测量骨骼肌力量、肌肉质量、力量和疲劳性(耐力)、身体表现和安全标志的变化来评估。这项研究的结果应该有助于从机制上理解雄激素缺乏和营养不良在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。这一结果也应该为未来测试新的、新的治疗策略提供有价值的信息，新的治疗策略比肠外疗法更耐受、更方便治疗年龄相关性石棺减少症。