HORMA

霍玛

• 批准号: 7603347
• 负责人: ELLEN F BINDER
• 金额: $ 3.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603347
• 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; Daily; Dose; Double-Blind Method; Elderly; Elderly man; Fiber; Funding; Future; Grant; Hormonal; Hormones; IGFBP4 gene; Institution; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor I; Intervention Studies; Measures; Methods; Muscle; Muscle Proteins; Musculoskeletal; Myosin Heavy Chains; Performance; Persons; Physical Endurance; Physical Function; Placebos; Proteins; Randomized; Randomized Controlled Trials; Rate; Relative (related person); Research; Research Personnel; Resources; Risk; Safety; Skeletal Muscle; Skeletal system; Somatotropin; Source; Study Subject; Supplementation; System; Testing; Testosterone; Ubiquitin; United States National Institutes of Health; Week; clinical effect; day; design; experience; frailty; functional disability; gonad function; leydig interstitial cell; multicatalytic endopeptidase complex; muscle strength; myostatin; novel; protein degradation; r-hGH-M; sarcopenia

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 asociated 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 levles 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. The proposed study is a 16-week randomized, controlled trial to evaluate the independent effects and interaction of these two anabolic hormone systems in community dwelling elderly men 65-90 years of age who ar ehyposomatotropic (IGF-1 in lower tertile) with low eugonadal status (total testosterone of 250-550 mg/dL). The study will utilized 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 5g daily doses of topical testosterone, whereas high gonadal status (650-950 ng/dL) will be achieved with 10g 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 ug/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-1, 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 and androgen deficiency and hyposomatotrpism 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 paretheral therapies for age associated sarcopenia.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 老年人经历了骨骼肌质量，肌肉力量和日常生活活动的功能能力的逐渐丧失。 衰老也与生长激素（GH）/ IGF-1轴的性腺功能的丧失和完整性相关。 但是，尚未建立这些激素轴中缺陷与肌肉减少症与衰老中功能障碍的关系，或者是否在维持正常的骨骼肌质量和身体功能方面是否存在这两种激素系统的相互作用。 我们假设两种激素系统都通过不同的和免费的机制来调节肌肉骨骼蛋白质质量和收缩纤维，并且在老化过程中，睾丸激素和GH的最佳作用对于维持骨骼肌质量，肌肉力量和动力以及日常生活的全部功能活动都是必要的。 拟议的研究是一项为期16周的随机对照试验，旨在评估这两种合成代谢激素系统在​​社区住宅老年男性65-90岁的独立效果和相互作用，而Ar Ehyposomatotropic（IGF-1中的IGF-1）与低EUGONADAL状态（总睾丸激素的总睾丸激素为250-550 mg/dl）。 该研究将使用两个分层随机化利用阶乘设计（2x3），其中108个研究受试者将使用新型的Leydig细胞夹方法（GNRH Agonist Plus局部睾丸激素补充剂）将108个研究受试者随机分配给低或高的Eugonadal睾丸激素水平，以实现睾丸激素的靶标水平。 低性腺状态（250-550 ng/dl）将以每日5G剂量的局部睾丸激素维持，而高性腺状态（650-950 ng/dl）将以每日10克的剂量实现。 在这两组中，受试者将被随机接受安慰剂或两种剂量的RHGH疗法之一（0,3.0,5.0 ug/kg/day）以双重盲人方式接受。 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速率以及骨骼肌（泛素和蛋白酶体亚基）的降解以及通过分析骨骼肌肉肌肉合成的骨骼肌肉肌肉的局部调节器（蛋白酶体亚单位）的降解。 研究干预措施产生的临床影响将通过测量骨骼肌肉强度，肌肉质量，功率和疲劳性（耐力），身体性能和安全标记来评估。 这项研究的结果应导致对老年人的相对贡献和雄激素缺乏症以及由于肌肉质量和力量降低而处于脆弱风险的情况下的相对贡献和雄激素缺乏症的重要理解。 结果还应提供有价值的信息，用于对新型新型治疗策略的未来测试，这些策略比与年龄相关的肌肉减少症相比，这些策略比乳房疗法更容易容忍和方便。