Effects of Albuterol on Muscle Protein Synthesis

沙丁胺醇对肌肉蛋白质合成的影响

• 批准号: 7094588
• 负责人: CHARLES Paul LAMBERT
• 金额: $ 15.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094588
• 关键词: albuterol; beta adrenergic receptor; biopsy; body composition; calpain; clinical research; clinical trials; drug screening /evaluation; frail elderly; human old age (65+); human therapy evaluation; hypertrophy; insulinlike growth factor; muscle disorder chemotherapy; muscle metabolism; muscle pharmacology; muscle proteins; polymerase chain reaction; protease inhibitor; protein biosynthesis; proteolysis; sarcopenia; serine threonine protein kinase; striated muscles; western blottings

DESCRIPTION (provided by applicant): One of the major goals of PAS-03-122, Frailty in Old Age: Pathophysiology and Interventions, is to enhance the development and evaluation of unique interventions that target processes that appear to play an important role in the mechanism(s) of the development and progression of frailty. Frailty has been defined as consisting of low muscle strength, slow walking speed, weight loss, and low physical activity. Clearly, sarcopenia, or the age related loss of muscle mass and muscle strength contributes substantially to the muscle strength and walking speed decrements of frailty. Beta-two adrenergic agonists (B2A) significantly increase muscle mass in the elderly; however, the mechanism(s) for this increase in muscle mass in humans is/are not known. We will examine: 1) the effects of 2.5 and 8.5 days of albuterol administration (16 mg/24h) on skeletal muscle protein synthesis (MPS) and the mRNAs for insulin like growth factor II, and Ca2+ dependent proteolysis using Real Time PCR as well as the phosphorylation status of P70 S6 Kinase using the Western Blot technique in elderly (age 60-85) men and women who have body mass indices that correspond to the presence of sarcopenia. Animal data suggest that B2A stimulate MPS for 2-3 days with inhibition of protein degradation occurring at later time points. The 8.5 day measurement will be to determine whether MPS remains elevated later in humans. Elucidating, the way in which B2A affect muscle protein metabolism may possibly lead to other therapeutic strategies to target specific components of protein synthetic and/or protein degradative pathways that are activated or deactivated by B2A. Additionally, if we determine the primary site of action of B2A we will able to hypothesize whether B2A will likely work in different aging related muscle wasting conditions. Because of the exploratory nature of this study the R21 granting mechanism is appropriate. Muscle mass loss as a result of aging is a major problem. Some strategies for attenuating muscle mass loss such as testosterone replacement may have unwanted side effects. Albuterol, an FDA approved drug, has been shown to increase muscle mass in the elderly with minimal side effects. Because this is the case, it is important to know the mechanism by which albuterol increases muscle mass in humans so that similar strategies may be developed. By finding the precise target(s) of albuterol action alternative strategies can be developed to attenuate the incidence of sarcopenia.

描述（由申请方提供）：PAS-03-122《老年虚弱：病理生理学和干预》的主要目标之一是加强独特干预措施的开发和评价，这些干预措施针对似乎在虚弱发展和进展机制中发挥重要作用的过程。虚弱被定义为包括低肌肉力量，缓慢的步行速度，体重减轻和低体力活动。显然，肌肉减少症或与年龄相关的肌肉质量和肌肉力量的损失实质上导致了肌肉力量和步行速度的下降。β 2肾上腺素能激动剂（B2 A）可显著增加老年人的肌肉质量;然而，人体肌肉质量增加的机制尚不清楚。我们将研究：1）沙丁胺醇给药2.5天和8.5天的影响（16 mg/24 h）对骨骼肌蛋白质合成（MPS）和胰岛素样生长因子II的mRNA的影响，用真实的时间PCR检测老年人蛋白水解和钙离子依赖性蛋白水解，用蛋白质印迹技术检测老年人P70 S6激酶磷酸化状态（年龄60-85）具有对应于肌肉减少症存在的体重指数的男性和女性。动物数据表明，B2 A刺激MPS 2-3天，在稍后的时间点抑制蛋白质降解。第8.5天的测量将确定MPS在人体中是否在以后保持升高。阐明B2 A影响肌肉蛋白质代谢的方式可能导致其他治疗策略，以靶向由B2 A激活或失活的蛋白质合成和/或蛋白质降解途径的特定组分。此外，如果我们确定B2 A的主要作用部位，我们将能够假设B2 A是否可能在不同的衰老相关的肌肉萎缩条件下起作用。由于本研究的探索性质，R21授予机制是适当的。由于衰老而导致的肌肉质量损失是一个主要问题。一些减轻肌肉质量损失的策略，如睾酮替代可能会产生不必要的副作用。沙丁胺醇，FDA批准的药物，已被证明可以增加老年人的肌肉质量，副作用最小。因为情况就是这样，所以了解沙丁胺醇增加人体肌肉质量的机制是很重要的，这样就可以制定类似的策略。通过发现沙丁胺醇作用的精确靶点，可以开发替代策略来减轻肌肉减少症的发生率。