Effects of Albuterol on Muscle Protein Synthesis

描述(申请人提供)：PAS-03-122PAS-03-122，老年脆弱：病理生理学和干预措施的主要目标之一，是加强对独特干预措施的开发和评估，这些干预措施针对似乎在脆弱的发展和进展的机制(S)中发挥重要作用的过程。虚弱被定义为肌肉力量不足、行走速度慢、体重减轻和体力活动不足。显然，骨质疏松症，或与年龄相关的肌肉质量和肌肉力量的丧失，在很大程度上导致了肌肉力量和步行速度下降的虚弱。β-2肾上腺素能激动剂(B2A)显著增加老年人的肌肉质量；然而，人类肌肉质量增加的机制(S)尚不清楚。我们将检测：1)服用沙丁胺醇2.5天和8.5天(16 mg/24小时)对骨骼肌蛋白质合成(MPS)和胰岛素样生长因子II的mRNAs的影响，使用Real Time PCR检测钙依赖的蛋白分解，以及使用Western Blot技术检测P70 S6 Kinase的磷酸化状态(60-85岁)，这些老年男性和女性的体重指数与石棺减少相对应。动物数据表明，B2A刺激MPS 2-3天，并在以后的时间点抑制蛋白质的降解。8.5天的测量将确定稍后人类的MPS是否保持升高。阐明B2A影响肌肉蛋白质代谢的方式可能会导致针对B2A激活或失活的蛋白质合成和/或蛋白质降解途径的特定成分的其他治疗策略。此外，如果我们确定B2a的主要作用部位，我们将能够假设B2a是否可能在不同的衰老相关肌肉萎缩条件下发挥作用。由于这项研究的探索性，R21授予机制是合适的。衰老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，如睾酮替代疗法，可能会产生不想要的副作用。沙丁胺醇是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。由于情况如此，了解沙丁胺醇增加人体肌肉质量的机制很重要，以便开发类似的策略。通过找到沙丁胺醇作用的精确靶点(S)，可以开发出替代策略来减少石棺减少的发生率。

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.