Effects of Albuterol on Muscle Protein Synthesis

描述（由申请人提供）：PAS-03-122的主要目标之一，老年衰弱：病理生理学和干预，是加强独特干预措施的发展和评估，这些干预措施针对在衰弱的发展和进展机制中发挥重要作用的过程。虚弱被定义为肌肉力量不足，走路速度慢，体重减轻，体力活动少。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，在很大程度上导致了虚弱的肌肉力量和步行速度的下降。β - 2肾上腺素能激动剂（B2A）显著增加老年人的肌肉量；然而，人类肌肉量增加的机制尚不清楚。我们将研究：1)使用Real Time PCR检测2.5和8.5天沙丁胺醇给药（16 mg/24小时）对骨骼肌蛋白合成（MPS）和胰岛素样生长因子II mrna的影响，以及使用Western Blot技术检测老年人（60-85岁）体重指数对应于肌肉减少症的男性和女性的P70 S6激酶磷酸化状态。动物数据表明，B2A刺激MPS 2-3天，抑制蛋白降解发生在较晚的时间点。8.5天的测量将确定MPS在人体后期是否仍然升高。阐明B2A影响肌肉蛋白质代谢的方式可能会导致其他治疗策略，以靶向由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。此外，如果我们确定了B2A的主要作用部位，我们将能够假设B2A是否可能在不同的与衰老相关的肌肉萎缩情况下起作用。由于本研究的探索性，R21授予机制是合适的。衰老导致的肌肉质量下降是一个主要问题。一些减轻肌肉质量损失的策略，如睾酮替代，可能会产生意想不到的副作用。沙丁胺醇是美国食品和药物管理局批准的一种药物，已被证明可以增加老年人的肌肉质量，而且副作用很小。正因为如此，了解沙丁胺醇增加人类肌肉质量的机制是很重要的，这样就可以开发出类似的策略。通过寻找沙丁胺醇作用的精确靶点，可以制定替代策略来减少肌肉减少症的发生率。

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.