Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults

描述(申请人提供)：随着老年人口的增长，到2030年，美国估计每年将进行348万次膝关节置换(TKA)手术。尽管这种手术在缓解慢性膝关节疼痛方面取得了近乎普遍的成功，但TKA在恢复老年人长期身体功能方面并不成功，主要是因为股四头肌萎缩，这可以解释77%的力量不足。总体而言，TKA患者的力量和功能活动度比年龄匹配的健康对照组低30%-50%。功能性任务，如爬楼梯，被认为是一种高跌倒风险的活动，对于75%的TKA患者来说仍然是一个临床问题。肌肉萎缩在手术和非手术腿中都会发生，对于老年患者来说基本上是永久性的，因为他们增加肌肉质量的能力显著受损。因此，迫切需要安全有效的治疗方法来防止肌肉丧失和保持力量，因为它们可能显著影响数百万老年人的生活质量，因此具有临床意义。这项拟议的临床研究的目的是确定补充必需氨基酸(EAA)对老年人TKA术后肌肉质量、力量和功能活动的影响。我们的假设基于强大的初步数据，即每天两次摄入20g的EAA，在TKA前1wk到TKA后6wk，将通过使分解代谢信号失活、合成代谢和细胞保护蛋白上调而增加肌肉蛋白质合成的基础速率。我们进一步假设，与安慰剂相比，短期的萎缩预防和功能活动的加速恢复将导致较长期的结构和功能适应，并改善老年TKA患者的生活质量。这项拟议研究的基本原理是，预防日益常见的TKA手术后肌肉萎缩的有效治疗将导致短期和长期的肌肉细胞适应，从而提高功能活动和生活质量。确定EAA治疗上调维持肌肉容量和活动能力的机制将对康复科学产生重大影响。这项拟议的研究将通过实现两个特定目标来实证检验我们的假设：(1)确定与安慰剂相比，EAA是否在短期内(与安慰剂相比)上调合成代谢途径和细胞保护蛋白，并使分解代谢途径失活，从而提高肌肉蛋白质合成的基础速率；(2)与安慰剂相比，确定短期预防萎缩、虚弱和功能流动性是否能导致肌肉细胞结构和功能的积极变化，以及生活质量(WOMAC&SF-36)的改善。这项拟议的工作意义重大，因为它促进了临床环境中肌肉萎缩(安慰剂)和萎缩预防(EAA)期间发生的分子和细胞变化的知识，使用的治疗方法广泛适用，耐受性好，并且可以立即实施。

DESCRIPTION (provided by applicant): As a function of our growing population of older adults, an estimated 3.48 million total knee arthroplasty (TKA) procedures will be performed annually in the U.S. by 2030. Despite the near-universal success of this surgery in mitigating chronic knee pain, TKA is not successful in restoring long-term physical function in older adults, primarily because of quadriceps muscle atrophy, which explains 77% of the strength deficits. Overall, strength and functional mobility in TKA patients is 30-50% below age-matched healthy controls. Functional tasks such as stair-climbing, which is considered a high fall-risk activity, remain a clinical problem for 75% of patients following TKA. Muscle atrophy occurs in both operative and non-operative legs, and is essentially permanent for older patients because their ability to increase muscle mass is significantly impaired. Thus, safe and effective treatments to prevent muscle loss and preserve strength are urgently needed and clinically meaningful, as they have the potential to significantly impact the quality of life for millions of older adults. Te purpose of the proposed clinical research is to determine the effects of essential amino acid (EAA) supplementation on muscle mass, strength, and functional mobility following TKA in older adults. Our hypothesis, based on strong preliminary data, is that twice-daily ingestion of 20 g of EAA for 1 wk before through 6 wk after TKA will increase basal rates of muscle protein synthesis via inactivation of catabolic signaling, and up-regulation of anabolic and cyto-protective proteins. We further hypothesize that short-term atrophy prevention and accelerated return of functional mobility will lead to longer-term structural and functional adaptations, and improved quality of life in older TKA patients vs. Placebo. The rationale for the proposed research is that effective treatments to prevent muscle atrophy after increasingly common TKA surgery will result in short- and longer-term muscle cell adaptations that boost functional mobilit and quality of life. Identifying the mechanisms up-regulated by EAA treatment that preserve muscle volume and mobility will have a major impact on rehabilitation science. The proposed research will empirically test our hypotheses by accomplishing two specific aims: (1) determine if EAA elevates basal rates of muscle protein synthesis by up- regulating anabolic pathways and cyto-protective proteins, and inactivating catabolic pathways in the short term (6 wk post-TKA) vs. Placebo and (2) determine if short-term prevention of atrophy, weakness, and functional mobility leads to positive changes in muscle cell structure and function, and improved quality of life (WOMAC & SF-36) in the longer term (6 mo and 1 yr post-TKA) vs. Placebo. The proposed work is significant because it advances knowledge of the molecular and cellular changes occurring during muscle atrophy (Placebo) and atrophy prevention (EAA) in a clinical setting using a treatment that is broadly applicable, is well tolerated, and can be implemented immediately.