Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults

预防老年人萎缩和恢复功能的机械方法

• 批准号: 9441247
• 负责人: Hans Christian Dreyer
• 金额: $ 8.78万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9441247
• 关键词: Acceleration; Acute; Age; Amino Acid Transporter; Angiogenesis Pathway; Area; Atrophic; Attenuated; Behavior; Biological Models; Biological Preservation; Cell Size; Cell physiology; Cellular Structures; Chronic; Clinical; Clinical Research; Costs and Benefits; DNA Damage; Data; Development; Elderly; Equilibrium; Essential Amino Acids; Essential amino acids supplementation; Event; Fatigue; Fibrinogen; Functional disorder; Gait; Growth; Health; Health Benefit; Impairment; Ingestion; Injury; Insulin-Like Growth Factor I; Knowledge; Laboratories; Leg; Link; Mission; Mitochondria; Molecular; Muscle; Muscle Cells; Muscle Proteins; Muscle Weakness; Muscular Atrophy; Nature; Nutritional; Older Population; Operative Surgical Procedures; Organism; Pathway interactions; Patients; Physical Function; Placebos; Population; Prevention; Procedures; Protein Biosynthesis; Proteins; Public Health; Quality of life; Recovery of Function; Rehabilitation therapy; Research; Research Proposals; Resistance; Respiration; SF-36; Signal Transduction; Somatomedins; Strategic Planning; Testing; Thigh structure; Translating; Translational Research; United States National Institutes of Health; Up-Regulation; Vascular Endothelial Growth Factors; Western Ontario and McMaster Universities Arthritis Index; Work; activating transcription factor 4; base; burden of illness; effective therapy; equilibration disorder; fall risk; functional adaptation; functional disability; functional restoration; hamstring; improved; interest; knee pain; knee replacement arthroplasty; muscle form; older men; older patient; older women; patient subsets; prevent; public health relevance; quadriceps muscle; rehabilitation science; response; success

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.

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力量不足。总体而言，TKA患者的强度和功能迁移率低于年龄匹配的健康对照30-50％。对于TKA之后，75％的患者中，诸如高降落风险活动之类的功能性任务（例如爬升阶梯式活动）仍然是一个临床问题。肌肉萎缩发生在手术和非手术腿上，对于老年患者而言，基本上是永久性的，因为它们增加肌肉质量的能力会大大受损。因此，迫切需要和临床有意义的安全和有效的治疗方法，以防止肌肉损失和保持力量，因为它们有可能显着影响数百万老年人的生活质量。拟议的临床研究的目的是确定补充剂在老年人TKA后补充必需氨基酸（EAA）对肌肉质量，力量和功能迁移率的影响。我们的假设基于强大的初步数据，是在TKA之后通过6周之前，每天两次摄入20 g的EAA，将通过灭活肌肉蛋白质的基础速率，通过灭活分解代谢信号传导，并上调合成代谢和CYTO蛋白质。我们进一步假设，短期萎缩预防和功能迁移率的加速回报将导致长期的结构和功能适应，并改善了老年TKA患者与安慰剂的生活质量。拟议的研究的理由是，在越来越常见的TKA手术后，有效预防肌肉萎缩的有效治疗将导致短期和长期的肌肉细胞适应，从而促进功能动态和生活质量。确定通过EAA治疗上调的机制，可以保留肌肉量和流动性，将对康复科学产生重大影响。拟议的研究将通过实现两个具体目的来从经验上检验我们的假设：（1）确定EAA是否通过提高肌肉蛋白质合成的基础速率来提高肌肉蛋白质合成的基础速率，从而调节合成代谢途径和细胞增生蛋白质，并在短期内（6 wk tka and tka and Temperitiation and（2）确定较短的序列（如果是2），则在短期内灭活分解途径，确定是否有效。与安慰剂相比，长期（6个月和1岁）的肌肉细胞结构和功能的变化以及改善的生活质量（WOMAC和SF-36）。提出的工作很重要，因为它可以在临床环境中使用广泛适用的治疗方法在肌肉萎缩（安慰剂）和预防萎缩（EAA）期间发生的分子和细胞变化的知识，并且可以立即实施。