Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults

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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.