Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation

Study Overview
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Brief Summary
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The general hypothesis is that in older adults muscle regrowth after an acute musculoskeletal stress will be positively influenced by traditional physical rehabilitation, and further enhanced by nutritional supplementation. Using state-of-the-art stable isotope methodologies for the study of muscle metabolism and methodologies for the measurement of cell signaling, we will test the following specific hypotheses: 1) Total knee arthroplasty (TKA) induces an acute net protein catabolism mainly by reducing muscle protein synthesis; 2) TKA induced catabolism is attenuated by the ingestion of essential amino acids (EAA); 3) EAA supplementation in combination with physical therapy (PT) will stimulate muscle protein synthesis and mTOR signaling to a greater extent than PT with Placebo; and 4) EAA supplementation during TKA PT rehabilitation will improve muscle strength, muscle volume and functional outcomes to a greater extent than PT with Placebo. Public Benefit: This research will focus rehabilitation efforts on specific and currently unresolved mechanisms responsible for muscle loss following total knee replacement in older adults. While knee pain due to bone arthritis is often alleviated after knee replacement, complete return of physical function and independence is difficult to achieve. This research will help to restore physical function and independence in the rapidly growing population of older adults with knee arthritis.

Detailed Description
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The goal of this translational research project is to identify key mechanisms involved in regulating skeletal muscle loss and regrowth following total knee arthroplasty (TKA). Total knee arthroplasty induces significant declines in muscle mass and strength, which is directly responsible for reduced function, specifically functional independence. Such declines in muscle strength and volume and activities of daily living (getting up from a chair, climbing stairs and walking) can persist for up to 2 years. Atrophy is the direct result of an imbalance between muscle protein synthesis and breakdown. However, there are two quite distinct mechanisms leading to muscle loss: accelerated protein breakdown (e.g. burn injury), primarily resulting from the stress response, or decreased protein synthesis (e.g., immobilization). In case of severe stress, muscle protein synthesis actually increases, although not adequately to impede muscle loss, and anabolic stimuli, such as nutrition, cannot counteract muscle atrophy. On the other hand, decreased protein synthesis from inactivity can be stimulated by nutrition and exercise, thereby reducing or preventing atrophy. Currently, we do not know which condition predominates following TKA: surgical stress-induced catabolism or immobility-associated declines in synthesis . What is not known is which signaling pathway predominates following TKA; stress induced catabolism or immobility associated declines in synthesis. Our goal is to determine which model (stress or inactivity) accounts for the acute and rapid muscle loss following TKA in order to better focus rehabilitation efforts. Our general hypothesis is that quadriceps atrophy following TKA surgery is primarily due to inactivity, which can be counteracted by physical therapy (PT) and essential amino acid (EAA) supplementation. Our goal is to delineate the basic mechanisms underlying muscle loss with TKA, and based on this new information, to find novel rehabilitation strategies to accelerate recovery of normal function from TKA. Thus, our plan is to test in older adults the following specific hypothesis: TKA induces an acute and severe net protein catabolism by reducing muscle protein synthesis TKA induced catabolism is attenuated with the ingestion of EAA EAA supplementation following PT will stimulate muscle protein synthesis and mTOR signaling to a greater extent than PT with Placebo EAA supplementation during TKA PT rehabilitation will improve muscle strength, muscle volume and functional outcomes to a greater extent than PT with Placebo To test our specific hypothesis we will address the following specific aims: To determine if TKA surgery reduces muscle protein synthesis and/or increases muscle protein breakdown To determine if muscle protein synthesis is acutely increased with the ingestion of EAA following TKA surgery To determine if muscle protein synthesis and mTOR signaling will be stimulated by PT rehabilitation and enhanced by EAA supplementation To determine if EAA supplementation during TKA with traditional PT for 6 weeks improves muscle strength, muscle volume and functional outcomes This application will provide preliminary data for the submission of an R01 grant to further determine the mechanisms leading to successful return of quadriceps muscle strength and function following TKA. Essential amino acids are inexpensive, well tolerated and easily digestible and have been shown to independently stimulate muscle protein synthesis and components of the anabolic mTOR signaling pathway. My goal of increasing muscle strength and functional mobility is specifically outlined in the National Center for Medical Rehabilitation Research Seven Priority Areas and are in line with the NIH roadmap and priorities, and will help us to understand muscle protein metabolism during physical therapy rehabilitation. By adopting a mechanism-driven, translational research design that links changes in cell signaling with functional outcome measures (cell → system → function) we will capture key physiological events responsible for the regulation of muscle mass and function following TKA.

Official Title
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Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation

Conditions
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Osteoarthritis

Intervention / Treatment
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* Dietary Supplement: Essential amino acids
* Dietary Supplement: Alanine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Total Knee Arthroplasty surgical candidate Exclusion Criteria: Overt muscle disease

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EAA+PT<br>20 g EAA daily for 7 days prior to TKA surgery and for 14 days after surgery. | Dietary Supplement: Essential amino acids<br>* Subjects will ingest 20 grams of essential amino acids (EAA) daily for 7 days prior to total knee arthroplasty (TKA) surgery and for 14 days after surgery daily. On the days they are seen by physical therapy (PT) they will ingest the EAA supplement 30 minutes after the end of each PT rehabilitation session.<br>* Other names: Valine;|
| Placebo Comparator: ALA+PT<br>20 g NEAA daily for 7 days prior to TKA surgery and for 14 days after surgery. | Dietary Supplement: Alanine<br>* Subjects will ingest 20 grams of non-essential amino acid (NEAA) daily for 7 days prior to total knee arthroplasty (TKA) surgery and for 14 days after surgery daily. On the days they are seen by physical therapy (PT) they will ingest the NEAA supplement 30 minutes after the end of each PT rehabilitation session.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stair Time up |  | 6 weeks | 
| Quadriceps Muscle Strength |  | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mid-thigh Muscle Volume | Analysis was performed using the Analyze 11 software package with semi-automated delineation of quadriceps, hamstrings, and adductors boarders. Using thresholding methods, the software can differentiate operator-delineated parameters set to distinguish muscle from non-muscle (i.e., adipose tissue) using voxel intensity within each border region for quantitative determination of muscle volume. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Total Knee Arthroplasty, Osteoarthritis, Muscle Metabolism, Rehabilitation, Physical Therapy