Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation
Condition: Osteoarthritis
MeSH terms: Osteoarthritis
Study type: Interventional

Summary: 
      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: 
      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:

        1. TKA induces an acute and severe net protein catabolism by reducing muscle protein
           synthesis

        2. TKA induced catabolism is attenuated with the ingestion of EAA

        3. EAA supplementation following PT will stimulate muscle protein synthesis and mTOR
           signaling to a greater extent than PT with Placebo

        4. 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:

        1. To determine if TKA surgery reduces muscle protein synthesis and/or increases muscle
           protein breakdown

        2. To determine if muscle protein synthesis is acutely increased with the ingestion of EAA
           following TKA surgery

        3. To determine if muscle protein synthesis and mTOR signaling will be stimulated by PT
           rehabilitation and enhanced by EAA supplementation

        4. 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.
    

Intervention name(s): Essential amino acids; Alanine
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 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.; 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.
Other intervention name(s): Histidine; Isoleucine; Leucine; Lysine; Methionine; Phenylalanine; Threonine; Valine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Total Knee Arthroplasty; Osteoarthritis; Muscle Metabolism; Rehabilitation; Physical Therapy