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Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00760383
Recruitment Status : Completed
First Posted : September 26, 2008
Results First Posted : December 4, 2014
Last Update Posted : December 4, 2014
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Hans Dreyer, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Tracking Information
First Submitted Date  ICMJE September 25, 2008
First Posted Date  ICMJE September 26, 2008
Results First Submitted Date  ICMJE April 17, 2014
Results First Posted Date  ICMJE December 4, 2014
Last Update Posted Date December 4, 2014
Study Start Date  ICMJE June 2008
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 1, 2014)
  • Stair Time up [ Time Frame: 6 weeks ]
  • Quadriceps Muscle Strength [ Time Frame: 6 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: September 25, 2008)
Muscle Protein Synthesis and Breakdown [ Time Frame: Post-op Day #1 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 1, 2014)
Mid-thigh Muscle Volume [ Time Frame: 6 weeks ]
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 25, 2008)
  • Physical function [ Time Frame: 6 weeks ]
  • Quadriceps muscle strength [ Time Frame: 6 weeks ]
  • muscle cross-sectional area [ Time Frame: 6 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation
Official Title  ICMJE Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation
Brief 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Osteoarthritis
Intervention  ICMJE
  • Dietary Supplement: Essential amino acids
    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.
    Other Names:
    • Histidine
    • Isoleucine
    • Leucine
    • Lysine
    • Methionine
    • Phenylalanine
    • Threonine
    • Valine
  • Dietary Supplement: Alanine
    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.
Study Arms  ICMJE
  • Experimental: EAA+PT
    20 g EAA daily for 7 days prior to TKA surgery and for 14 days after surgery.
    Intervention: Dietary Supplement: Essential amino acids
  • Placebo Comparator: ALA+PT
    20 g NEAA daily for 7 days prior to TKA surgery and for 14 days after surgery.
    Intervention: Dietary Supplement: Alanine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 25, 2008)
60
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 2013
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Total Knee Arthroplasty surgical candidate

Exclusion Criteria:

  • Overt muscle disease
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00760383
Other Study ID Numbers  ICMJE 1K01HD057332( U.S. NIH Grant/Contract )
1K01HD057332 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hans Dreyer, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study Sponsor  ICMJE University of Oregon
Collaborators  ICMJE Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE
Principal Investigator: Hans C Dreyer, PT, PhD Assistant Professor, Department of Human Physiology
PRS Account University of Oregon
Verification Date December 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP