Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation

December 1, 2014 updated by: Hans Dreyer, University of Oregon

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

60

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Oregon
      • Eugene, Oregon, United States, 97401-1240
        • University of Oregon
      • Eugene, Oregon, United States, 97401
        • Slocum Center for Orthopedics and Sports Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

60 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Total Knee Arthroplasty surgical candidate

Exclusion Criteria:

  • Overt muscle disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: EAA+PT
20 g EAA daily for 7 days prior to TKA surgery and for 14 days after surgery.
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:
  • Leucine
  • Methionine
  • Histidine
  • Isoleucine
  • Lysine
  • Phenylalanine
  • Threonine
  • Valine
PLACEBO_COMPARATOR: ALA+PT
20 g NEAA daily for 7 days prior to TKA surgery and for 14 days after surgery.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Stair Time up
Time Frame: 6 weeks
6 weeks
Quadriceps Muscle Strength
Time Frame: 6 weeks
6 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
6 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oregon

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

  • Principal Investigator: Hans C Dreyer, PT, PhD, Assistant Professor, Department of Human Physiology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2008

Primary Completion (ACTUAL)

December 1, 2013

Study Completion (ACTUAL)

December 1, 2013

Study Registration Dates

First Submitted

September 25, 2008

First Submitted That Met QC Criteria

September 25, 2008

First Posted (ESTIMATE)

September 26, 2008

Study Record Updates

Last Update Posted (ESTIMATE)

December 4, 2014

Last Update Submitted That Met QC Criteria

December 1, 2014

Last Verified

December 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1K01HD057332 (NIH)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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