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Alterations in Muscle After Total Knee Arthroplasty

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ClinicalTrials.gov Identifier: NCT02281877
Recruitment Status : Recruiting
First Posted : November 4, 2014
Last Update Posted : November 29, 2017
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver

Brief Summary:
The overall goals of this work are: 1) to elucidate alterations in gene expression and downstream protein synthesis 2 weeks after Total Knee Arthroplasty (TKA) to better explain quadriceps muscle atrophy after TKA and 2) understand the mechanisms responsible for improved maintenance of muscle strength with Neuromuscular Electrical Stimulation (NMES) utilization. Furthermore, this investigation seeks to expand previous findings regarding attenuation of strength and functional performance deficits with NMES application to better understand how altered gene expression influences muscle function.

Condition or disease Intervention/treatment Phase
Knee Osteoarthritis Procedure: Neuromuscular electrical stimulation (NMES) Behavioral: Standard Rehabilitation Protocol Not Applicable

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: Alterations in Skeletal Muscle Gene Expression Following Total Knee Arthroplasty
Study Start Date : October 2014
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : October 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Neuromuscular Electrical Stimulation

Neuromuscular Electrical Stimulation (NMES) 48 hours after TKA, 5x/week, 2x/day, for 45 minutes/session.

Standard Rehabilitation Protocol

Procedure: Neuromuscular electrical stimulation (NMES)
5x/week, 2x/day, for 45 minutes/session

Behavioral: Standard Rehabilitation Protocol
Standard physical therapy after TKA

Active Comparator: Control
Standard Rehabilitation Protocol
Behavioral: Standard Rehabilitation Protocol
Standard physical therapy after TKA




Primary Outcome Measures :
  1. Catabolic gene expression [ Time Frame: Change in gene expression from immediately pre surgery to 2 weeks after surgery ]
    Standard procedures including total RNA isolation, cDNA synthesis, cRNA labeling, microarray hybridization and image acquisition will be performed. Protein content (translation of MAFbx, MuRF1, myostatin) will be analyzed. Total RNA (500 ng) will be reverse transcribed with the iScript cDNA synthesis kit (Bio-Rad, Hercules, CA), and quantitative PCR will be performed using primer sets for genes of interest, reference genes and iQ SYBR Supermix (Bio-Rad) following manufacturer's protocols.


Secondary Outcome Measures :
  1. Changes in quadriceps strength [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Isometric quadriceps strength will be using a doublet interpolation test performed by research assistants blinded to participants' treatment randomization. Briefly, patients will be seated and stabilized in a HUMAC NORM (Computer Sports Medicine Incorporated, Stoughton, MA) dynamometer with their knee flexed to 60 degrees. After proper warm up, patients will be asked to perform a maximum voluntary isometric contraction of their quadriceps while receiving verbal reinforcement.

  2. Changes in quadriceps size [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Peripheral Quantitative Computed Tomography scans of the distal femur will be used to assess the changes in quadriceps muscle morphology quantitatively. The maximal cross-sectional area of the quadriceps will be determined prior to TKA and ~14 days after TKA by manually placing the scanner at a line marked on the vastus lateralis one third of the distance between the greater trochanter and the lateral epicondyle of the femur. The pQCT software will analyze the image and calculate muscle cross-sectional area. A previous investigation by Cramer, et al. validated the pQCT to measurement of muscle cross-sectional area by comparison to MRI and (R2 values of 0.979 and 0.983). In addition, the use of the pQCT to measure muscle cross sectional area had high test-retest reliability, with ICC values of 0.996 and 0.998.

  3. Changes in quadriceps activation [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Isometric quadriceps activation testing will be using a doublet interpolation test performed by research assistants blinded to participants' treatment randomization. Briefly, patients will be seated and stabilized in a HUMAC NORM (Computer Sports Medicine Incorporated, Stoughton, MA) dynamometer with their knee flexed to 60 degrees. After proper warm up, patients will be asked to perform a maximum voluntary isometric contraction of their quadriceps while receiving verbal reinforcement. During the contraction, a 2 pulse, 600 µs duration/pulse, supramaximal 100Hz stimulus will be delivered to the muscle to assess whether the subject is indeed maximally contracting the quadriceps muscle and again at rest.

  4. Functional Performance Measures (4 meter walk test, timed up and go, stair climbing test) [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    The timed Stair Climbing Test (SCT) places a high demand on the quadriceps and therefore measures a higher level of function and, therefore, minimizes the possibility of a ceiling effect. The SCT has been shown to significantly correlate to the Timed Up and Go (TUG). The TUG measures the time it takes a patient to rise from an arm chair (seat height of 46 cm), walk 3 m, turn and return to sitting in the same chair without physical assistance.25 This test has excellent inter-rater (ICC=0.99) and intra-rater reliability (ICC=0.99), as measured in a group of 60 functionally disabled older adults (mean age 80 years).25 The 4 meter Walk Test (4mWT) will be assessed at the fastest safe speed for each participant.

  5. Anabolic Gene Expression [ Time Frame: Immediately pre surgery to 2 weeks after surgery ]
    Standard procedures including total RNA isolation, cDNA synthesis, cRNA labeling, microarray hybridization and image acquisition will be performed. Protein content (translation of mTOR, myogenin, and MyoD) will be analyzed. Total RNA (500 ng) will be reverse transcribed with the iScript cDNA synthesis kit (Bio-Rad, Hercules, CA), and quantitative PCR will be performed using primer sets for genes of interest, reference genes and iQ SYBR Supermix (Bio-Rad) following manufacturer's protocols.

  6. Muscle Fiber Cross-Sectional Area [ Time Frame: Immediately pre surgery to 2 weeks after surgery ]
    Cross sectional area of individual myofibrils taken from the vastus lateralis muscle using immunohistochemical staining and microscopy to determine change in cross sectional area comparing one hour before surgery to two weeks after surgery

  7. Changes in neural cell adhesion molecule (NCAM) concentration [ Time Frame: Preop and 2 weeks postop ]
    NCAM will be assessed by immunohistochemistry with anti-CD56/NCAM antibody (555514; BD Biosciences, San Jose, CA), followed by goat anti-mouse AF555 (A-21127, ThermoFisher). NCAM is a multifunctional cell-surface protein that has been shown to be associated with muscle regeneration, through its roles in neurite outgrowth and synaptic plasticity. NCAM immunohistochemistry will be able to assess 1) denervation status, 2) skeletal muscle response to an intervention, and 3) the capacity for skeletal muscle to improve.



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Ages Eligible for Study:   50 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 50 to 75 years of age
  • Scheduled for unilateral TKA at University of Colorado Hospital
  • Diagnosed with osteoarthritis
  • Cognitive status that allows patients to consistently comprehend and repeat back directions regarding the details of the study

Exclusion Criteria:

  • Neurological, vascular or cardiac problems that significantly limit function
  • BMI > 35
  • Testosterone supplementation
  • Pregnancy
  • Anticoagulant therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02281877


Contacts
Contact: Maggie H Reineke 719-251-7533 maggie.reineke@ucdenver.edu
Contact: Victor Cheuy, PhD 303-724-9590 victor.cheuy@ucdenver.edu

Locations
United States, Colorado
Univeristy of Colorado Anschutz Medical Campus Recruiting
Aurora, Colorado, United States, 80045
Contact: Kristine Gerron, BS    303-724-9590    Kristine.Gerron@ucdenver.edu   
Contact: Victor Cheuy, PhD    303-724-9590    victor.cheuy@ucdenver.edu   
Principal Investigator: Victor Cheuy, PhD         
University of Colorado School of Medicine Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Kristine Gerron, BS    303-724-9590    Kristine.Gerron@ucdenver.edu   
Contact: Victor Cheuy, PhD    303.724.9590    Victor.Cheuy@ucdenver.edu   
Principal Investigator: Victor Cheuy, PhD         
Sponsors and Collaborators
University of Colorado, Denver
Investigators
Principal Investigator: Victor Cheuy, PhD University of Colorado, Denver

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT02281877     History of Changes
Other Study ID Numbers: 14-0905
First Posted: November 4, 2014    Key Record Dates
Last Update Posted: November 29, 2017
Last Verified: November 2017

Keywords provided by University of Colorado, Denver:
Total Knee Arthroplasty (TKA)
Gene Expression

Additional relevant MeSH terms:
Osteoarthritis
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases