Skeletal Muscle Atrophy and Dysfunction Following Total Knee Arthroplasty

Study Overview
=================
Brief Summary
-----------------
Total knee replacement, or arthroplasty, is the final clinical intervention available to relieve pain and functional limitations related to advanced stage knee osteoarthritis. Despite its beneficial effects, the early post-surgical period is characterized by the erosion of lower extremity muscle size and strength that cause further disability and slow functional recovery. While the detrimental effects of this period on muscle are widely recognized, the mechanisms underlying these adaptations are poorly understood and there are currently no widely-accepted clinical interventions to counter them

Detailed Description
-----------------
Total knee arthroplasty (TKA) is currently the most common elective surgery in the US and will increase in frequency nearly five-fold by 2030 to 3.5 million surgeries annually. This surgery is most prevalent among older adults with advanced knee osteoarthritis (OA) and its increase is explained primarily by growth in this population. Although TKA reliably reduces joint pain, it fails to correct objectively-measured functional disability due, in part, to dramatic declines in lower-extremity neuromuscular function during the early, postsurgical period. These deficits are never fully remediated, remaining for years after surgery and contributing to persistent disability. Despite these detrimental effects of TKA, the fundamental skeletal muscle adaptations that occur in the early, post-surgical period are poorly defined and understudied and there is currently no widely-accepted, evidence-based intervention to counter these changes. To address this clinical problem, the investigators goals in this application are to define the skeletal muscle structural and functional adaptations following TKA at the whole body, tissue, cellular, organellar and molecular levels in humans in an effort to identify factors contributing to functional disability and to assess the utility of neuromuscular electrical stimulation (NMES) to counter post-surgical muscle adaptations at these same anatomic levels. We hypothesize that TKA fails to remediate physical disability in patients, in part, because of the profound skeletal muscle myofilament and mitochondrial loss and dysfunction that develops during the early, post-surgical period. Moreover, the investigators posit that NMES will improve functional recovery following TKA by countering these early skeletal muscle adaptations. To test this model, the investigators will evaluate participants with knee OA prior to and following TKA for skeletal muscle structure and function at multiple anatomic levels, with patients randomized to receive NMES or sham control intervention during the first 5 weeks post-surgery.

Official Title
-----------------
Skeletal Muscle Atrophy and Dysfunction Following Total Knee Arthroplasty

Conditions
-----------------
Knee Osteoarthritis

Intervention / Treatment
-----------------
* Device: Neuromuscular electrical stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: symptomatic, primary knee osteoarthritis (OA) being considered for total knee arthroplasty Exclusion Criteria: knee OA secondary to inflammatory/autoimmune disease untreated/uncontrolled hypertension, diabetes or thyroid disease chronic heart failure, actively-treated malignancy, exercise-limiting peripheral vascular disease, stroke or neuromuscular disease body mass index >38 kg/m2 lower extremity blood clot or known coagulopathies implanted pacemaker/ICD

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NMES<br>Neuromuscular electrical stimulation (NMES) will be administered for 5 weeks post-TKA in the quadriceps of the surgical leg. Treatment will occur 5 days per week, twice daily for 45 minutes on each occasion. | Device: Neuromuscular electrical stimulation<br>* NMES will be conducted on the quadriceps of the operative leg using a portable stimulation device, starting within 48-72 hrs of surgery. The operative leg will be immobilized at a neutral angle ( 30º), with electrodes affixed to the anterior surface of the thigh. Symmetrical, biphasic pulses (400 µs duration at 50 Hz) will be used, with a duty cycle of 25% (10 s on, 30 s off), with patient-selected stimulation intensity to cause visible contractions below pain threshold. NMES sessions will occur 5 d/week, twice daily for 45 min (5 min warm-up) for 5 wks.<br>* Other names: NMES;|
| No Intervention: Control<br>No intervention will be administered during the 5 weeks post-TKA in the surgical leg. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cross-sectional area of muscle fibers | Cross-sectional area of skeletal muscle fibers will be evaluated using immunohistochemistry, with specification of all relevant muscle fiber types | Change from baseline cross-sectional area at 5 weeks | 
| Intermyofibrillar mitochondrial content | Area fraction of intermyofibrillar mitochondria will be assessed by electron microscopy | Change from baseline cross-sectional area at 5 weeks | 
| Maximal calcium-activated tension single muscle fiber tension and shortening velocity | Tension (force per unit muscle fiber cross-sectional area) from segments of chemically-skinned single human muscle fibers will be assessed under maximal calcium-activated condition and shortening velocity will be evaluated from isotonic load clamps, with muscle fiber type determined post-measurement by gel electrophoresis | Change from baseline cross-sectional area at 5 weeks | 
| Mitochondrial function | Oxygen consumption rate of isolated muscle mitochondria under adenosine diphosphate stimulation and hydrogen peroxide production | Change from baseline cross-sectional area at 5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical activity level | Physical activity will be assessed by accelerometry. | Change from baseline cross-sectional area at 5 weeks | 
| Quadriceps muscle cross-sectional area | Quadriceps muscle cross-sectional area will be assessed by computed tomography at the mid-thigh. | Change from baseline cross-sectional area at 5 weeks | 
| Physical functional measures | Whole body physical function will be assessed. | Change from baseline cross-sectional area at 5 weeks | 
| Whole muscle strength | Knee extensor isometric and isokinetic strength will be assessed by dynamometry. | Change from baseline cross-sectional area at 5 weeks |