Overcoming TWEAK Signaling to Restore Muscle and Mobility After Joint Replacement

Study Overview
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Brief Summary
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This single-blind, randomized, controlled trial is designed to test the effect of an intensive, 16 week exercise rehabilitation program (progressive resistance training + functional mobility training) vs. usual care on restoration of muscle mass and mobility after total hip (THA) or knee (TKA) arthroplasty in men and women with end-stage osteoarthritis. The molecular basis underlying the trial is the presence of significant muscle inflammation susceptibility in many of these individuals, and the expectation that the more intensive intervention will overcome this inflammatory burden to facilitate recovery.

Detailed Description
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While elective total hip (THA) and knee (TKA) arthroplasty relieve pain and improve mobility function for thousands with end-stage osteoarthritis (OA), up to 35% endure persistent muscle atrophy and mobility limitations for several years that impact life quality, increase morbidity, and burden the healthcare system. Given that THA/TKA volumes are increasing exponentially with >1.1 million in the US annually, refractory mobility impairment is a major public health problem. Together, the available data raise two important knowledge gaps in THA/TKA rehabilitation: (i) poorly understood factors that limit responsiveness of a large number of patients to current usual care; and (ii) the absence of rehabilitation programs proven to overcome these limitations. The proposed project is designed to fill these gaps. The investigators' fundamental tenet is that restoration of mobility function following THA/TKA requires: (i) regeneration of surgically damaged muscle; and (ii) regrowth of muscles that have atrophied over years of OA and limited usage. The investigators suggest a major cause of muscle regeneration impairment in some individuals is what the investigators identified as muscle inflammation susceptibility (MuIS) - hyperactive inflammatory signaling in muscle of MuIS(+) individuals despite no systemic inflammation - which also manifests in isolated primary satellite cells and inhibits myogenesis in vitro, indicative of a true cellular phenotype beyond the niche. The investigators' preliminary findings in THA/TKA patients strongly suggest the tumor necrosis factor-like weak inducer of apoptosis (TWEAK) signaling pathway may be central to MuIS and impaired THA/TKA recovery, as high perioperative muscle TWEAK signaling in the ipsilateral thigh was the most sensitive indicator of impaired muscle protein synthesis and failed strength recovery after 8 wk of usual care. Progressive resistance exercise training (PRT) is a putative anabolic intervention that the investigators find consistently increases muscle mass to meet healthy standards in atrophied and mobility-impaired adults, by activating muscle protein synthesis and the myogenic activity of muscle satellite cells. Together, these findings raise the central hypothesis that PRT plus adjunctive functional mobility training (PRT+FM) after THA/TKA will more effectively restore muscle mass and mobility function to healthy standards than usual care and, because MuIS(+) are predicted to suffer failed muscle recovery and persistent dismobility under usual care, the impact of PRT+FM will be greatest in MuIS(+). The investigators will thoroughly test this hypothesis in a randomized controlled trial of 88 THA/TKA patients with the following aims. Aim 1: To determine the effects of 16 wk of PRT+FM vs. usual care after elective THA/TKA on muscle mass, performance, and mobility function. Aim 2: To determine whether MuIS status modifies the effects of PRT+FM or usual care after THA/TKA. Cellular and molecular mechanisms of muscle mass regulation will be studied in detail. Aim 3. To determine the long-term impact of 16 wk PRT+FM by re-assessing outcomes at 6 mo and 1 y. The investigators fully expect the novel findings to lead a paradigm shift in THA/TKA rehabilitation that will have a profound impact on a growing segment of the population.

Official Title
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Overcoming TWEAK Signaling to Restore Muscle and Mobility After Joint Replacement

Conditions
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Osteoarthritis

Intervention / Treatment
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* Behavioral: PRT + FM
* Other: Usual Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between the ages 40 and 80 y. Scheduled to undergo elective total hip or knee replacement specifically for the surgical indication of end-stage osteoarthritis. First-time hip or knee replacement. Capable of providing informed consent (cognitively intact if consenting to surgery). Exclusion Criteria: Any surgical indication other than first-time total joint replacement specifically for end-stage osteoarthritis. Bilateral knee/ hip replacement History of alcoholism or liver disease. Any history of hypo- or hyper-coagulation disorders including subjects taking Coumadin. Any individual with end-stage disease and/or a life expectancy less than one year. Pregnancy. Lactating Women. Neurological, musculoskeletal, or other disorder that would preclude them from completing the exercise training intervention and all performance tests. Uncontrolled hypertension, unstable or exercise-induced angina pectoris or myocardial ischemia, congestive heart failure. Uncontrolled diabetes mellitus. Any other condition or events considered exclusionary by the PIs and/or physician Co-Is. Lidocaine allergy (1% lidocaine is the local anesthetic used during the muscle biopsy procedure). Phenylketonuria (phenylalanine tracer for metabolic studies). Currently receiving androgen (e.g., testosterone) or anabolic (e.g., growth hormone (GH), insulin-like growth factor-I (IGF-I)) therapy. Body mass index ≥ 35. History of lower body progressive resistance training within the past year.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRT + FM<br>Progressive resistance training + functional mobility training 3 d/wk x 16 wk | Behavioral: PRT + FM<br>* Supervised progressive resistance training + functional mobility training (PRT+FM) 3 days per week for 16 weeks post-surgery.<br>Other: Usual Care<br>* Post-surgical usual care activities including any prescribed physical therapy<br>|
| Active Comparator: Usual Care<br>Post-surgical usual care including physical therapy | Other: Usual Care<br>* Post-surgical usual care activities including any prescribed physical therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in unilateral (surgical) thigh muscle mass (unit of measure = grams) | Primary muscle mass outcome of Aim 1 | Pre-surgery to 16 weeks post-surgery | 
| Change in unilateral (surgical) knee extension power (unit of measure = watts) | Primary functional outcome of Aim 1 | Pre-surgery to 16 weeks post-surgery | 
| Change in short physical performance battery (SPPB) (unit of measure = score) | Primary outcome of Aim 3 | From 16 weeks post-surgery to 26 and 52 weeks post-surgery | 
| Muscle inflammation susceptibility (MuIS) status (unit of measure = relative value) | Primary outcome of Aim 2: Muscle inflammation susceptibility (MuIS) defined by TWEAK receptor gene expression | At the time of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in muscle fiber size (unit of measure = micrometers squared) |  | From the time of surgery to 16 weeks post-surgery | 
| Change in unilateral (surgical) knee extension isometric strength (unit of measure = Newton-meters) |  | Pre-surgery to 16 weeks post-surgery | 
| Change in maximum 10-meter gait speed (unit of measure = meters per second) |  | Pre-surgery to 16 weeks post-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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total hip arthroplasty, total knee arthroplasty