Overcoming TWEAK Signaling to Restore Muscle and Mobility After Joint Replacement
Condition: Osteoarthritis
MeSH terms: Osteoarthritis
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): PRT + FM; Usual Care
Intervention type(s): Behavioral; Other
Intervention description(s): Supervised progressive resistance training + functional mobility training (PRT+FM) 3 days per week for 16 weeks post-surgery.; Post-surgical usual care activities including any prescribed physical therapy
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: total hip arthroplasty; total knee arthroplasty