Overcoming TWEAK Signaling to Restore Muscle and Mobility After Joint Replacement

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.

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.