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.