All ETDs from UAB

Advisory Committee Chair

S Louis Bridges Jr

Advisory Committee Members

Matthew S Alexander

Marcas M Bamman

Zachary A Graham

Merry-Lynn N McDonald

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Osteoarthritis (OA) is a debilitating, inflammatory, joint degeneration disorder, and is the most common form of arthritis. Individuals reaching end-stage OA often pursue elective total hip/knee arthroplasty (THA/TKA) to relieve pain and improve mobility and quality of life. However, approximately one third of THA/TKA patients suffer long-term mobility impairments following surgery, likely in part due to an inability to repair the damaged muscle surrounding the diseased joint. Mechanisms driving this impaired recovery remain poorly understood, therefore it is prudent to interrogate the molecular signatures in skeletal muscle at the time of surgery to provide candidate markers that may improve upon therapeutic strategies in a precision medicine manner. Here, I have contributed toward this goal through: 1) expanding upon our lab’s previous work characterizing an overt inflammatory condition localized to the skeletal muscle surrounding the OA joint, which we termed muscle inflammation susceptibility (MuIS+) status, using targeted gene expression assays (qPCR), histological assessment of skeletal muscle fibrosis, and phenotyping of physical function; 2) I have augmented our understanding from this targeted work using transcriptomic methods to elucidate skeletal muscle gene expression circuits highlighting potential OA driven molecular perturbations iv in the surrounding skeletal muscle. Through these efforts I have highlighted that some participants exhibit heightening inflammatory gene expression in the skeletal muscle overlaying the diseased joint which was associated with greater fibrosis and decreased knee extensor function; and 3) I further demonstrated a divergence in gene expression circuits between the contralateral (non-surgical, CTRL) muscle and the muscle overlaying the arthritic joint as well as highlighted expression circuits which may be contributing to declines in strength and power on the surgical side. Altogether, my work provides a strong foundation for follow-on analyses to determine the efficacy of pharmacologic and/or exercise prescriptions targeting the maladapted molecular signatures described herein.

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