This study assessed the skeletal muscle molecular characteristics associated with end-stage osteoarthritis and refined an important phenotype, in some patients, termed muscle inflammation susceptibility (MuIS+) that may be an important consideration following surgery. Furthermore, we provide evidence of differential inflammatory and catabolic gene expression between the contralateral and surgical limbs along with differences between the skeletal muscle surrounding the diseased hip versus knee joints.

Many individuals with end-stage osteoarthritis undergo elective total hip/knee arthroplasty (THA/TKA) to relieve pain and improve mobility and quality of life. However, ~35% suffer long-term mobility impairment following surgery. This may be in part due to muscle inflammation susceptibility (MuIS+), an overt pro-inflammatory pathology localized to skeletal muscle surrounding the diseased joint, present in some TKA/THA patients. PURPOSE: We are interrogating the hypotheses that a) MuIS+/- status will result in a differential perioperative expression profile that may partially explain low functional outcomes, and b) resistance training rehabilitation will more effectively overcome MuIS+ status than usual care for successful recovery post-surgery. METHODS: Muscle, serum, and functional data were leveraged from our ongoing two-site, randomized, controlled trial (N = 75 randomized). Participants were dichotomized based on surgical (SX) muscle gene expression of TNFRSF1A (TNFαR). MuIS+/- samples were probed for transcript expression and indices of skeletal muscle integrity. Preliminary perioperative comparisons were made using two-tailed T-tests; alpha P < 0.05. Preliminary miRNA-seq data were analyzed using Partek Flow; differentially expressed (DE) miRNAs were defined as Fold change (FC) ≥ 1.5 and P ≤ 0.05. RESULTS: 70 participants (27 M/43F; mean age 62 ± 9 yrs; mean BMI 31.3 ± 4.9 kg/m2) undergoing THA/TKA were clustered as MuIS+ (n = 24) or MuIS- (n = 46). MuIS+ muscle exhibited significantly higher pro-inflammatory (IL-6R) and catabolic (TRIM63) gene expression (P = 0.0001 and 0.03, respectively) compared to MuIS-. Further, significantly lower skeletal muscle integrity exists on the SX vs non-SX limb, illustrated by 20% higher fibrosis (P = 0.0003), and 3.5% lower thigh muscle mass (P = 0.005). Preliminary serum miRNA-seq (for N = 9) indicate 193 DE miRNAs (P ≤ 0.05, FC ≥ 1.5) following the intervention. CONCLUSIONS: Preliminary results suggest MuIS+ patients exhibit more inflammation and catabolic signaling in skeletal muscle of the SX limb, accompanied by decreased skeletal muscle integrity. This highlights the profound impact of MuIS+ status and emphasizes the potential value of perioperative MuIS assessment to inform optimal post-surgical care. Funding: T32HD071866, R01HD084124