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Randomized Controlled Trial
. 2022 Apr 1;132(4):984-994.
doi: 10.1152/japplphysiol.00428.2021. Epub 2022 Mar 3.

Perioperative assessment of muscle inflammation susceptibility in patients with end-stage osteoarthritis

Devin J Drummer  1   2 , Jeremy S McAdam  1   2   3 , Regina Seay  1 , Inmaculada Aban  1   4 , Kaleen M Lavin  1   2   3 , Derek Wiggins  1   2 , Gabriel Touliatos  1   2 , Sufen Yang  1   2 , Christian Kelley  1   2 , S Craig Tuggle  1   2   3 , Brandon Peoples  1   2 , Herrick Siegel  1   5 , Elie Ghanem  1   5 , Jasvinder A Singh  1   6   7   8 , Scott Schutzler  9 , C Lowry Barnes  10 , Arny A Ferrando  9 , S Louis Bridges Jr  11   12 , Marcas M Bamman  1   2   3
Affiliations
Randomized Controlled Trial

Perioperative assessment of muscle inflammation susceptibility in patients with end-stage osteoarthritis

Devin J Drummer et al. J Appl Physiol (1985). .

Abstract

Many individuals with end-stage osteoarthritis (OA) undergo elective total hip/knee arthroplasty (THA/TKA) to relieve pain, improve mobility and quality of life. However, ∼30% suffer long-term mobility impairment following surgery. This may be in part due to muscle inflammation susceptibility (MuIS+), an overt proinflammatory pathology localized to skeletal muscle surrounding the diseased joint, present in some patients with TKA/THA. We interrogated the hypothesis that MuIS+ status results in a perturbed perioperative gene expression profile and decreases skeletal muscle integrity in patients with end-stage OA. Samples were leveraged from the two-site, randomized, controlled trial R01HD084124, NCT02628795. Participants were dichotomized based on surgical (SX) muscle gene expression of TNFRSF1A (TNF-αR). MuIS+/- samples were probed for gene expression and fibrosis. Paired and independent two-tailed t tests were used to determine differences between contralateral (CTRL) and surgical (SX) limbs and between-subject comparisons, respectively. Significance was declared at P < 0.05. Seventy participants (26M/44F; mean age 62.41 ± 8.86 yr; mean body mass index 31.10 ± 4.91 kg/m2) undergoing THA/TKA were clustered as MuIS+ (n = 24) or MuIS- (n = 46). Lower skeletal muscle integrity (greater fibrosis) exists on the SX versus CTRL limb (P < 0.001). Furthermore, MuIS+ versus MuIS- muscle exhibited higher proinflammatory (IL-6R and TNF-α) and catabolic (TRIM63) gene expression (P < 0.001, P = 0.004, and 0.024 respectively), with a trend for greater fibrosis (P = 0.087). Patients with MuIS+ exhibit more inflammation and catabolic gene expression in skeletal muscle of the SX limb, accompanied by decreased skeletal muscle integrity (Trend). This highlights the impact of MuIS+ status emphasizing the potential value of perioperative MuIS assessment to inform optimal postsurgical care.NEW & NOTEWORTHY 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.

Keywords: inflammation; osteoarthritis; rehabilitation; skeletal muscle.

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Conflict of interest statement

J. A. Singh has received consultant fees from Crealta/Horizon, Medisys, Fidia, PK Med, Two laboratories Inc., Adept Field Solutions, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, MedIQ, Jupiter Life Science, UBM LLC, Trio Health, Medscape, WebMD, and Practice Point communications; and the National Institutes of Health and the American College of Rheumatology. J. A. Singh owns stock options in TPT Global Tech, Vaxart pharmaceuticals, and Charlotte’s Web Holdings, Inc. J. A. Singh previously owned stock options in Amarin, Viking, and Moderna pharmaceuticals. J. A. Singh is on the speaker’s bureau of Simply Speaking. J. A. Singh is a member of the executive of Outcomes Measures in Rheumatology (OMERACT), an organization that develops outcome measures in rheumatology and receives arms-length funding from eight companies. J. A. Singh serves on the Food and Drug Administration Arthritis Advisory Committee. J. A. Singh is the chair of the Veterans Affairs Rheumatology Field Advisory Committee. J. A. Singh is the editor and the Director of the University of Alabama at Birmingham (UAB) Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. J. A. Singh previously served as a member of the following committees: member, the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee (AMPC) and Quality of Care Committees, the Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee and the co-chair of the ACR Criteria and Response Criteria subcommittee. None of the other authors have any conflicts of interest, financial or otherwise, to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
The influence of end-stage osteoarthritis on gene expression and skeletal muscle fibrosis. A: fold difference in expression of proinflammatory and catabolic skeletal muscle genes between contralateral (CTRL) and surgical (SX) limbs; boxplots represent SX gene expression relative to CTRL, while the –– line represents CTRL gene expression (n = 70). B: percent skeletal muscle fibrosis between the CTRL and SX limbs (n = 62). C: representative image of CTRL skeletal muscle fibrosis. D: representative image of SX skeletal muscle fibrosis. Boxplots = median (solid line), mean (square), box-ends = 1st and 3rd quartile, whiskers = ±1.5 interquartile range. *Significant P < 0.05. #Trend P < 0.1.
Figure 2.
Figure 2.
The influence of knee or hip osteoarthritis on inflammatory and catabolic gene expression. A: expression of proinflammatory receptors comparing TKA and THA. B: proinflammatory ligands comparing total knee arthroplasty (TKA) and total hip arthroplasty (THA). C: markers of skeletal muscle catabolism; E3 ubiquitin ligases comparing TKA and THA. Boxplots = median (solid line), mean (square), box-ends = 1st and 3rd quartile, whiskers = ±1.5 interquartile range. *Significant P < 0.05. #Trend P < 0.1. Data are representing n = 22 THA and n = 48 TKA participants.
Figure 3.
Figure 3.
The influence of muscle inflammation susceptibility (MuIS) status on gene expression and muscle integrity. A: inflammatory transcript receptor expression following initial dichotomization combining tumor necrosis factor alpha receptor (TNF-αR), fibroblast growth factor-inducible 14 (Fn14), and interleukin-6 receptor (IL-6R) that resulted in n = 56 MuIS− and n = 14 MuIS+. B: waterfall plot illustrating the inflection point between MuIS+ and MuIS− status using TNF-αR expression to cluster resulting in n = 46 MuIS− and n = 24 MuIS+ participants. C: expression of proinflammatory receptors comparing MuIS+ and MuIS− status, as dichotomized based on TNF-αR expression. D: proinflammatory ligands comparing MuIS+ and MuIS− status. E: markers of skeletal muscle catabolism; E3 ubiquitin ligases comparing MuIS+ and MuIS− status. F: percent skeletal muscle fibrosis across MuIS+ and MuIS− status. Boxplots = median (solid line), mean (square), box-ends = 1st and 3rd quartile, whiskers = ±1.5 interquartile range. *Significant P < 0.05. #Trend P < 0.1.
Figure 4.
Figure 4.
Association of proinflammatory receptor gene expression with skeletal muscle integrity and function. A: surgical (SX) tumor necrosis factor alpha receptor (TNF-αR) gene expression associated with fibrosis. B: SX fibroblast growth factor-inducible 14 (Fn14) gene expression associated with fibrosis. C: SX TNF-αR gene expression associated with thigh muscle mass relative to height. D: SX Fn14 gene expression associated with thigh muscle mass relative to height. E: SX TNF-αR gene expression associated with knee extension power. F: SX Fn14 gene expression associated with knee extension power. G: SX TNF-αR gene expression associated with knee extension strength. H: SX Fn14 gene expression associated with knee extension strength. *Significant P < 0.05. #Trend P < 0.1. Data are representing n = 62 (A and B), n = 60 (C and D), n = 54 (E and F), n = 58 (G and H).
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