Background/Purpose: Age-related declines in muscle mass and function are leading causes for hospitalizations and mortality in elderly individuals. The risk of developing knee osteoarthritis also increases with age and those affected display reductions in skeletal muscle mass, quality and function yet the mechanisms behind these changes are broadly unknown. Characterizing the transcriptional landscape of skeletal muscle from patients with knee OA to identify molecular targets of skeletal muscle dysfunction and then formulate a targeted treatment approach.

Methods: Study participants (n=528, 56% Female; mean age 76.6 ± 4.9 years) were enrolled in the Study of Muscle, Mobility and Aging (SOMMA), a longitudinal cohort study of subjects, >70 years of age, free of life-threatening diseases and mobile. Study subjects had obtained a muscle biopsy at the baseline study visit and knee radiographs at the year 1 follow-up visit. Radiographic OA (ROA) was determined by Kellgren and Lawrence scores (0-4), and knee pain was self-reported to be at least monthly in the right knee. RNA sequencing data were analyzed using DESeq2 to assess differential gene expression, contrasting a control group (Kellgren-Lawrence (KL) score 0–1, n=322) with three nested “case” groups: (1) all KL ≥2 (n=206), (2) KL ≥2 with pain (n=114), and (3) KL ≥3 with pain (n=74). Covariates in the statistical models included sex, race/ethnicity, age, weight, waist circumference, abdominal adiposity from MRI, right anterior thigh fat free muscle volume, clinical site, batch, steps per day (using GGIR actigraph), and pain medications. Resulting pathway enrichment analysis was performed using CAMERA.

Results: DESeq2 revealed differential transcript expression across the three case-control contrasts, with 20, 10 and 22 differentially expressed genes for contrasts 1-3 respectively. Two genes, Mettl21c, a methyltransferase, and pseudogene Rpl29p11 displayed differential expression in all three contrasts. Pathway enrichment analysis revealed significant differences between the three contrasts, with gene expression regulatory terms and pathways related to ribosomes and translation being downregulated in groups 2&3. Group 3 also displayed unique enrichment of GABA secretion (z-score: 3.6, FDR=0.03) and glucocorticoid (GC) signaling (z-score: 3.4, FDR< 0.05).

Conclusion: Gene expression profiling of ROA skeletal muscle reveals differential molecular profiles based on KL grade and self-reported knee pain. Patients presenting with KL 3+ and pain displayed unique pathway enrichments indicative of transcriptional and translational repression, GC signaling and GABA secretion. Given adjustment for physical activity in statistical modeling, these findings suggests that elevated GC and GABA signaling may be potential mechanisms for skeletal muscle dysfunction and atrophy in advanced stage ROA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptomic-profiling-of-the-skeletal-muscle-of-knee-oa-patients-uncovers-elevated-glucocorticoid-and-gaba-signaling-as-mediators-of-skeletal-muscle-dysfunction-in-advanced-disease/