Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability

Abstract

BackgroundTo identify molecular alterations in skeletal muscle in rheumatoid arthritis (RA) that may contribute to ongoing disability in RA.MethodsPersons with seropositive or erosive RA (n = 51) and control subjects matched for age, gender, race, body mass index (BMI), and physical activity (n = 51) underwent assessment of disease activity, disability, pain, physical activity and thigh muscle biopsies. Muscle tissue was used for measurement of pro-inflammatory markers, transcriptomics, and comprehensive profiling of metabolic intermediates. Groups were compared using mixed models. Bivariate associations were assessed with Spearman correlation.ResultsCompared to controls, patients with RA had 75% greater muscle concentrations of IL-6 protein (p = 0.006). In patients with RA, muscle concentrations of inflammatory markers were positively associated (p < 0.05 for all) with disease activity (IL-1β, IL-8), disability (IL-1β, IL-6), pain (IL-1β, TNF-α, toll-like receptor (TLR)-4), and physical inactivity (IL-1β, IL-6). Muscle cytokines were not related to corresponding systemic cytokines. Prominent among the gene sets differentially expressed in muscles in RA versus controls were those involved in skeletal muscle repair processes and glycolytic metabolism. Metabolic profiling revealed 46% higher concentrations of pyruvate in muscle in RA (p < 0.05), and strong positive correlation between levels of amino acids involved in fibrosis (arginine, ornithine, proline, and glycine) and disability (p < 0.05).ConclusionRA is accompanied by broad-ranging molecular alterations in skeletal muscle. Analysis of inflammatory markers, gene expression, and metabolic intermediates linked disease-related disruptions in muscle inflammatory signaling, remodeling, and metabolic programming to physical inactivity and disability. Thus, skeletal muscle dysfunction might contribute to a viscous cycle of RA disease activity, physical inactivity, and disability.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1215-7) contains supplementary material, which is available to authorized users.

Metabolomic serum profiling after ACL injury in rats: A pilot study implicating inflammation and immune dysregulation in post‐traumatic osteoarthritis

“…Reduced serum concentration of tryptophan metabolites may further support immune dysregulation in animals with ACL rupture, as decreased levels of tryptophan metabolites are frequently observed in inflammatory arthropathies and are associated with increased pro‐inflammatory cytokine production and decreased levels of immunomodulating T regs . Glycine, carnosine, and D‐mannose were strong metabolites differentiating ACLR from Control rats, and each has been associated with immune and inflammatory conditions . The findings from this preliminary investigation indicate a role of immune and inflammatory processes in the response to injury and progressive joint degeneration.…”

“…At 72 h, glycine had the highest VIP score and was involved in the significant perturbation of several pathways (Table ). Glycine has been recently implicated in muscle fibrosis in RA patients and as an amino acid crucial for collagen synthesis, it may be linked to acute tissue remodeling in our model, but further experimentation is necessary to elucidate its precise role in PTOA. At 72 h, carnosine had the third‐highest VIP rank and had significantly lower univariate concentrations in ACLR compared to Control ( p = 0.007).…”

Chronic Inflammation in Rheumatoid Arthritis and Mediators of Skeletal Muscle Pathology and Physical Impairment: A Review

“…TNF can also affect skeletal muscle function by depressing muscle fiber contractility through increasing general oxidant activity and nitric oxide activity (). Interestingly, in a study involving individuals with RA (), muscle cytokine levels did not reflect systemic cytokine levels, but were two times higher in the muscles of RA patients. This finding suggests that muscle cytokines were produced locally by myofibers, resident inflammatory cells, and/or adipocytes.…”

“…Muscle oxidative metabolic capacity is essential for the generation of ATP in order to fuel skeletal muscle contraction, locomotion, and maintain homeostatic cellular electrolyte balance (i.e., sodium‐potassium pumps). In a metabolic profiling study (), the concentration of pyruvate in muscle in individuals with RA was significantly higher than in muscle from controls, and the expression of genes controlling glycolytic metabolism was also significantly up‐regulated in those with RA versus controls. Pyruvate is the end‐product of glycolysis, and normally feeds into the tricarboxylic acid cycle, generating energy intermediates that are critical for mitochondrial ATP synthesis through oxidative phosphorylation.…”

Effects of a two-year health-enhancing physical activity program on skeletal muscle protein profiles in people with rheumatoid arthritis

“…A recent study revealed broad-ranging molecular alterations regarding pro-in ammatory markers, transcriptional pro les and metabolic signatures in skeletal muscle of people with RA compared to matched healthy individuals 8 . Furthermore, disease activity, disability and physical inactivity in people with RA were associated with altered levels of the muscle pro-in ammatory mediators and metabolic intermediates.…”