Explore the vast range of titles available.

BackgroundSarcopenia is a muscle disease characterized by reduction of muscle strength and muscle mass. In RA, 25.9 to 43.3% of the patients present sarcopenia. The loss of muscle mass observed in RA patients occurs either by activation of catabolic pathways or by inhibition of anabolic pathways. Despite having a list of drugs capable of treating RA inflammation, their effect on muscle is unclear. Our objective was to evaluate the tofacitinib effect on the muscle mass of collagen-induced arthritis (CIA) mice.MethodsCIA was induced in male DBA/1J mice by subcutaneous injection of Type 2 Collagen plus Freund Adjuvant. Animals were randomized into 3 groups: CIA + tofacitinib; CIA + vehicle; and healthy controls. Treatment was administered twice a day, between days 18 and 45 after induction. Clinical score, edema, and body weight were evaluated during the experimental period. After euthanasia, tibiotarsal joints were collected for assessment of disease histopathological score, and tibialis anterior (TA) and gastrocnemius (GA) muscles were weighed to assess muscle mass. Muscle atrophy was evaluated by measurement of TA myofiber cross-sectional area (CSA). Protein expression was evaluated by western blot using GA homogenates. Serum inflammatory markers were evaluated by ELISA. Statistical analysis included ANOVA followed by Tukey’s or with Kruskal-Wallis. The statistical difference was assumed for p < 0.05.ResultsTofacitinib treatment decreased arthritis severity by reducing clinical score, and hind paw edema in comparison with the vehicle group. Tofacitinib showed weight gain, higher TA and GA weights, and increased CSA compared to the vehicle group. On day 45, Tofacitinib presented increased muscle strength compared to the vehicle group, however, no difference was found in muscle fatigue. Pax7 expression was unchanged, while MyoD expression showed an increasing trend, and myogenin expression was significantly increased in Tofacitinib compared to vehicle and control groups. The treatment didn’t modify Murf-1 expression. Tofacitinib mice showed decreased serum levels of TNF and increased IL-6 serum levels.ConclusionTofacitinib attenuated muscle loss in arthritic mice, increased muscle weight and muscle CSA. Activation of satellite cell regeneration, based on the increased expression of myogenin, is a potential mechanism involved in tofacitinib action against muscle loss.

BackgroundRheumatoid arthritis is an autoimmune inflammatory disease that often leads patients to muscle impairment and physical disability. This study aimed to evaluate changes in the activity of proteasome system in skeletal muscles of mice with collagen-induced arthritis (CIA) and treated with etanercept or methotrexate.MethodsMale DBA1/J mice were divided into four groups (n = 8 each): CIA-Vehicle (treated with saline), CIA-ETN (treated with etanercept, 5.5 mg/kg), CIA-MTX (treated with methotrexate, 35 mg/kg) and CO (healthy control group). Mice were treated two times a week for 6 weeks. Clinical score and hind paw edema were measured. Muscles were weighted after euthanasia and used to quantify proteasome activity, gene (MuRF-1, PMSα4, PSMβ5, PMSβ6, PSMβ7, PSMβ8, PSMβ9, and PSMβ10), and protein (PSMβ1, PSMβ5, PSMβ1i, PSMβ5i) expression of proteasome subunits.ResultsBoth treatments slowed disease development, but only CIA-ETN maintained muscle weight compared to CIA-MTX and CIA-Vehicle groups. Etanercept treatment showed caspase-like activity of 26S proteasome similar to CO group, while CIA-Vehicle and CIA-MTX had higher activity compared to CO group (p: 0.0057). MuRF-1 mRNA expression was decreased after etanercept administration compared to CIA-Vehicle and CO groups (p: 0.002, p: 0.007, respectively). PSMβ8 and PSMβ9 mRNA levels were increased in CIA-Vehicle and CIA-MTX compared to CO group, while CIA-ETN presented no difference from CO. PMSβ6 mRNA expression was higher in CIA-Vehicle and CIA-MTX groups than in CO group. Protein levels of the PSMβ5 subunit were increased in CO group compared to CIA-Vehicle; after both etanercept and methotrexate treatments, PSMβ5 expression was higher than in CIA-Vehicle group and did not differ from CO group expression (p: 0.0025, p: 0.001, respectively). The inflammation-induced subunit β1 (LMP2) was enhanced after methotrexate treatment compared to CO group (p: 0.043).ConclusionsThe results of CIA-Vehicle show that arthritis increases muscle proteasome activation by enhanced caspase-like activity of 26S proteasome and increased PSMβ8 and PSMβ9 mRNA levels. Etanercept treatment was able to maintain the muscle weight and to modulate proteasome so that its activity and gene expression were compared to CO after TNF inhibition. The protein expression of inflammation-induced proteasome subunit was increased in muscle of CIA-MTX group but not following etanercept treatment. Thus, anti-TNF treatment may be an interesting approach to attenuate the arthritis-related muscle wasting.

Metabolomic analysis provides a wealth of information that can be predictive of distinctive phenotypes of pathogenic processes and has been applied to better understand disease development. Rheumatoid arthritis (RA) is an autoimmune disease with the establishment of chronic synovial inflammation that affects joints and peripheral tissues such as skeletal muscle and bone. There is a lack of useful disease biomarkers to track disease activity, drug response and follow-up in RA. In this review, we describe potential metabolic biomarkers that might be helpful in the study of RA pathogenesis, drug response and risk of comorbidities. TMAO (choline and trimethylamine oxide) and TCA (tricarboxylic acid) cycle products have been suggested to modulate metabolic profiles during the early stages of RA and are present systemically, which is a relevant characteristic for biomarkers. Moreover, the analysis of lipids such as cholesterol, FFAs and PUFAs may provide important information before disease onset to predict disease activity and treatment response. Regarding therapeutics, TNF inhibitors may increase the levels of tryptophan, valine, lysine, creatinine and alanine, whereas JAK/STAT inhibitors may modulate exclusively fatty acids. These observations indicate that different disease modifying antirheumatic drugs have specific metabolic profiles and can reveal differences between responders and non-responders. In terms of comorbidities, physical impairment represented by higher fatigue scores and muscle wasting has been associated with an increase in urea cycle, FFAs, tocopherols and BCAAs. In conclusion, synovial fluid, blood and urine samples from RA patients seem to provide critical information about the metabolic profile related to drug response, disease activity and comorbidities.