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Abstract Background Rheumatoid 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. Methods Male 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. Results Both 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). Conclusions The 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. disability collageninduced collagen induced CIA (CIA DBA1J DBAJ DBA1 J DBA n each each) CIAVehicle Vehicle saline, saline , saline) CIAETN ETN 55 5 5. mg/kg, mgkg mg/kg mg kg CIAMTX MTX 3 healthy . group) weeks measured MuRF1, MuRF1 MuRF 1, 1 (MuRF-1 PMSα4 PMSα PSMβ PMSβ PSMβ7 PSMβ10, PSMβ10 PSMβ10) PSMβ1, PSMβ1 (PSMβ1 PSMβ1i PSMβi i PSMβ5i subunits development caspaselike caspase like S p (p 0.0057. 00057 0.0057 0 0057 0.0057) MuRF- 0002 002 0.002 0007 007 0.007 respectively. respectively respectively) 00025 0025 0.0025 0001 001 0.001 inflammationinduced inflammation β LMP2 LMP (LMP2 0.043. 0043 0.043 043 0.043) inhibition Thus antiTNF anti arthritisrelated related wasting (MuRF- (PSMβ 0005 0.005 005 000 00 0.00 (LMP 004 0.04 04 (MuRF 0.0 0.