Abstract
BackgroundIn addition to the primary symptoms arising from inflamed joints, muscle weakness is prominent and frequent in patients with rheumatoid arthritis (RA). Here, we investigated the mechanisms of arthritis-induced muscle dysfunction in rats with adjuvant-induced arthritis (AIA).MethodsAIA was induced in the knees of rats by injection of complete Freund’s adjuvant and was allowed to develop for 21 days. Muscle contractile function was assessed in isolated extensor digitorum longus (EDL) muscles. To assess mechanisms underlying contractile dysfunction, we measured redox modifications, redox enzymes and inflammatory mediators, and activity of actomyosin ATPase and sarcoplasmic reticulum (SR) Ca2+-ATPase.ResultsEDL muscles from AIA rats showed decreased tetanic force per cross-sectional area and slowed twitch contraction and relaxation. These contractile dysfunctions in AIA muscles were accompanied by marked decreases in actomyosin ATPase and SR Ca2+-ATPase activities. Actin aggregates were observed in AIA muscles, and these contained high levels of 3-nitrotyrosine and malondialdehyde-protein adducts. AIA muscles showed increased protein expression of NADPH oxidase 2/gp91phox, neuronal nitric oxide synthase, tumor necrosis factor α (TNF-α), and high-mobility group box 1 (HMGB1). Treatment of AIA rats with EUK-134 (3 mg/kg/day), a superoxide dismutase/catalase mimetic, prevented both the decrease in tetanic force and the formation of actin aggregates in EDL muscles without having any beneficial effect on the arthritis development.ConclusionsAntioxidant treatment prevented the development of oxidant-induced actin aggregates and contractile dysfunction in the skeletal muscle of AIA rats. This implies that antioxidant treatment can be used to effectively counteract muscle weakness in inflammatory conditions.
Highlights
In addition to the primary symptoms arising from inflamed joints, muscle weakness is prominent and frequent in patients with rheumatoid arthritis (RA)
Absolute extensor digitorum longus (EDL) muscle weight was ~10 % lower in the rats with adjuvant-induced arthritis (AIA) than that in controls (115 ± 5 versus 128 ± 3 mg (n = 6); P < 0.05), but this difference disappeared when muscle weight was normalized to body weight (0.4 ± 0.01 versus 0.4 ± 0.01 mg/g (n = 6); P > 0.05)
Membranes were incubated with primary antibody (anti-ryanodine receptor 1 (RyR1), MA3-925, Thermo; anti-dihydropyridine receptor (DHPR) α2 subunit, ab2864, Abcam; anti-SERCA1, MA3-911, Thermo; anti-SERCA2, ab3625, Abcam; antiactin, A4700, Sigma; anti-troponin I, MAB1691, Millipore; anti-3-NT, ab52309, Abcam; anti-malondialdehyde (MDA), MD20A-R1a, Academy Bio-Medical; anti-tumor necrosis factor α (TNF-α), 11948, Cell Signaling; anti-high-mobility group box 1 (HMGB1), 326059652, SHINO-TEST; antiNADPH oxidase 2 catalytic subunit gp91phox (NOX2/ gp91phox), ab31092, Abcam; anti-neuronal, anti-endothelial, and anti-inducible nitric oxide synthases, 610308, 610296, 610328, respectively, BD Biosciences; anti-manganese superoxide dismutase (SOD) (SOD2), 06-984, Upstate)
Summary
In addition to the primary symptoms arising from inflamed joints, muscle weakness is prominent and frequent in patients with rheumatoid arthritis (RA). Patients with rheumatoid arthritis (RA) show significant muscle weakness, and this has a major impact on the disability in these patients [1]. We previously showed that the depressed myofibrillar force production in CIA muscles was accompanied by an increased 3-nitrotyrosine (3-NT) content [5, 6], which is regarded. Yamada et al Skeletal Muscle (2015) 5:20 as a footprint of increased ONOO− production [9]. ONOO− exposure depressed Ca2+-activated force production in skinned muscle fibers from rat [10]. Impaired myofibrillar function mediated by ONOO− is likely to be important in arthritis-induced muscle dysfunction. Tiago et al [11] showed that actin is more sensitive to ONOO− than other proteins in the contractile machinery (i.e., myofibrillar proteins including myosin) and that ONOO−-induced oxidation of actin inhibits the ability of actin to stimulate actomyosin ATPase activity
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