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Muscle dysfunction associated with adjuvant-induced arthritis is prevented by antioxidant treatment.

Yamada T, Abe M, Lee J, Tatebayashi D, Himori K, Kanzaki K, Wada M, Bruton JD, Westerblad H, Lanner JT - Skelet Muscle (2015)

Bottom Line: These contractile dysfunctions in AIA muscles were accompanied by marked decreases in actomyosin ATPase and SR Ca(2+)-ATPase activities.AIA muscles showed increased protein expression of NADPH oxidase 2/gp91(phox), neuronal nitric oxide synthase, tumor necrosis factor α (TNF-α), and high-mobility group box 1 (HMGB1).This implies that antioxidant treatment can be used to effectively counteract muscle weakness in inflammatory conditions.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Health Sciences, Sapporo Medical University, South 1 West 17, Chuo-ku, 060-8556, Sapporo Japan.

ABSTRACT

Background: In 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).

Methods: AIA 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) Ca(2+)-ATPase.

Results: EDL 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 Ca(2+)-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/gp91(phox), 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.

Conclusions: Antioxidant 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.

No MeSH data available.


Related in: MedlinePlus

Antioxidant treatment prevents contractile dysfunction in AIA EDL muscles. Representative original records of twitch (a) and 100 Hz tetanic (c) force from a control (CNT, dashed line) and an AIA (full line) EDL muscle. The peak rates of twitch force development (dP/dt) and relaxation (−dP/dt) (b) and specific force-frequency relationship (d) in CNT and AIA EDL muscles. Maximum knee diameter (e) and specific force-frequency relationship (f) in EDL muscles from CNT and AIA rats with or without treatment with EUK-134 (EUK). Data are presented as mean ± SEM for four to seven muscles in each group. *P < 0.05, **P < 0.01 versus CNT, ##P < 0.01 versus AIA
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Fig2: Antioxidant treatment prevents contractile dysfunction in AIA EDL muscles. Representative original records of twitch (a) and 100 Hz tetanic (c) force from a control (CNT, dashed line) and an AIA (full line) EDL muscle. The peak rates of twitch force development (dP/dt) and relaxation (−dP/dt) (b) and specific force-frequency relationship (d) in CNT and AIA EDL muscles. Maximum knee diameter (e) and specific force-frequency relationship (f) in EDL muscles from CNT and AIA rats with or without treatment with EUK-134 (EUK). Data are presented as mean ± SEM for four to seven muscles in each group. *P < 0.05, **P < 0.01 versus CNT, ##P < 0.01 versus AIA

Mentions: There was no significant difference in the absolute twitch force of the EDL muscle between the rats with AIA and control rats (0.38 ± 0.02 versus 0.37 ± 0.02 N (n = 6); P > 0.05) (Fig. 2a). In contrast, the rates of force development (dP/dt) and relaxation (–dP/dt) in twitches were decreased by 27 and 29 % in AIA EDL muscles, respectively (Fig. 2a, b). Absolute tetanic force was ~20 % lower in AIA EDL muscles than that in controls at stimulation frequencies from 70 to 120 Hz (Fig. 2c). Although the cross-sectional area of AIA EDL muscles was somewhat decreased, tetanic force per cross-sectional area (i.e., specific force) was ~15 % lower than in control muscles at 100 and 120 Hz (P < 0.05 and P < 0.01, respectively) (Fig. 2d). Moreover, there was a left-ward shift of the force-frequency relationship in AIA EDL muscles with the frequency giving 50 % of the maximum force being significantly lower than in control muscles (31.9 ± 1.7 versus 40.9 ± 1.6 Hz (n = 6); P < 0.05).Fig. 2


Muscle dysfunction associated with adjuvant-induced arthritis is prevented by antioxidant treatment.

Yamada T, Abe M, Lee J, Tatebayashi D, Himori K, Kanzaki K, Wada M, Bruton JD, Westerblad H, Lanner JT - Skelet Muscle (2015)

Antioxidant treatment prevents contractile dysfunction in AIA EDL muscles. Representative original records of twitch (a) and 100 Hz tetanic (c) force from a control (CNT, dashed line) and an AIA (full line) EDL muscle. The peak rates of twitch force development (dP/dt) and relaxation (−dP/dt) (b) and specific force-frequency relationship (d) in CNT and AIA EDL muscles. Maximum knee diameter (e) and specific force-frequency relationship (f) in EDL muscles from CNT and AIA rats with or without treatment with EUK-134 (EUK). Data are presented as mean ± SEM for four to seven muscles in each group. *P < 0.05, **P < 0.01 versus CNT, ##P < 0.01 versus AIA
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4496877&req=5

Fig2: Antioxidant treatment prevents contractile dysfunction in AIA EDL muscles. Representative original records of twitch (a) and 100 Hz tetanic (c) force from a control (CNT, dashed line) and an AIA (full line) EDL muscle. The peak rates of twitch force development (dP/dt) and relaxation (−dP/dt) (b) and specific force-frequency relationship (d) in CNT and AIA EDL muscles. Maximum knee diameter (e) and specific force-frequency relationship (f) in EDL muscles from CNT and AIA rats with or without treatment with EUK-134 (EUK). Data are presented as mean ± SEM for four to seven muscles in each group. *P < 0.05, **P < 0.01 versus CNT, ##P < 0.01 versus AIA
Mentions: There was no significant difference in the absolute twitch force of the EDL muscle between the rats with AIA and control rats (0.38 ± 0.02 versus 0.37 ± 0.02 N (n = 6); P > 0.05) (Fig. 2a). In contrast, the rates of force development (dP/dt) and relaxation (–dP/dt) in twitches were decreased by 27 and 29 % in AIA EDL muscles, respectively (Fig. 2a, b). Absolute tetanic force was ~20 % lower in AIA EDL muscles than that in controls at stimulation frequencies from 70 to 120 Hz (Fig. 2c). Although the cross-sectional area of AIA EDL muscles was somewhat decreased, tetanic force per cross-sectional area (i.e., specific force) was ~15 % lower than in control muscles at 100 and 120 Hz (P < 0.05 and P < 0.01, respectively) (Fig. 2d). Moreover, there was a left-ward shift of the force-frequency relationship in AIA EDL muscles with the frequency giving 50 % of the maximum force being significantly lower than in control muscles (31.9 ± 1.7 versus 40.9 ± 1.6 Hz (n = 6); P < 0.05).Fig. 2

Bottom Line: These contractile dysfunctions in AIA muscles were accompanied by marked decreases in actomyosin ATPase and SR Ca(2+)-ATPase activities.AIA muscles showed increased protein expression of NADPH oxidase 2/gp91(phox), neuronal nitric oxide synthase, tumor necrosis factor α (TNF-α), and high-mobility group box 1 (HMGB1).This implies that antioxidant treatment can be used to effectively counteract muscle weakness in inflammatory conditions.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Health Sciences, Sapporo Medical University, South 1 West 17, Chuo-ku, 060-8556, Sapporo Japan.

ABSTRACT

Background: In 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).

Methods: AIA 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) Ca(2+)-ATPase.

Results: EDL 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 Ca(2+)-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/gp91(phox), 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.

Conclusions: Antioxidant 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.

No MeSH data available.


Related in: MedlinePlus