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Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis
Maarten M. Steinz, … , Thomas Gustafsson, Johanna T. Lanner
Maarten M. Steinz, … , Thomas Gustafsson, Johanna T. Lanner
Published March 28, 2019
Citation Information: JCI Insight. 2019;4(9):e126347. https://doi.org/10.1172/jci.insight.126347.
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Research Article Muscle biology

Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis

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Abstract

Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here, we show that oxidative posttranslational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde (MDA) adduct modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located in 3 distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritic mice and patients with RA. Moreover, molecular dynamics simulations revealed that these areas, here coined “hotspots,” are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and may provide novel leads for targeted therapeutic treatment to improve muscle function.

Authors

Maarten M. Steinz, Malin Persson, Bejan Aresh, Karl Olsson, Arthur J. Cheng, Emma Ahlstrand, Mats Lilja, Tommy R. Lundberg, Eric Rullman, Kristina Ängeby Möller, Katalin Sandor, Sofia Ajeganova, Takashi Yamada, Nicole Beard, Björn C.G. Karlsson, Pasi Tavi, Ellinor Kenne, Camilla I. Svensson, Dilson E. Rassier, Roger Karlsson, Ran Friedman, Thomas Gustafsson, Johanna T. Lanner

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Figure 1

Muscle weakness and accompanied oxidative modifications in skeletal muscle from mice with arthritis.

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Muscle weakness and accompanied oxidative modifications in skeletal musc...
(A) An illustration of the induction site of arthritis by complete Freund’s adjuvant (CFA) (ankle: used for flexor digitorum brevis [FDB] muscle fiber force measurements; knee: used for extensor digitorum longus [EDL] whole-muscle force measurements). Immunoblots and quantification of 3-nitrotyrosine (3-NT) in interosseous (B and C) and gastrocnemius (D and E) muscle from mice with arthritis (CFA) and healthy controls (Ctrl) (n = 6). 3-NT levels were normalized to total protein Coomassie staining. (F) Ex vivo specific force (contractions induced at 15–150 Hz, n = 4–5) of intact individual muscle fibers from arthritis leg (pink) and healthy controls (blue). (G) Calculated cross-sectional area of FDB fibers from CFA and control legs. (H) Typical examples (120-Hz stimulation frequency, 350-ms train duration) of intracellular (tetanic) Ca2+ (upper) and specific force (lower) in control (blue) and CFA (pink) fibers (n = 4–5). (I) Mean (±SEM) force versus intracellular Ca2+ data obtained in 15- to 150-Hz contractions produced in control fibers and CFA fibers. Mean values of intracellular Ca2+ (J) and specific force (K) in the presence or absence of caffeine (5 mM, 2-minute exposure) in CFA and control FDB fibers. Data are mean ± SEM. Statistical analysis in C, E, G, J, and K was performed using 2-tailed Student’s t test and in F and I by 2-way ANOVA. A P value less than 0.05 was considered significant. *P < 0.05; **P < 0.01; ***P < 0.001.

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