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

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 5

Patients with RA exhibit muscle weakness and matching oxidative hotspots on the actin monomer.

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Patients with RA exhibit muscle weakness and matching oxidative hotspots...
(A) An illustration of the composite disease activity score (DAS), with a 44-joint count (red circles) to assess swelling and 53-joint count to assess pain (DAS can range from 0.23 to 9.87). Mean ± SEM DAS was 3.3 ± 0.4 (n = 11, see Supplemental Table 3 for details). (B) Mean ± SEM of isometric specific force of quadriceps femoris from patients with RA and healthy controls (n = 11 per group). (C) Cross-sectional area (CSA) of quadriceps femoris measured by CT scans (mean ± SEM, n = 11). (D) Total daily activity in minutes measured with Actilife accelerometers (mean ± SEM, n = 11) and (E) percentage time spent in each defined activity category. (F) Overview of the oxidative 3-nitrotyrosine (3-NT) and malondialdehyde (MDA) modified amino acids on skeletal muscle actin (SD1–SD4) identified by mass spectrometry in patients with RA (n = 5). The actin model is adapted from the 2ZWH crystal structure of the Protein Data Bank Europe (PDBe). Tyrosine residues (Y) were nitrated (3-NT), whereas histidine (H), glutamine (Q) and asparagine (N) were MDA modified. (G–I) The actin monomer model illustrating that the oxidative hotspots in patients with RA (green) coincide with hotspots in mice with arthritis (pink). Amino acids depicted in red ribbons represent the residues that had the identical modification on actin in RA patients and CFA mice (5 out of 11). Generated with UCSF Chimera (82). Statistical analysis was performed using 2-tailed Student’s t test. A P value less than 0.05 was considered significant. *P < 0.05.