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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 4

Three oxidative hotspots on the actin monomer.

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Three oxidative hotspots on the actin monomer.
The actin monomer with th...
The actin monomer with the 3 oxidative hotspots identified by mass spectrometry, visualized with zooms. (A) Hotspot 1 in subdomain 1 (SD1) with histidine (H) 101/MDA, glutamine (Q) 360/MDA, and tyrosine (Y) 362/3-NT. (B) Hotspot 2 in SD2 with H40/MDA, Q41/MDA, and Y53/3-NT. (C) Hotspot 3 in SD3 with Y294/3-NT, asparagine (N) 296/MDA, and N297/3-NT. Amino acids in red represent those residues that had the same modification in SIN-1–treated actin and actin from CFA mice (6 out of 9). The models were generated with UCSF Chimera (82).

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