Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article numbere126347
JournalJCI Insight
Volume4
Issue number9
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Cite this

Steinz, M. M., Persson, M., Aresh, B., Olsson, K., Cheng, A. J., Ahlstrand, E., ... Lanner, J. T. (2019). Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis. JCI Insight, 4(9), [e126347]. https://doi.org/10.1172/jci.insight.126347