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 Karlsson & 3 others Ran Friedman, Thomas Gustafsson, Johanna T. Lanner

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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 post-translational 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 adduct (MDA) modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located to three distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritis mice and RA patients. Moreover, molecular dynamic 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 provide novel leads for targeted therapeutic treatment to improve muscle function.

Original languageEnglish
Article numbere126347
Pages (from-to)1-16
Number of pages16
JournalJCI Insight
Volume4
Issue number9
DOIs
Publication statusPublished - 2019

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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), 1-16. [e126347]. https://doi.org/10.1172/jci.insight.126347