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

Research output: Contribution to journalArticle

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
Pages (from-to)1-16
Number of pages16
JournalJCI Insight
Volume4
Issue number9
DOIs
Publication statusPublished - 2 May 2019

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Muscle Weakness
Actins
Rheumatoid Arthritis
Skeletal Muscle
Arthritis
Molecular Dynamics Simulation
Myosins
Post Translational Protein Processing
Malondialdehyde
Polymerization
Mass Spectrometry
Oxidative Stress
Quality of Life
Muscles
Therapeutics

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), 1-16. [e126347]. https://doi.org/10.1172/jci.insight.126347
Steinz, Maarten M. ; Persson, Malin ; Aresh, Bejan ; Olsson, Karl ; Cheng, Arthur J. ; Ahlstrand, Emma ; Lilja, Mats ; Lundberg, Tommy R. ; Rullman, Eric ; Möller, Kristina Angeby ; Sandor, Katalin ; Ajeganova, Sofia ; Yamada, Takashi ; Beard, Nicole ; Karlsson, Björn C.G. ; Tavi, Pasi ; Kenne, Ellinor ; Svensson, Camilla I. ; Rassier, Dilson E. ; Karlsson, Roger ; Friedman, Ran ; Gustafsson, Thomas ; Lanner, Johanna T. / Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis. In: JCI Insight. 2019 ; Vol. 4, No. 9. pp. 1-16.
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Steinz, MM, Persson, M, Aresh, B, Olsson, K, Cheng, AJ, Ahlstrand, E, Lilja, M, Lundberg, TR, Rullman, E, Möller, KA, Sandor, K, Ajeganova, S, Yamada, T, Beard, N, Karlsson, BCG, Tavi, P, Kenne, E, Svensson, CI, Rassier, DE, Karlsson, R, Friedman, R, Gustafsson, T & Lanner, JT 2019, 'Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis', JCI Insight, vol. 4, no. 9, e126347, pp. 1-16. https://doi.org/10.1172/jci.insight.126347

Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis. / Steinz, Maarten M.; Persson, Malin; Aresh, Bejan; Olsson, Karl; Cheng, Arthur J.; Ahlstrand, Emma; Lilja, Mats; Lundberg, Tommy R.; Rullman, Eric; Möller, Kristina Angeby; Sandor, Katalin; Ajeganova, Sofia; Yamada, Takashi; Beard, Nicole; Karlsson, Björn C.G.; Tavi, Pasi; Kenne, Ellinor; Svensson, Camilla I.; Rassier, Dilson E.; Karlsson, Roger; Friedman, Ran; Gustafsson, Thomas; Lanner, Johanna T.

In: JCI Insight, Vol. 4, No. 9, e126347, 02.05.2019, p. 1-16.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis

AU - Steinz, Maarten M.

AU - Persson, Malin

AU - Aresh, Bejan

AU - Olsson, Karl

AU - Cheng, Arthur J.

AU - Ahlstrand, Emma

AU - Lilja, Mats

AU - Lundberg, Tommy R.

AU - Rullman, Eric

AU - Möller, Kristina Angeby

AU - Sandor, Katalin

AU - Ajeganova, Sofia

AU - Yamada, Takashi

AU - Beard, Nicole

AU - Karlsson, Björn C.G.

AU - Tavi, Pasi

AU - Kenne, Ellinor

AU - Svensson, Camilla I.

AU - Rassier, Dilson E.

AU - Karlsson, Roger

AU - Friedman, Ran

AU - Gustafsson, Thomas

AU - Lanner, Johanna T.

PY - 2019/5/2

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N2 - 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.

AB - 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.

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KW - Rheumatoid arthritis

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DO - 10.1172/jci.insight.126347

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Steinz MM, Persson M, Aresh B, Olsson K, Cheng AJ, Ahlstrand E et al. Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis. JCI Insight. 2019 May 2;4(9):1-16. e126347. https://doi.org/10.1172/jci.insight.126347