Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis

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Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis

Steinz, Maarten M (author): Karolinska Institutet

Persson, Malin, 1983- (author): Department of Kinesiology and Physical Education, McGill University, Montreal, Canada

Aresh, Bejan (author): Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut

Olsson, Karl (author): Karolinska Institutet

Cheng, Arthur J (author): Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology, Karolinska Institutet, Stockholm, Sweden

Ahlstrand, Emma (author): Linnéuniversitetet,Institutionen för kemi och biomedicin (KOB),Linnaeus Ctr Biomat Chem, BMC

Lilja, Mats (author): Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet, Stockholm, Sweden

Lundberg, Tommy R (author): Karolinska Institutet

Rullman, Eric (author): Karolinska Institutet

Möller, Kristina Ängeby (author): Department of Physiology and Pharmacology, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

Sandor, Katalin (author): Karolinska Institutet

Ajeganova, Sofia (author): Karolinska Institutet

Yamada, Takashi (author): Department of Physical Therapy, Sapporo Medical University, Sapporo, Japan

Beard, Nicole (author): Faculty of Science and Technology, University of Canberra, Australia

Karlsson, Björn C. G. (author): Linnéuniversitetet,Institutionen för kemi och biomedicin (KOB),Avancerade material,PPL;Linnaeus Ctr Biomat Chem, BMC

Tavi, Pasi (author): Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology, Karolinska Institutet, Stockholm, Sweden; 0A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland

Kenne, Ellinor (author): Karolinska Institutet

Svensson, Camilla I (author): Karolinska Institutet

Rassier, Dilson E (author): Department of Kinesiology and Physical Education, McGill University, Montreal, Canada

Karlsson, Roger (author): Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut

Friedman, Ran (author): Linnéuniversitetet,Institutionen för kemi och biomedicin (KOB),CCBG;Linnaeus Ctr Biomat Chem, BMC

Gustafsson, Thomas (author): Karolinska Institutet

Lanner, Johanna T (author): Karolinska Institutet

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(creator_code:org_t)

2019-05-02
2019
English.
In: JCI Insight. - : American Society for Clinical Investigation (ASCI). - 2379-3708 .- 2324-7703 .- 2325-4556. ; 4:9

Related links:: http://insight.jci.o...; show more...; https://doi.org/10.1...; https://urn.kb.se/re...; https://doi.org/10.1...; https://urn.kb.se/re...; https://urn.kb.se/re...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Physiology

Articles in the publication: JCI Insight

By the university: Örebro University; Linnaeus University; Stockholm University; Karolinska Institutet

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Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis

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