Oxidative stress and muscle weakness associated with rheumatoid arthritis
Author: Steinz, Maarten Michiel
Date: 2020-02-21
Location: Karolinska Institutet Biomedicum 1, Solnavägen 9, Karolinska Institutet, Solna
Time: 9.00
Department: Inst för fysiologi och farmakologi / Dept of Physiology and Pharmacology
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Thesis (1.539Mb)
Abstract
Muscle weakness is a common comorbidity of several severe diseases which results in a reduced independence and quality of life and for the afflicted patients. For instance, patients with rheumatoid arthritis (RA), a disease characterized by a chronic inflammation of the joints, commonly report of muscle weakness as a complication. Muscle weakness is the result of reduced muscle size and intramuscular impairments (i.e. intrinsic muscle dysfunction). However, the mechanisms whereby a chronic inflammatory condition as RA leads to muscle weakness is not fully understood.
Oxidative stress due to an imbalanced production and scavenging of reactive oxygen species (ROS), is associated with intrinsic muscle dysfunction in RA. It can cause oxidative post translational modifications (oxPTMs) on RyR1 and actin which regulate muscle force production. In paper I, we show that mice with arthritis and patients with RA have a significantly decreased muscle strength which can be attributed to oxidative post-translational 3-nitro tyrosine (3NT) and malondialdehyde (MDA) modifications on actin. Combined with the results of paper II, we could conclude that the oxPTMs are introduced on specific hotspots regions of actin which impair actin-myosin cross-bridge formation and decrease actin polymerization. In addition to actin, oxidative stress on the ryanodine receptor 1 (RyR1) is associated increased RyR1 open-probability and Ca2+ leak which can ultimately lead to muscle weakness. In paper III we showed that specific 3NT and MDA modifications on RyR1 increase the channel’s open probability and lead to dissociation of the RyR1 stabilizing protein FKBP12.
The results together stress the need to study how muscle weakness caused by oxidative stress can be counteracted. Therefore, we in paper IV identified the effect of arthritis on the sources and scavengers of ROS in skeletal muscle. In paper IV we showed that while the expression of ROS scavengers SOD2, catalase and GPX1 was increased, treatment of mice with the SOD/catalase mimetic EUK-134 significantly restored muscle force. All results together stress the importance of targeted therapy against oxidative stressinduced muscle weakness in RA.
Oxidative stress due to an imbalanced production and scavenging of reactive oxygen species (ROS), is associated with intrinsic muscle dysfunction in RA. It can cause oxidative post translational modifications (oxPTMs) on RyR1 and actin which regulate muscle force production. In paper I, we show that mice with arthritis and patients with RA have a significantly decreased muscle strength which can be attributed to oxidative post-translational 3-nitro tyrosine (3NT) and malondialdehyde (MDA) modifications on actin. Combined with the results of paper II, we could conclude that the oxPTMs are introduced on specific hotspots regions of actin which impair actin-myosin cross-bridge formation and decrease actin polymerization. In addition to actin, oxidative stress on the ryanodine receptor 1 (RyR1) is associated increased RyR1 open-probability and Ca2+ leak which can ultimately lead to muscle weakness. In paper III we showed that specific 3NT and MDA modifications on RyR1 increase the channel’s open probability and lead to dissociation of the RyR1 stabilizing protein FKBP12.
The results together stress the need to study how muscle weakness caused by oxidative stress can be counteracted. Therefore, we in paper IV identified the effect of arthritis on the sources and scavengers of ROS in skeletal muscle. In paper IV we showed that while the expression of ROS scavengers SOD2, catalase and GPX1 was increased, treatment of mice with the SOD/catalase mimetic EUK-134 significantly restored muscle force. All results together stress the importance of targeted therapy against oxidative stressinduced muscle weakness in RA.
List of papers:
I. 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 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, and Johanna T. Lanner. JCI Insight. 2019, 5. piii:126347.
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II. Force generated by myosin cross-bridges is reduced in myofibrils exposed to ROS/ RNS. Malin Persson, MAARTEN M STEINZ, Håkan Westerblad, Johanna T Lanner and Dilson E Rassier. American Journal of Physiology Cell Physiology. 2019.
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III. Oxidative MDA and nitration modifications on RyR1 lead to higher open probability and FKBP12 dissociation. MAARTEN M STEINZ; Nicole Beard; Johanna T. Lanner. [Manuscript]
IV. The role of ROS sources and scavengers in skeletal muscle of mice with arthritis. MAARTEN M STEINZ*, Michaeljohn Kalakoutis*, Anna-Lena Boller, Theresa Mader, George G. Roodney, Pasi Tavi, Johanna T. Lanner. [Manuscript]
I. 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 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, and Johanna T. Lanner. JCI Insight. 2019, 5. piii:126347.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Force generated by myosin cross-bridges is reduced in myofibrils exposed to ROS/ RNS. Malin Persson, MAARTEN M STEINZ, Håkan Westerblad, Johanna T Lanner and Dilson E Rassier. American Journal of Physiology Cell Physiology. 2019.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Oxidative MDA and nitration modifications on RyR1 lead to higher open probability and FKBP12 dissociation. MAARTEN M STEINZ; Nicole Beard; Johanna T. Lanner. [Manuscript]
IV. The role of ROS sources and scavengers in skeletal muscle of mice with arthritis. MAARTEN M STEINZ*, Michaeljohn Kalakoutis*, Anna-Lena Boller, Theresa Mader, George G. Roodney, Pasi Tavi, Johanna T. Lanner. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Lanner, Johanna
Co-supervisor: Svensson, Camilla; Gustafsson, Thomas
Issue date: 2020-01-31
Rights:
Publication year: 2020
ISBN: 978-91-7831-716-5
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