Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis

Steinz, Maarten M.; Persson, Malin; Aresh, Bejan; Olsson, Karin; Cheng, Arthur J.; Ahlstrand, Emma; Lilja, Mats; Lundberg, Tommy R.; Möller, Kristina Ängeby; Sándor, Katalin; Ajeganova, Sofia; Yamada, Takashi; Beard, Nicole A.; Karlsson, Britt; Tavi, Pasi; Kenne, Ellinor; Svensson, Camilla I.; Rassier, Dilson E.; Karlsson, Roger; Friedman, Ran; Gustafsson, Thomas; Lanner, Johanna T.

doi:10.1172/jci.insight.126347

Cited by 28 publications

(27 citation statements)

References 101 publications

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“…Increased protein oxidation in muscle tissue results in alterations to structure and function, which enhances proteolytic breakdown by calpain, caspase-3, the ubiquitinproteasome system and the autophagy/lysosomal system [36][37][38]. Oxidation of actin and tropomyosin has been demonstrated in heart failure and skeletal muscle weakness which likely contributes to contractile impairment [39][40][41]. In addition, increased ROS production can disrupt muscle contraction by altering calcium homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

et al. 2020

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Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction. Author contributions AJS, HHS and ARJ designed the study. AJS, BMR, MPW, OK, JY, DDC and DDF performed the experiments and analyzed the data. HHS provided the SS-31. AJS and ARJ wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

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Section: Discussionmentioning

confidence: 99%

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

et al. 2020

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“…Moreover, post-translational modifications on important contractile proteins accompanying the arthritis-induced muscle weakness have been observed in rodent models of arthritis [ 23 , 24 ]. Recently, we also showed that oxidative stress-induced post-translational modifications on the contractile protein actin results in decreased ability of actin and myosin to form force-generating cross-bridges and thereby directly contribute to muscle weakness in a mouse model of arthritis and in patients with RA [ 11 ]. Thus, RA appears to induce both muscle atrophy and intrinsic muscle dysfunction which leads to reduced force production and muscle weakness.…”

Section: Rheumatoid Arthritis Does Not Only Affect the Jointsmentioning

confidence: 99%

Skeletal muscle redox signaling in rheumatoid arthritis

2020

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis and the presence of serum autoantibodies. In addition, skeletal muscle weakness is a common comorbidity that contributes to inability to work and reduced quality of life. Loss in muscle mass cannot alone account for the muscle weakness induced by RA, but instead intramuscular dysfunction appears as a critical factor underlying the decreased force generating capacity for patients afflicted by arthritis. Oxidative stress and associated oxidative post-translational modifications have been shown to contribute to RA-induced muscle weakness in animal models of arthritis and patients with RA. However, it is still unclear how and which sources of reactive oxygen and nitrogen species (ROS/RNS) that are involved in the oxidative stress that drives the progression toward decreased muscle function in RA. Nevertheless, mitochondria, NADPH oxidases (NOX), nitric oxide synthases (NOS) and phospholipases (PLA) have all been associated with increased ROS/RNS production in RA-induced muscle weakness. In this review, we aim to cover potential ROS sources and underlying mechanisms of oxidative stress and loss of force production in RA. We also addressed the use of antioxidants and exercise as potential tools to counteract oxidative stress and skeletal muscle weakness.

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“…Furthermore, disease activity, disability and physical inactivity in people with RA were associated with altered levels of the muscle pro-in ammatory mediators and metabolic intermediates. Also, oxidative stress induced modi cations in actin and promoted muscle weakness in people with RA by breaking actin lament stability and disrupting myosin interactions 9 .…”

Section: Introductionmentioning

confidence: 99%

Effects of a two-year health-enhancing physical activity program on skeletal muscle protein profiles in people with rheumatoid arthritis

Ossipova

Idborg

Fridén

et al. 2020

Preprint

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Background Rheumatoid arthritis (RA) induces loss of muscle mass and impairments, which discourage physical activity. Consequently, RA is associated with decreased levels of exercise. Positive effects of exercise on physical and mental health without increasing pain or disease activity have been demonstrated but the influence of moderate-intensity physical activity on the molecular effects in skeletal muscle in people with RA remains unclear. In this pilot study we investigated the impact of a two-year health-enhancing physical activity (HEPA) program on protein profiles in skeletal muscle biopsies from people with RA based on a unique set of interdisciplinary variables. Methods Six people with RA participated. Muscle biopsies were taken from m. vastus lateralis, and perceived disease impact, anthropometrics and physical capacity tests were assessed at baseline and year 1 and 2. Mass spectrometry-based quantitative proteomics and immunohistochemistry analysis were employed to examine molecular changes in the skeletal muscle in response to long-term HEPA. Results The study participants had moderate to low adherence to the HEPA program, the perceived disease impact and anthropometric parameters were not altered. Among the physical capacity tests, the Timed-stands test showed a significant improvement after one year. Mean pressure pain threshold was significantly reduced after 1- and 2-year HEPA participation. Proteome analysis of the muscle biopsies showed an up-regulation of proteins in the mitochondrial respiratory chain and predicted increased ATP production and improved muscle contractility in response to HEPA. Molecular pathways identified by proteome analysis revealed correlations to pain variables. Conclusions Our results indicate that long-term physical activity in people with RA may up-regulate proteins in the mitochondrial respiratory chain predicting increased ATP production and muscle contractility similar to what has been reported in healthy young men and might have a positive impact on muscle tissue by decreased muscle cell death.

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Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis

Cited by 28 publications

References 101 publications

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

Skeletal muscle redox signaling in rheumatoid arthritis

Effects of a two-year health-enhancing physical activity program on skeletal muscle protein profiles in people with rheumatoid arthritis

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