期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 74, 期 10, 页码 1907-1914出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2013-205007
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资金
- Swedish Research Council
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [R01 AR062083]
- Canadian Institute for Health Research (CIHR)
- Karolinska Institutet Foundation
- Swedish Foundation for Strategic Research
- Magnus Bergvall Foundation
- Swedish Heart and Lung Foundation
- French Muscular Dystrophy Association (AFM)
- Ake Wiberg Foundation
- Swedish Rheumatism Association
- Combine Sweden
- Stockholm County Council
- Karolinska Institutet
- Grants-in-Aid for Scientific Research [26702021] Funding Source: KAKEN
Objective Skeletal muscle weakness is a prominent clinical feature in patients with rheumatoid arthritis (RA), but the underlying mechanism(s) is unknown. Here we investigate the mechanisms behind arthritis-induced skeletal muscle weakness with special focus on the role of nitrosative stress on intracellular Ca2+ handling and specific force production. Methods Nitric oxide synthase (NOS) expression, degree of nitrosative stress and composition of the major intracellular Ca2+ release channel (ryanodine receptor 1, RyR1) complex were measured in muscle. Changes in cytosolic free Ca2+ concentration ([Ca2+](i)) and force production were assessed in single-muscle fibres and isolated myofibrils using atomic force cantilevers. Results The total neuronal NOS (nNOS) levels were increased in muscles both from collagen-induced arthritis (CIA) mice and patients with RA. The nNOS associated with RyR1 was increased and accompanied by increased [Ca2+](i) during contractions of muscles from CIA mice. A marker of peroxynitrite-derived nitrosative stress (3-nitrotyrosine, 3-NT) was increased on the RyR1 complex and on actin of muscles from CIA mice. Despite increased [Ca2+](i), individual CIA muscle fibres were weaker than in healthy controls, that is, force per cross-sectional area was decreased. Furthermore, force and kinetics were impaired in CIA myofibrils, hence actin and myosin showed decreased ability to interact, which could be a result of increased 3-NT content on actin. Conclusions Arthritis-induced muscle weakness is linked to nitrosative modifications of the RyR1 protein complex and actin, which are driven by increased nNOS associated with RyR1 and progressively increasing Ca2+ activation.
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