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Ann Rheum Dis. 2015 Oct;74(10):1907-14. doi: 10.1136/annrheumdis-2013-205007. Epub 2014 May 22.

Nitrosative modifications of the Ca2+ release complex and actin underlie arthritis-induced muscle weakness.

Author information

1
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
2
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
3
Department of Kinesiology and Physical Education and Department of Physics and Physiology, McGill University, Montreal, Canada.
4
Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
5
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
6
Department of Clinical Sciences, Section of Rheumatology, Lund University, Malmö, Sweden.
7
Department of Medicine, Cardiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
8
Department of Clinical Science and Education, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

Abstract

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 Ca(2+) handling and specific force production.

METHODS:

Nitric oxide synthase (NOS) expression, degree of nitrosative stress and composition of the major intracellular Ca(2+) release channel (ryanodine receptor 1, RyR1) complex were measured in muscle. Changes in cytosolic free Ca(2+) concentration ([Ca(2+)]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 [Ca(2+)]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 [Ca(2+)]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 Ca(2+) activation.

KEYWORDS:

Arthritis; Cardiovascular Disease; Rheumatoid Arthritis

PMID:
24854355
PMCID:
PMC4602262
DOI:
10.1136/annrheumdis-2013-205007
[Indexed for MEDLINE]
Free PMC Article

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