Nitrosative modifications of the Ca2+ release complex and actin underlie arthritis-induced muscle weakness.
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.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
Takashi
T
Yamada
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Olga
O
Fedotovskaya
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Arthur J
AJ
Cheng
Department of Kinesiology and Physical Education and Department of Physics and Physiology, McGill University, Montreal, Canada.
Anabelle S
AS
Cornachione
Department of Kinesiology and Physical Education and Department of Physics and Physiology, McGill University, Montreal, Canada.
Fabio C
FC
Minozzo
Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
Cecilia
C
Aulin
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Cecilia
C
Fridén
Department of Clinical Sciences, Section of Rheumatology, Lund University, Malmö, Sweden.
Carl
C
Turesson
Department of Medicine, Cardiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Daniel C
DC
Andersson
Department of Clinical Science and Education, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Birgitta
B
Glenmark
Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
Ingrid E
IE
Lundberg
Department of Kinesiology and Physical Education and Department of Physics and Physiology, McGill University, Montreal, Canada.
Dilson E
DE
Rassier
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Håkan
H
Westerblad
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Johanna T
JT
Lanner
D000199:Actins / Q000378:metabolism*; D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D005260:Female; D006801:Humans; D008811:Mice, Inbred DBA; D008875:Middle Aged; D018908:Muscle Weakness / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D015538:Nitrosation; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology
D000199:Actins; D019837:Ryanodine Receptor Calcium Release Channel; C000592747:ryanodine receptor 1, mouse; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D002118:Calcium
Arthritis; Cardiovascular Disease; Rheumatoid Arthritis