Impaired myofibrillar function in the soleus muscle of mice with collagen-induced arthritis.
OBJECTIVE
Progressive muscle weakness is a common feature in patients with rheumatoid arthritis (RA). However, little is known about whether the intrinsic contractile properties of muscle fibers are affected in RA. This study was undertaken to investigate muscle contractility and the myoplasmic free Ca2+ concentration ([Ca2+](i)) in the soleus, a major postural muscle, in mice with collagen-induced arthritis (CIA).


METHODS
Muscle contractility and [Ca2+](i) were assessed in whole muscle and intact single-fiber preparations, respectively. The underlying mechanisms of contractile dysfunction were assessed by investigating redox modifications using Western blotting and antibodies against nitric oxide synthase (NOS), superoxide dismutase (SOD), 3-nitrotyrosine (3-NT), carbonyl, malondialdehyde (MDA), and S-nitrosocysteine (SNO-Cys).


RESULTS
The tetanic force per cross-sectional area was markedly decreased in the soleus muscle of mice with CIA, and the change was not due to a decrease in the amplitude of [Ca2+](i) transients. The reduction in force production was accompanied by slowing of the twitch contraction and relaxation and a decrease in the maximum shortening velocity. Immunoblot analyses showed a marked increase in neuronal NOS expression but not in inducible or endothelial NOS expression, which, together with the observed decrease in SOD2 expression, favors peroxynitrite formation. These changes were accompanied by increased 3-NT, carbonyl, and MDA adducts content in myofibrillar proteins from the muscles of mice with CIA. Moreover, there was a significant increase in SNO-Cys content in myosin heavy-chain and troponin I myofibrillar proteins from the soleus muscle of mice with CIA.


CONCLUSIONS
These findings show impaired contractile function in the soleus muscle of mice with CIA and suggest that this abnormality is due to peroxynitrite-induced modifications in myofibrillar proteins.
Yamada
Takashi
T
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Takashi.Yamada@ki.se
Place
Nicolas
N
Kosterina
Natalia
N
Ostberg
Therese
T
Zhang
Shi-Jin
SJ
Grundtman
Cecilia
C
Erlandsson-Harris
Helena
H
Lundberg
Ingrid E
IE
Glenmark
Birgitta
B
Bruton
Joseph D
JD
Westerblad
Håkan
H
D000199:Actins / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000503:physiopathology; D001835:Body Weight / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008811:Mice, Inbred DBA; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009210:Myofibrils / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
D000199:Actins; D030421:Peroxynitrous Acid; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D018995:Myosin Heavy Chains