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2015 ; 74
(10
): 1907-14
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Nitrosative modifications of the Ca2+ release complex and actin underlie
arthritis-induced muscle weakness
#MMPMID24854355
Yamada T
; Fedotovskaya O
; Cheng AJ
; Cornachione AS
; Minozzo FC
; Aulin C
; Fridén C
; Turesson C
; Andersson DC
; Glenmark B
; Lundberg IE
; Rassier DE
; Westerblad H
; Lanner JT
Ann Rheum Dis
2015[Oct]; 74
(10
): 1907-14
PMID24854355
show ga
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.
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