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 Ca 2؉ concentration ([Ca 2؉ ] i ) in the soleus, a major postural muscle, in mice with collagen-induced arthritis (CIA).Methods. Muscle contractility and [Ca 2؉ ] 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 (SNOCys).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 [Ca 2؉ ] 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.Conclusion. 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.

The effects of the general antioxidant N-acetylcysteine (NAC) on muscle function and metabolism were examined. Isolated paired mouse extensor digitorum longus muscles were studied in the absence or presence of 20 mM NAC. Muscles were electrically stimulated to perform 100 isometric tetanic contractions (300 ms duration) at frequencies resulting in ∼85% of maximal force (70-150 Hz at 25-40 °C). NAC did not significantly affect peak force in the unfatigued state at any temperature but significantly slowed tetanic force development in a temperature-dependent fashion (e.g., time to 50% of peak tension averaged 35 ± 2 ms [control] and 37 ± 1 ms [NAC] at 25 °C vs. 21 ± 1 ms [control] and 52 ± 6 ms [NAC, P < 0.01] at 40 °C). During repeated contractions, NAC maximally enhanced peak force by the fifth tetanus at all temperatures (by ∼30%). Thereafter, the effect of NAC disappeared rapidly at high temperatures (35-40 °C) and more slowly at the lower temperatures (25-30 °C). At all temperatures, the enhancing effect of NAC on peak force was associated with a slowing of relaxation. NAC did not significantly affect myosin light chain phosphorylation at rest or after five contractions (∼50% increase vs. rest). After five tetani, lactate and inorganic phosphate increased about 20-fold and 2-fold, respectively, both in control and NAC-treated muscles. Interestingly, after five tetani, the increase in glucose 6-P was ∼2-fold greater, whereas the increase in malate was inhibited by ∼75% with NAC vs. control, illustrating the metabolic effects of NAC. NAC slightly decreased the maximum shortening velocity in early fatigue (five to seven repeated tetani). These data demonstrate that the antioxidant NAC transiently enhances muscle force generation by a mechanism that is independent of changes in myosin light chain phosphorylation and inorganic phosphate. The slowing of relaxation suggests that NAC enhances isometric force by facilitating fusion (i.e., delaying force decline between pulses). The initial slowing of tension development and subsequent slowing of relaxation suggest that NAC would result in impaired performance during a high-intensity dynamic exercise.

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Skeletal muscle modelling requires a detailed description of muscular force production. We have performed a series of experiments on mouse skeletal muscles to give a basis for an improved description of the muscular force production. Our previous work introduced a force modification in isometric phases, which was based on the work performed by or on the muscle during transient-length-varying contractions. Here, state-space diagrams were used to investigate the timing aspects of the force production. These show a dominant exponential nature of the force development in isometric phases of the contractions, reached after a non-exponential phase, assumed as an activation or deactivation stage and not further analysed here. The time constants of the exponential functions describing isometric force redevelopment after length variations appear to be related to the one for an initial isometric contraction, but depending on the previous history. The timing of force production calculated from the state-space diagrams was in agreement with the generally accepted muscle properties, thereby demonstrating the reliability of the method. A macroscopic muscular model consisting of a contractile element, parallel and series elastic elements was developed. The parameters from the experiment analysis, particularly the force modification after non-isometric contractions and the time constants, were reproduced by the simulations. The relationship between time constants introduced in a mechanistic model and the measured macroscale timings is discussed.