Background and objective Muscle weakness is a common symptom in patients with rheumatoid arthritis. In mice with collagen-induced arthritis, (CIA, a mouse model of rheumatoid arthritis) the authors demonstrated that muscle weakness is overwhelmingly due to nitric oxide (NO)-derived radicals modifying myofibrillar proteins (nitrosative stress) in skeletal muscle from mice. Here, the authors investigate whether this nitrosative stress might result from altered sarcoplasmic reticulum Ca2+ handling properties
Materials and methods. Myoplasmic free Ca2+ concentration ((Ca2+)i) was measured in intact, single muscle fibres from flexor digitrum brevis (FDB) and soleus muscles. Mechanisms underlying changes in Ca2+ handling were assessed using immunoprecipitation and Western blotting to investigate the ryanodine receptor (RyR) macromolecular complex in FDB, extensor digitorum longus (EDL) and soleus muscles.
Results Increased tetanic (Ca2+)i was observed in FDB and soleus fibers from mice with CIA compare to those from control mice. The neuronal isoform of nitric oxide synthase (nNOS) co-localisation with RyR was greatly increased in soleus, FDB, and EDL muscles from CIA compared to control mice. In addition, there was an increased content of 3-nitrotyrosine in RyR macromolecular complex in CIA muscles compared to control muscles.
Conclusions The increased presence of nNOS-RyR complexes results in NO-modifications of the RyR macromolecular complex which in turn increases tetanic (Ca2+)i in CIA skeletal muscles. This results in a positive feedback loop to enhance NO-derived radical production since increased tetanic (Ca2+)i will in turn increase activation of the Ca2+-dependent nNOS. Pharmacological intervention targeting nNOS may be useful to protect against arthritis-induced muscle weakness and wasting.