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Crosstalk between nitrosative stress and altered Ca2+ handling in arthritis-induced skeletal muscle dysfunction
  1. Joseph Bruton1,
  2. Takashi Yamada1,2,
  3. Niklas Ivarsson1,
  4. Cecilia Grundtman3,4,
  5. Shi-Jin Zhang1,
  6. Helena Erlandsson-Harris4,
  7. Ingrid E Lundberg4,
  8. Johana T Lanner1,
  9. Arthur J Cheng1,
  10. Håkan Westerblad1
  1. 1Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
  2. 2School of Health Sciences, Sapporo Medical University, Sapporo, Japan
  3. 3Department of Experimental Pathophysiology and Immunology, Innsbruck Medical University, Innsbruck, Austria
  4. 4Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden

Abstract

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.

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