S-nitrosoglutathione reductase deficiency-induced S-nitrosylation results in neuromuscular dysfunction

Costanza Montagna, Giuseppina Di Giacomo, Salvatore Rizza, Simone Cardaci, Elisabetta Ferraro, Paolo Grumati, Daniela De Zio, Emiliano Maiani, Carolina Muscoli, Filomena Lauro, Sara Ilari, Sergio Bernardini, Stefano Cannata, Cesare Gargioli, Maria R. Ciriolo, Francesco Cecconi, Paolo Bonaldo, Giuseppe Filomeni

Research output: Contribution to journalArticlepeer-review


Aims: Nitric oxide (NO) production is implicated in muscle contraction, growth and atrophy, and in the onset of neuropathy. However, many aspects of the mechanism of action of NO are not yet clarified, mainly regarding its role in muscle wasting. Notably, whether NO production-associated neuromuscular atrophy depends on tyrosine nitration or S-nitrosothiols (SNOs) formation is still a matter of debate. Here, we aim at assessing this issue by characterizing the neuromuscular phenotype of S-nitrosoglutathione reductase-null (GSNOR-KO) mice that maintain the capability to produce NO, but are unable to reduce SNOs. Results: We demonstrate that, without any sign of protein nitration, young GSNOR-KO mice show neuromuscular atrophy due to loss of muscle mass, reduced fiber size, and neuropathic behavior. In particular, GSNOR-KO mice show a significant decrease in nerve axon number, with the myelin sheath appearing disorganized and reduced, leading to a dramatic development of a neuropathic phenotype. Mitochondria appear fragmented and depolarized in GSNOR-KO myofibers and myotubes, conditions that are reverted by N-acetylcysteine treatment. Nevertheless, although atrogene transcription is induced, and bulk autophagy activated, no removal of damaged mitochondria is observed. These events, alongside basal increase of apoptotic markers, contribute to persistence of a neuropathic and myopathic state. Innovation: Our study provides the first evidence that GSNOR deficiency, which affects exclusively SNOs reduction without altering nitrotyrosine levels, results in a clinically relevant neuromuscular phenotype. Conclusion: These findings provide novel insights into the involvement of GSNOR and S-nitrosylation in neuromuscular atrophy and neuropathic pain that are associated with pathological states; for example, diabetes and cancer.

Original languageEnglish
Pages (from-to)570-587
Number of pages18
JournalAntioxidants and Redox Signaling
Issue number4
Publication statusPublished - Aug 1 2014

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry
  • Medicine(all)


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