title: S-nitrosoglutathione reductase deficiency-induced S-nitrosylation results in neuromuscular dysfunction.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1 Research Center , IRCCS San Raffaele Pisana, Rome, Italy .
authors.forename: Costanza
authors.initials: C
authors.lastname: Montagna
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Di Giacomo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Rizza
authors.forename: Simone
authors.initials: S
authors.lastname: Cardaci
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferraro
authors.forename: Paolo
authors.initials: P
authors.lastname: Grumati
authors.forename: Daniela
authors.initials: D
authors.lastname: De Zio
authors.forename: Emiliano
authors.initials: E
authors.lastname: Maiani
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.forename: Filomena
authors.initials: F
authors.lastname: Lauro
authors.forename: Sara
authors.initials: S
authors.lastname: Ilari
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
authors.forename: Stefano
authors.initials: S
authors.lastname: Cannata
authors.forename: Cesare
authors.initials: C
authors.lastname: Gargioli
authors.forename: Maria R
authors.initials: MR
authors.lastname: Ciriolo
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Filomeni
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000426:Alcohol Dehydrogenase; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001284:Atrophy; D001343:Autophagy / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005980:Glutathione Reductase / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D012038:Regeneration / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D051267:NF-E2-Related Factor 2; D009569:Nitric Oxide; D014443:Tyrosine; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D005980:Glutathione Reductase; D055372:AMP-Activated Protein Kinases