Abstract
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 language | English |
|---|---|
| Pages (from-to) | 570-587 |
| Number of pages | 18 |
| Journal | Antioxidants and Redox Signaling |
| Volume | 21 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Aug 1 2014 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
- Physiology
- Clinical Biochemistry
- Medicine(all)
Cite this
S-nitrosoglutathione reductase deficiency-induced S-nitrosylation results in neuromuscular dysfunction. / Montagna, Costanza; Di Giacomo, Giuseppina; Rizza, Salvatore; Cardaci, Simone; Ferraro, Elisabetta; Grumati, Paolo; De Zio, Daniela; Maiani, Emiliano; Muscoli, Carolina; Lauro, Filomena; Ilari, Sara; Bernardini, Sergio; Cannata, Stefano; Gargioli, Cesare; Ciriolo, Maria R.; Cecconi, Francesco; Bonaldo, Paolo; Filomeni, Giuseppe.
In: Antioxidants and Redox Signaling, Vol. 21, No. 4, 01.08.2014, p. 570-587.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - S-nitrosoglutathione reductase deficiency-induced S-nitrosylation results in neuromuscular dysfunction
AU - Montagna, Costanza
AU - Di Giacomo, Giuseppina
AU - Rizza, Salvatore
AU - Cardaci, Simone
AU - Ferraro, Elisabetta
AU - Grumati, Paolo
AU - De Zio, Daniela
AU - Maiani, Emiliano
AU - Muscoli, Carolina
AU - Lauro, Filomena
AU - Ilari, Sara
AU - Bernardini, Sergio
AU - Cannata, Stefano
AU - Gargioli, Cesare
AU - Ciriolo, Maria R.
AU - Cecconi, Francesco
AU - Bonaldo, Paolo
AU - Filomeni, Giuseppe
PY - 2014/8/1
Y1 - 2014/8/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84904007368&partnerID=8YFLogxK
U2 - 10.1089/ars.2013.5696
DO - 10.1089/ars.2013.5696
M3 - Article
C2 - 24684653
AN - SCOPUS:84904007368
VL - 21
SP - 570
EP - 587
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
SN - 1523-0864
IS - 4
ER -