GSNOR Deficiency Enhances<i>In Situ</i>Skeletal Muscle Strength, Fatigue Resistance, and RyR1 S-Nitrosylation Without Impacting Mitochondrial Content and Activity

Moon, Yong; Cao, Yunmeng; Zhu, Jingjing; Xu, Yuanyuan; Balkan, Wayne; Buys, Emmanuel; Díaz, Francisca; Kerrick, W. Glenn L.; Hare, Joshua M.; Percival, Justin M.

doi:10.1089/ars.2015.6548

Cited by 19 publications

(8 citation statements)

References 69 publications

(122 reference statements)

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“…In line with data arguing for a pivotal role of GSNOR and S -nitrosylation in myoblast differentiation 30 and muscle regeneration 12,31 , we also observed that GSNOR is involved in myogenesis. This is probably due to its recruitment in the same complex with nNOS, which becomes detectable at day 4 when other markers of differentiation are still expressed (Fig.…”

Section: Resultssupporting

confidence: 91%

“…The role of NO and S -nitrosylation in skeletal muscle homeostasis has been exhaustively studied. However, the implication of GSNOR and denitrosylation remains controversial 12,31 . Here, we provide evidence that, in the same way of kinases and phosphatases (and/or ligases and de-ubiquitinylases), the denitrosylating enzyme GSNOR co-localizes with the source of NO, nNOS, to precisely control S -nitrosylation.…”

Section: Resultsmentioning

confidence: 99%

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nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis

et al. 2019

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Neuronal nitric oxide synthase (nNOS) plays a crucial role in the maintenance of correct skeletal muscle function due, at least in part, to S -nitrosylation of specific protein targets. Similarly, we recently provided evidence for a muscular phenotype in mice lacking the denitrosylase S -nitrosoglutathione reductase (GSNOR). Here, we demonstrate that nNOS and GSNOR are concomitantly expressed during differentiation of C2C12. They colocalizes at the sarcolemma and co-immunoprecipitate in cells and in myofibers. We also provide evidence that GSNOR expression decreases in mouse models of muscular dystrophies and of muscle atrophy and wasting, i.e., aging and amyotrophic lateral sclerosis, suggesting a more general regulatory role of GSNOR in skeletal muscle homeostasis.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis

et al. 2019

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“…The finding that protein denitrosylation regulates hepatic autophagy provides a new perspective on obesity-associated insulin resistance. In line with our data, Montagna et al (47) reported that GSNOR deletion impairs exercise-induced mitophagy in skeletal muscle (although this result contrasts with data showing that GSNOR deficiency enhances skeletal muscle strength) (48). Therefore, future studies should pay attention to the role of nitrosative stress in the regulation of autophagy activation and autophagic flux in a tissue and stress signaling-specific manner.…”

Section: Discussionsupporting

confidence: 86%

S-Nitrosoglutathione Reductase Dysfunction Contributes to Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy

et al. 2017

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Obesity is associated with elevated intracellular nitric oxide (NO) production, which promotes nitrosative stress in metabolic tissues such as liver and skeletal muscle, contributing to insulin resistance. The onset of obesity-associated insulin resistance is due, in part, to the compromise of hepatic autophagy, a process that leads to lysosomal degradation of cellular components. However, it is not known how NO bioactivity might impact autophagy in obesity. Here, we establish that -nitrosoglutathione reductase (GSNOR), a major protein denitrosylase, provides a key regulatory link between inflammation and autophagy, which is disrupted in obesity and diabetes. We demonstrate that obesity promotes-nitrosylation of lysosomal proteins in the liver, thereby impairing lysosomal enzyme activities. Moreover, in mice and humans, obesity and diabetes are accompanied by decreases in GSNOR activity, engendering nitrosative stress. In mice with a GSNOR deletion, diet-induced obesity increases lysosomal nitrosative stress and impairs autophagy in the liver, leading to hepatic insulin resistance. Conversely, liver-specific overexpression of GSNOR in obese mice markedly enhances lysosomal function and autophagy and, remarkably, improves insulin action and glucose homeostasis. Furthermore, overexpression of -nitrosylation-resistant variants of lysosomal enzymes enhances autophagy, and pharmacologically and genetically enhancing autophagy improves hepatic insulin sensitivity in GSNOR-deficient hepatocytes. Taken together, our data indicate that obesity-induced protein-nitrosylation is a key mechanism compromising the hepatic autophagy, contributing to hepatic insulin resistance.

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“…Skeletal muscle tissue has also been evaluated for GSNOR function. With the use of GSNOR knockout mice, the tibialis anterior muscle of GSNOR À/À mice was found to be more resistant to fatigue, with no alterations in mitochondrial function or in capillary density, associated with hypernitrosylation ryanodine receptor (RyR1), which could increase skeletal muscle contractility without altering mitochondrial function [78]. However, another study using GSNOR À/À mice showed the opposite effect, since the silencing of GSNOR revealed a muscular atrophy and loss of muscle mass, associated with increased S-nitrosothiols, along with mitochondrial fragmentation and depolarization [79].…”

Section: The Complex Role Of Gsnormentioning

confidence: 99%

Cardioprotective Effects of S-Nitrosothiols in Ischemia- Reperfusion: Role for Mitochondria and Calcium Channels

Arriagada¹,

Treuer²,

González³

2018

Free Radicals, Antioxidants and Diseases

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The most important clinical consequence of coronary disease is acute myocardial infarction caused by an occlusion that limits the irrigation to the heart. Although the gold standard treatment is to restore blood flow, this reperfusion causes inherent damage by increasing the size of the infarcted area primarily through the opening of the mitochondrial permeability transition pore (MPTP). The cardioprotective effect of nitric oxide (NO) has been described to operate through S-nitrosylation of several important proteins in the cardiomyocytes such as the calcium channels RyR2 and the L-type Ca 2+ channel and mitochondrial proteins, including the MPTP. In this sense, an attractive strategy to prevent the ischemia-reperfusion damage is to increase the bioavailability of endogenous Snitrosothiols. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of NO through denitrosylation, which would limit the cardioprotective effect of NO. Although inhibition of GSNOR has been studied in different organs, its effects on myocardial reperfusion have not yet been fully elucidated. In this chapter, we review the pathophysiology underlying myocardial reperfusion injury and the opening of the MPTP along with the cardioprotective role of S-nitrosothiols and the potential role for GSNOR.

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GSNOR Deficiency EnhancesIn SituSkeletal Muscle Strength, Fatigue Resistance, and RyR1 S-Nitrosylation Without Impacting Mitochondrial Content and Activity

Cited by 19 publications

References 69 publications

nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis

nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis

S-Nitrosoglutathione Reductase Dysfunction Contributes to Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy

Cardioprotective Effects of S-Nitrosothiols in Ischemia- Reperfusion: Role for Mitochondria and Calcium Channels

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