scholarly journals Potential roles of neuronal nitric oxide synthase and the PTEN-induced kinase 1 (PINK1)/Parkin pathway for mitochondrial protein degradation in disuse-induced soleus muscle atrophy in adult rats

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243660
Author(s):  
Munehiro Uda ◽  
Toshinori Yoshihara ◽  
Noriko Ichinoseki-Sekine ◽  
Takeshi Baba ◽  
Toshitada Yoshioka
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Protein Degradation ◽  
Muscle Atrophy ◽  
Soleus Muscle ◽  
Neuronal Nitric Oxide Synthase ◽  
Oxidative Modification ◽  
No Production ◽  
Adult Rats ◽  
Oxide Synthase

Excessive nitric oxide (NO) production and mitochondrial dysfunction can activate protein degradation in disuse-induced skeletal muscle atrophy. However, the increase in NO production in atrophied muscles remains controversial. In addition, although several studies have investigated the PTEN-induced kinase 1 (PINK1)/Parkin pathway, a mitophagy pathway, in atrophied muscle, the involvement of this pathway in soleus muscle atrophy is unclear. In this study, we investigated the involvement of neuronal nitric oxide synthase (nNOS) and the PINK1/Parkin pathway in soleus muscle atrophy induced by 14 days of hindlimb unloading (HU) in adult rats. HU lowered the weight of the soleus muscles. nNOS expression showed an increase in atrophied soleus muscles. Although HU increased malondialdehyde as oxidative modification of the protein, it decreased 6-nitrotryptophan, a marker of protein nitration. Additionally, the nitrosocysteine content and S-nitrosylated Parkin were not altered, suggesting the absence of excessive nitrosative stress after HU. The expression of PINK1 and Parkin was also unchanged, whereas the expression of heat shock protein 70 (HSP70), which is required for Parkin activity, was reduced in atrophied soleus muscles. Moreover, we observed accumulation and reduced ubiquitination of high molecular weight mitofusin 2, which is a target of Parkin, in atrophied soleus muscles. These results indicate that excessive NO is not produced in atrophied soleus muscles despite nNOS accumulation, suggesting that excessive NO dose not mediate in soleus muscle atrophy at least after 14 days of HU. Furthermore, the PINK1/Parkin pathway may not play a role in mitophagy at this time point. In contrast, the activity of Parkin may be downregulated because of reduced HSP70 expression, which may contribute to attenuated degradation of target proteins in the atrophied soleus muscles after 14 days of HU. The present study provides new insights into the roles of nNOS and a protein degradation pathway in soleus muscle atrophy.

scholarly journals Perlecan Facilitates Neuronal Nitric Oxide Synthase Delocalization in Denervation-Induced Muscle Atrophy

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2524 ◽  
Author(s):  
Satoshi Nakada ◽  
Yuri Yamashita ◽  
Shuichi Machida ◽  
Yuko Miyagoe-Suzuki ◽  
Eri Arikawa-Hirasawa
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Nitric Oxide Synthase ◽  
Protein Degradation ◽  
Muscle Atrophy ◽  
Neuronal Nitric Oxide Synthase ◽  
Skeletal Muscle Atrophy ◽  
Extracellular Matrix Molecule ◽  
Stress Dependent ◽  
Oxide Synthase

Perlecan is an extracellular matrix molecule anchored to the sarcolemma by a dystrophin–glycoprotein complex. Perlecan-deficient mice are tolerant to muscle atrophy, suggesting that perlecan negatively regulates mechanical stress-dependent skeletal muscle mass. Delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma to the cytosol triggers protein degradation, thereby initiating skeletal muscle atrophy. We hypothesized that perlecan regulates nNOS delocalization and activates protein degradation during this process. To determine the role of perlecan in nNOS-mediated mechanotransduction, we used sciatic nerve transection as a denervation model of gastrocnemius muscles. Gastrocnemius muscle atrophy was significantly lower in perinatal lethality-rescued perlecan-knockout (Hspg2−/−-Tg) mice than controls (WT-Tg) on days 4 and 14 following surgery. Immunofluorescence microscopy showed that cell membrane nNOS expression was reduced by denervation in WT-Tg mice, with marginal effects in Hspg2−/−-Tg mice. Moreover, levels of atrophy-related proteins—i.e., FoxO1a, FoxO3a, atrogin-1, and Lys48-polyubiquitinated proteins—increased in the denervated muscles of WT-Tg mice but not in Hspg2−/−-Tg mice. These findings suggest that during denervation, perlecan promotes nNOS delocalization from the membrane and stimulates protein degradation and muscle atrophy by activating FoxO signaling and the ubiquitin–proteasome system.

Inhibition of the Neuronal Nitric Oxide Synthase Potentiates Homocysteine Thiolactone- Induced Seizures in Adult Rats

2012 ◽  
Vol 8 (1) ◽  
pp. 59-64 ◽  
Author(s):  
Dragan Hrncic ◽  
Aleksandra Rasic- Markovic ◽  
Danijela Krstic ◽  
Djuro Macut ◽  
Veselinka Susic ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Adult Rats ◽  
Homocysteine Thiolactone ◽  
Oxide Synthase

Increased neuronal nitric oxide synthase-derived NO production in the failing human heart

The Lancet ◽  
2004 ◽  
Vol 363 (9418) ◽  
pp. 1365-1367 ◽  
Author(s):  
Thibaud Damy ◽  
Philippe Ratajczak ◽  
Ajay M Shah ◽  
Emmanuel Camors ◽  
Isabelle Marty ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Human Heart ◽  
Neuronal Nitric Oxide Synthase ◽  
No Production ◽  
Oxide Synthase

Abstract 1333: Modulation Of Cardiac Beta-adrenergic Responsiveness By The Neuronal Nitric Oxide Synthase/Sarcolemmal Calcium Pump Complex

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Tamer M Mohamed ◽  
Delvac Oceandy ◽  
Nasser Alatwi ◽  
Florence Baudoin ◽  
Elizabeth J Cartwright ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Neonatal Rat ◽  
No Production ◽  
Adrenergic Stimulation ◽  
Rat Cardiomyocytes ◽  
Adrenergic Response ◽  
Oxide Synthase

The pivotal role of neuronal nitric oxide synthase (nNOS) in regulating cardiac function has only recently been unveiled. Notably, others have shown that responsiveness to β-adrenergic stimulation is dependent on nNOS activity. In a cellular model, we showed that the Ca 2+ /calmodulin-dependent nNOS activity is reduced by overexpression of isoform 4b of the plasma membrane Ca 2+ /Calmodulin-dependent Ca 2+ -pump (PMCA4b), which binds to nNOS. We demonstrated that PMCA4b overexpression in the heart reduced β-adrenergic responsiveness in vivo via an nNOS dependent mechanism (Oceandy et al, Circulation 2007). Here we investigated the cellular mechanisms of the regulation of the β-adrenergic response by PMCA4b. We used an adenoviral system to overexpress PMCA4b (PMCA4b cells) or LacZ (control, C) in neonatal rat cardiomyocytes. PMCA4b cells showed an 18±5% and 24±5% reduction in nitric oxide (DAF-FM fluorescence) and cGMP levels, respectively (n=6, p<0.05 each) compared to C demonstrating the regulation of NO production by the PMCA4b in this system. Since nNOS has been shown to regulate phospholamban (PLB) phosphorylation, we examined phosphorylation of PLB at Ser16. PMCA4b cells showed a significant increase in Ser16-PLB at baseline (66±17%, p<0.05) compared to C. As a result of increased baseline Ser16-PLB in PMCA4b cells, β-adrenergic stimulation of PMCA4b cells using 2μM isoproter-enol (IP) showed reduced relative induction in Ser16-PLB (23±10% vs. 78±19% in C; n=5, p<0.05). Further analysis in adult cardiomyocytes isolated from our PMCA4b transgenic mice (PMCA4b TG) demonstrated that PMCA4b TG showed 3-fold higher Ser16-PLB phosphorylation at baseline compared to wild type (WT) myocytes and the relative response following β-adrenergic stimulation was significantly reduced (1.2±0.2 fold induction after IP treatment in PMCA4b TG, vs. 3.1±0.7 in WT, n=5, p<0.05). Thus, PMCA4b regulates NO production from nNOS, which in turn modulates cGMP levels and PLB phosphorylation. These findings provide mechanistic insight into the regulation of the β-adrenergic response in the heart by PMCA4b and place this Ca 2+ -pump upstream of the recently described pathway linking nNOS and Ser16-PLB phosphorylation and downstream of the β-adrenergic receptor(s).

Neuronal nitric oxide synthase can mediate no production in mechanically stimulated mouse osteoblasts

Bone ◽  
2011 ◽  
Vol 48 ◽  
pp. S174
Author(s):  
A.D. Bakker ◽  
C. Huesa ◽  
A. Hughes ◽  
R.M. Aspden ◽  
R.J. van 't Hof ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
No Production ◽  
Oxide Synthase

scholarly journals Neuronal nitric oxide synthase expression is lower in areas of the nucleus tractus solitarius excited by skeletal muscle reflexes in hypertensive rats

2013 ◽  
Vol 304 (11) ◽  
pp. H1547-H1557 ◽  
Author(s):  
Megan N. Murphy ◽  
Masaki Mizuno ◽  
Ryan M. Downey ◽  
John J. Squiers ◽  
Kathryn E. Squiers ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Nitric Oxide Synthase ◽  
Protein Expression ◽  
Nucleus Tractus Solitarius ◽  
Neuronal Nitric Oxide Synthase ◽  
No Production ◽  
Hypertensive Rats ◽  
Oxide Synthase ◽  
Muscle Reflexes

The functions of the skeletal muscle exercise pressor reflex (EPR) and its mechanically sensitive component are augmented in hypertension producing exaggerated increases in blood pressure during exercise. Afferent information from the EPR is processed in the nucleus tractus solitarius (NTS). Within the NT, nitric oxide (NO), produced via l-arginine oxidation by neuronal nitric oxide synthase (nNOS), buffers the pressor response to EPR activation. Therefore, EPR overactivity may manifest as a decrease in NO production due to reductions in nNOS. We hypothesized that nNOS protein expression is lower in the NTS of spontaneously hypertensive (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. Further, we examined whether nNOS is expressed with FOS, a marker of neuronal excitation induced by EPR activation. The EPR and mechanoreflex were intermittently activated for 1 h via hindlimb static contraction or stretch, respectively. These maneuvers produced significantly greater pressor responses in SHR during the first 25 min of stimulation. Within the NTS, nNOS expression was lower from −14.9 to −13.4 bregma in SHR compared with WKY. For example, at −14.5 bregma the number of NTS nNOS-positive cells in SHR (13 ± 1) was significantly less than WKY (23 ± 2). However, the number of FOS-positive cells after muscle contraction in this area was not different (WKY = 82 ± 18; SHR = 75 ± 8). In both groups, FOS-expressing neurons were located within the same areas of the NTS as neurons containing nNOS. These findings demonstrate that nNOS protein expression is lower within NTS areas excited by skeletal muscle reflexes in hypertensive rats.

Subcellular localization of neuronal nitric oxide synthase in turtle retina: Electron immunocytochemistry

2001 ◽  
Vol 18 (6) ◽  
pp. 949-960 ◽  
Author(s):  
LUXIANG CAO ◽  
WILLIAM D. ELDRED
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Bipolar Cell ◽  
Plexiform Layer ◽  
Neuronal Nitric Oxide Synthase ◽  
No Production ◽  
Inner Plexiform Layer ◽  
Ribbon Synapses ◽  
Cell Processes ◽  
Oxide Synthase

Recent studies imaging nitric oxide (NO) production in the retina have indicated a much wider distribution of NO production than would be suggested by previous light-microscopic localizations of neuronal nitric oxide synthase (nNOS). To help resolve this discrepancy, the present study analyzed the ultrastructural localization of nNOS-like immunoreactivity (-LI) in all layers of the retina. In the ellipsoids of rod photoreceptors and the accessory elements of double cones, nNOS-LI was associated with some atypical mitochondria. In the outer plexiform layer, nNOS-LI was in some postsynaptic horizontal and bipolar cell processes at photoreceptor ribbon synapses. In some amacrine and ganglion cell somata, nNOS-LI was diffusely localized in the cytoplasm and associated with the endoplasmic reticulum. In the inner plexiform layer, nNOS-LI diffusely filled some amacrine cell processes, while in other amacrine cells nNOS-LI was selectively localized at the presynaptic specializations of conventional synapses. Neuronal NOS-LI was also found at membrane specializations in bipolar cell terminals that were distinct from their normal ribbon synapses. Finally, some nNOS-LI was found in mitochondria in Müller cells. The diverse subcellular localizations of nNOS-LI indicates that NO may play distinct functional roles in many retinal cells, which correlates well with the widespread NO production found in previous NO imaging studies.

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