Abstract 459: Oxidized CaMKII Causes Atrial Fibrillation Susceptibility in a Diabetic Mouse Model

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Olurotimi O Mesubi ◽  
Adam G Rokita ◽  
Biyi Chen ◽  
Long-Sheng Song ◽  
Xander H Wehrens ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Mouse Model ◽  
Genetic Manipulation ◽  
Methionine Sulfoxide ◽  
Diabetic Mouse ◽  
Methionine Sulfoxide Reductase ◽  
Diabetic Mice ◽  
Citrate Buffer ◽  
Methionine Sulfoxide Reductase A ◽  
Triggered Arrhythmias

Background: Atrial fibrillation (AF) and diabetes mellitus (DM) are major, unsolved public health problems. DM is a known risk factor for AF, and both are associated with increased reactive oxygen species (ROS), suggesting a ROS responsive disease signal could be a mechanistic link between them. The multifunctional Ca2+ and calmodulin-dependent protein kinase-II (CaMKII) is activated by oxidation of paired methionines. Oxidized CaMKII (ox-CaMKII) is increased in atria from DM patients and causes ryanodine receptor (RyR2) hyperphosphorylation that promotes pathological intracellular Ca2+ release and Ca2+ triggered arrhythmias. We hypothesize that DM increases myocardial ox-CaMKII, RyR2 hyperphosphorylation and AF. Methods and Results: C57BL/6J mice with streptozocin-induced type 1 DM had increased AF susceptibility following atrial burst pacing compared with citrate buffer-treated wild-type (WT) controls [70% (14/20) vs. 25% (5/20), p = 0.01]. Ox-CaMKII was increased in atrial tissue from diabetic mice compared to controls, consistent with a role for ox-CaMKII in this model. Diabetic ox-CaMKII resistant knock-in (MM-VV) mice (37.5% (9/24) [p < 0.05]) and diabetic mice with myocardium-restricted transgenic overexpression of methionine sulfoxide reductase A (25% (5/20) [p < 0.05]), which reverses ox-CaMKII, were protected from DM increased AF susceptibility compared to diabetic WT controls. Atrial myocytes from diabetic WT mice demonstrated increased RyR2 mediated Ca2+ spark frequency, triggered action potentials and delayed intracellular [Ca2+] decay compared to controls. Diabetic knock-in mice resistant to CaMKII-mediated RyR2 phosphorylation (S2814A) had decreased AF susceptibility (25% (5/20) [p < 0.05]), compared with diabetic WT mice. All groups of diabetic mice had similar increases in plasma glucose. Conclusions: Hyperglycemia increases AF susceptibility and increased ox-CaMKII is associated with increased AF in this diabetic mouse model. Genetic manipulation of an ox-CaMKII pathway can protect against AF susceptibility in DM. These findings suggest that ox-CaMKII is a critical proarrhythmic signal in DM and a potential therapeutic target for AF management in DM patients.

scholarly journals Methionine sulfoxide reductase A affects β-amyloid solubility and mitochondrial function in a mouse model of Alzheimer's disease

2016 ◽  
Vol 310 (6) ◽  
pp. E388-E393 ◽  
Author(s):  
Jackob Moskovitz ◽  
Fang Du ◽  
Connor F. Bowman ◽  
Shirley S. Yan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Sulfoxide Reductase A ◽  
Model Of Alzheimer’S Disease ◽  
Amyloid Aβ ◽  
Β Amyloid

Accumulation of oxidized proteins, and especially β-amyloid (Aβ), is thought to be one of the common causes of Alzheimer's disease (AD). The current studies determine the effect of an in vivo methionine sulfoxidation of Aβ through ablation of the methionine sulfoxide reductase A (MsrA) in a mouse model of AD, a mouse that overexpresses amyloid precursor protein (APP) and Aβ in neurons. Lack of MsrA fosters the formation of methionine sulfoxide in proteins, and thus its ablation in the AD-mouse model will increase the formation of methionine sulfoxide in Aβ. Indeed, the novel MsrA-deficient APP mice ( APP+/ MsrAKO) exhibited higher levels of soluble Aβ in brain compared with APP+ mice. Furthermore, mitochondrial respiration and the activity of cytochrome c oxidase were compromised in the APP+/ MsrAKO compared with control mice. These results suggest that lower MsrA activity modifies Aβ solubility properties and causes mitochondrial dysfunction, and augmenting its activity may be beneficial in delaying AD progression.

scholarly journals The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1372
Author(s):  
Tengrui Shi ◽  
Jianxi Song ◽  
Guanying You ◽  
Yujie Yang ◽  
Qiong Liu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Mouse Models ◽  
Knockout Mouse ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Knockout Mouse Model ◽  
The Central Nervous System

MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.

A mitochondria-targeted near-infrared fluorescent probe for imaging viscosity in living cells and a diabetic mice model

2021 ◽  
Author(s):  
Bochao Chen ◽  
Shumei Mao ◽  
Yanyan Sun ◽  
Liyuan Sun ◽  
Ning Ding ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fluorescent Probe ◽  
Near Infrared ◽  
Diabetic Mouse ◽  
Living Cells ◽  
Pancreatic Tissue ◽  
Diabetic Mice ◽  
Mice Model ◽  
Viscosity Changes

A mitochondria-targeted near-infrared fluorescent probe NIR-V with 700 nm emission was designed to monitor cell viscosity changes, which was applied to detect the intracellular viscosity and imagine pancreatic tissue in diabetic mouse model.

scholarly journals An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii

2021 ◽  
Vol 78 (7) ◽  
pp. 3673-3689
Author(s):  
David Leitsch ◽  
Alvie Loufouma Mbouaka ◽  
Martina Köhsler ◽  
Norbert Müller ◽  
Julia Walochnik
Keyword(s):  
Oxidative Stress ◽  
Stop Codon ◽  
Acanthamoeba Castellanii ◽  
Methionine Sulfoxide ◽  
Redox System ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Sulfoxide Reductase A ◽  
Protein Levels ◽  
Thioredoxin System ◽  
Facultative Parasite

AbstractThe free-living amoeba Acanthamoeba castellanii occurs worldwide in soil and water and feeds on bacteria and other microorganisms. It is, however, also a facultative parasite and can cause serious infections in humans. The annotated genome of A. castellanii (strain Neff) suggests the presence of two different thioredoxin reductases (TrxR), of which one is of the small bacterial type and the other of the large vertebrate type. This combination is highly unusual. Similar to vertebrate TrxRases, the gene coding for the large TrxR in A. castellanii contains a UGA stop codon at the C-terminal active site, suggesting the presence of selenocysteine. We characterized the thioredoxin system in A. castellanii in conjunction with glutathione reductase (GR), to obtain a more complete understanding of the redox system in A. castellanii and the roles of its components in the response to oxidative stress. Both TrxRases localize to the cytoplasm, whereas GR localizes to the cytoplasm and the large organelle fraction. We could only identify one thioredoxin (Trx-1) to be indeed reduced by one of the TrxRases, i.e., by the small TrxR. This thioredoxin, in turn, could reduce one of the two peroxiredoxins tested and also methionine sulfoxide reductase A (MsrA). Upon exposure to hydrogen peroxide and diamide, only the small TrxR was upregulated in expression at the mRNA and protein levels, but not the large TrxR. Our results show that the small TrxR is involved in the A. castellanii’s response to oxidative stress. The role of the large TrxR, however, remains elusive.

Softened food reduces weight loss in the streptozotocin-induced male mouse model of diabetic nephropathy

2018 ◽  
Vol 52 (4) ◽  
pp. 373-383 ◽  
Author(s):  
Sisse A Nørgaard ◽  
Fredrik W Sand ◽  
Dorte B Sørensen ◽  
Klas SP Abelson ◽  
Henrik Søndergaard
Keyword(s):  
Weight Loss ◽  
Diabetic Nephropathy ◽  
Mouse Model ◽  
Diabetic Mouse ◽  
Diabetic Mice ◽  
Reduce Weight Loss ◽  
Normal Chow ◽  
Corticosterone Metabolites ◽  
Reducing Stress ◽  
Humane Endpoint

The streptozotocin (STZ)-induced diabetic mouse is a widely used model of diabetes and diabetic nephropathy (DN). However, it is a well-known issue that this model is challenged by high weight loss, which despite supportive measures often results in high euthanization rates. To overcome these issues, we hypothesized that supplementing STZ-induced diabetic mice with water-softened chow in addition to normal chow would reduce weight loss, lower the need for supportive treatment, and reduce the number of mice reaching the humane endpoint of 20% weight loss. In a 15 week STZ-induced DN study we demonstrated that diabetic male mice receiving softened chow had reduced acute weight loss following STZ treatment ( p = 0.045) and additionally fewer mice were euthanized due to weight loss. By supplementing the diabetic mice with softened chow, no mice reached 20% weight loss whereas 37.5% of the mice without this supplement reached this humane endpoint ( p = 0.0027). Excretion of corticosterone metabolites in faeces was reduced in diabetic mice on softened chow ( p = 0.0007), suggesting lower levels of general stress. Finally, it was demonstrated that the water-softened chow supplement did not significantly affect the induction of key disease parameters, i.e. %HbA1C and albuminuria nor result in abnormal teeth wear. In conclusion, supplementation of softened food is refining the STZ-induced diabetic mouse model significantly by reducing stress, weight loss and the number of animals sacrificed due to humane endpoints, while maintaining the key phenotypes of diabetes and nephropathy.

scholarly journals METABOLIC CONSEQUENCES OF METHIONINE REDOX IN METHIONINE RESTRICTION

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S106-S107
Author(s):  
Kevin Thyne ◽  
Yuhong Liu ◽  
Adam B Salmon
Keyword(s):  
Protein Function ◽  
Methionine Sulfoxide ◽  
Redox Status ◽  
Significant Loss ◽  
Methionine Sulfoxide Reductase ◽  
Wild Type ◽  
Entire Family ◽  
Methionine Sulfoxide Reductase A ◽  
Methionine Restriction

Abstract While caloric restriction (CR) provides highly robust improvements to longevity and health, dietary restriction of the essential amino acid methionine can provide similar benefits including improved metabolic function and increased longevity. Despite these similarities between CR and methionine restriction (MR), there is growing evidence to suggest they may be mediated by different mechanisms that require further elucidation. The sulfur side-chain of methionine is highly prone to oxidation, even in vivo, with redox changes of these residues potentially altering protein function and interfering with its use as a substrate. An entire family of enzymes, methionine sulfoxide reductases, have evolved in aerobic organisms to regulate the redox status of methionine. We tested the role of methionine sulfoxide reductase A (MsrA) in the physiological and metabolic benefits of MR. After three months of MR, mice lacking MsrA (MsrA KO) showed significant loss of weight, including both fat and lean mass, in comparison to wild-type mice under MR. Both MsrA KO and wild-type mice responded to MR with improvements to both glucose and insulin tolerance. However, MR MsrA KO mice showed lower HbA1c and reduced leptin compared to MR wild-type mice. Overall, our results show mice lacking MsrA have a stronger response to MR suggesting that methionine redox may play an important role in some of the mechanisms responsible for these metabolic outcomes. Further studies clarify whether MsrA could also be a potential regulator of the longevity benefits of MR.

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