Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glutaminase 2 Knockdown Reduces Hyperammonemia and Associated Lethality of Urea Cycle Disorder Mouse Model

ABSTRACT: Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. An ornithine transcarbamylase defect (Otcspf-ash) mouse model, a model of urea cycle disorder, was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (Gls2) or glutamine dehydrogenase 1 (Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. Reduced hepatic expression of Gls2, but not Glud1, by AAV8-mediated delivery of a short hairpin RNA in Otcspf-ash mice diminished hyperammonemia, reduced body weight loss, and reduced lethality. These data suggest that Gls2 hepatic knockdown could help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.

ORGANISM(S): Mus musculus

PROVIDER: GSE179342 | GEO | 2022/06/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Identification of hyperammonemia-induced changes in the cerebral transcriptome and proteome

Project description:In this study we applyed transcriptomics and proteomics to brains of mice with systemic hyperammonemia resulting from knockout of hepatic glutamine synthetase to identify new molecular players relevant for ammonia toxicity and hepatic encephalopathy.

2022-01-15 | GSE159625 | GEO

Glutaminase 2 Knockdown Reduces Hyperammonemia and Associated Lethality of Urea Cycle Disorder Mouse Model

Project description:Glutaminase 2 Knockdown Reduces Hyperammonemia and Associated Lethality of Urea Cycle Disorder Mouse Model

| PRJNA743310 | ENA

Hyperammonemia-dependent and independent skeletal muscle phosphoproteomic responses during exercise

Project description:Phosphorylation of skeletal muscle proteins mediates cellular signaling and adaptive responses to exercise. Bioinformatic and machine learning approaches identified preclinical models that recapitulate human exercise responses. Feature selection showed that muscles from treadmill running mice and maximum intensity contractions shared the most differentially phosphorylated phosphosites (DPPS) with human exercise. Benefits of exercise in chronic diseases may be reduced by hyperammonemia, a consistent perturbation in chronic diseases and a muscle cytotoxin generated during contractile activity. Comparative analysis of experimentally validated molecules identified 63 DPPS on 265 differentially expressed phosphoproteins (DEpP) shared between hyperammonemia in myotubes and skeletal muscle from exercise models. Functional enrichment analyses revealed distinct temporal patterns of enrichment shared between hyperammonemia and exercise models including protein kinase A(PKA), calcium signaling, mitogen activated protein kinase(MAPK) signaling, and protein homeostasis. Our approach of feature extraction of comparative unbiased data allows for model selection and target identification to optimize responses to interventions.

2022-10-25 | PXD031372 | Pride

Mitochondrial responses during hyperammonemia

Project description:Ammonia is a cytotoxic metabolite with pleotropic molecular and metabolic effects in non-hepatic tissue/cells targeting mitochondrial oxidative function that may contribute to post-mitotic senescence. Global molecular responses were determined by analysis of unbiased data followed by experimental validation of critical functional consequences in hyperammonemic differentiated myotubes and skeletal muscle from the portacaval anastomosis (PCA) rat. Integrating whole cell transcriptome with whole cell and mitochondrial proteome from hyperammonemic myotubes identified oxidative dysfunction and senescence pathways as being the most enriched with differentially expressed genes/proteins. Hyperammonemia and ammonia-lowering result in distinct clusters of molecular responses. Functional and metabolic studies in hyperammonemic myotubes showed that defects in electron transport chain (ETC) complexes I and III, loss of supercomplex assembly, decreased ATP synthesis, increased free radical generation with oxidative modification of proteins/lipids and increased expression of senescence associated molecular phenotype (SAMP) that were partially reversed by ammonia lowering. Studies in muscle from PCA rats established physiological relevance of our cellular studies. Dysregulated ammonia metabolism causes mitochondrial dysfunction by transcriptional and translational perturbations in multiple pathways that result in reversible senescence.

2022-02-17 | PXD026955 | Pride

GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels

Project description:Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the TCA cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalised myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment specific metabolic brake on MuSC differentiation.

2024-07-02 | GSE243640 | GEO

Integrated molecular landscape perturbations underlie cellular responses during hyperammonemia [ATAC-seq]

Project description:Ammonia is a cytotoxic molecule generated during cellular functions and by the gut microbiome. Dysregulated ammonia metabolism initiates a hyperammonemic stress response (HASR). Hyperammonemia occurs in many chronic diseases but there is limited understanding of the overall consequences of HASR. A comprehensive array of unbiased approaches was used to identify global responses during hyperammonemia with experimental validation of critical findings. Protein/gene expression and chromatin accessibility in hyperammonemic murine myotubes and mouse skeletal muscle tissue were analyzed by quantitative proteomics, RNA sequencing (RNAseq), and Assay for Transposase Accessible Chromatin Sequencing (ATACseq). Unique clusters of expression/accessibility changes were identified in hyperammonemic myotubes. In hyperammonemic mouse muscle and myotubes, we identified enrichment of pathways involved in oxidative phosphorylation, calcium signaling, hypoxia inducible factor-1, and apoptosis and regulation of protein synthesis were altered during HASR and were experimentally validated. Enrichment of senescence signaling and glycosylation pathways during HASR were novel observations. Comparisons with RNAseq data from skeletal muscle from human patients with cirrhosis revealed similar perturbations, demonstrating the translational relevance of our observations. We identified several novel regulatory pathways during HASR that are conserved in different models and across species, and whose dysregulation could significantly impact skeletal muscle structure and function.

2021-07-28 | GSE171642 | GEO

Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction by inhibiting sirtuin mediated deacetylation

Project description:Perturbed metabolism of ammonia, an endogenous cytotoxic molecule, causes mitochondrial dysfunction with decreased nicotinamide adenine dinucleotide (NAD+) in skeletal muscle. Consistent with our previous report of enrichment of NAD metabolism and sirtuin pathways during hyperammonemia, NAD+-dependent Sirtuin3 (Sirt3) expression and deacetylase activity weredecreased with increased muscle protein acetylation in murine and human skeletal muscle/myotubes. Acetylomics and cell fractions showed hyperammonemia-induced hyperacetylation of critical mitochondrial and signaling molecules. Overexpression of mitochondrial targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) reversed ammonia-induced oxidative dysfunction, electron transport chain (ETC) supercomplex disassembly, lower ATP content, NAD+, and redox ratio (NAD+/NADH). Protein hyperacetylation, post-mitotic senescence and lower mitochondrial sirtuin (Sirt3) expressionduring hyperammonemia were also reversed by MitoLbNOX. Sirt3 overexpression alone did not reverse ammonia-induced redox or mitochondrial dysfunction but reversed hyperacetylation and senescence. These data show that targeting redox ratio, rather than Sirt3, more consistently restores mitochondrial homeostasis and protein acetylation during hyperammonemia.

2023-10-24 | PXD033430 | Pride

Integrated molecular landscape perturbations underlie cellular responses during hyperammonemia [mouse RNA-seq]

2021-07-28 | GSE171644 | GEO

Integrated molecular landscape perturbations underlie cellular responses during hyperammonemia [human RNA-seq]

2021-07-28 | GSE171643 | GEO

Project description:LOX-1 reprograms glutamine metabolism and urea cycle to promote liver fibrosis

| PRJNA1093279 | ENA