Mus musculus
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ABSTRACT:
PROVIDER: PRJNA295275 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondrial Polymerase Gamma Dysfunction and Aging Cause Cardiac Nuclear DNA Methylation Changes
| PRJNA295271 | ENA
Project description:Mitochondrial Polymerase Gamma Dysfunction and Aging Cause Cardiac Nuclear DNA Methylation Changes [100929_MM9_Deluxe_Prom_Meth_HX1]
| PRJNA295274 | ENA
Project description:Cardiomyopathy (CM) is an intrinsic weakening of the myocardium with contractile dysfunction and congestive heart failure (CHF). CHF has been postulated to result from decreased mitochondrial energy production and oxidative stress. The effects of decreased mitochondrial oxygen consumption can also accelerate with aging, with the mitochondrial theory of aging forming the basis of this knowledge. We previously showed DNA methylation changes in human hearts with CM. This was associated with mitochondrial DNA depletion, being another molecular marker of CM. We examined the relationship between mitochondrial dysfunction and cardiac epigenetic DNA methylation changes in both young and old mice. We used genetically engineered C57Bl/6 mice transgenic for a cardiac-specific mutant of the mitochondrial polymerase (termed Y955C). Y955C mice undergo left ventricular hypertrophy (LVH) at a young age (~94 days old), and LVH decompensated to CHF at old age (~255 days old). In Y955C hearts, 95 differentially expressed genes were found, while 4,452 genes were differentially expressed in aged hearts. Moreover, cardiac DNA methylation patterns differed between Y955C (4,506 peaks with 68.5% hypomethylation) and aged hearts (73,286 peaks with 80.2% hypomethylated). Correlatively, of the 95 Y955C-dependent differentially expressed genes, 30 genes (31.6%) also displayed differential DNA methylation; in the 4,452 age dependent differentially expressed genes, 342 gene (7.7%) displayed associated DNA methylation changes. Both Y955C and aging demonstrated significant enrichment of CACGTG-associated E-box motifs in differentially methylated regions. Cardiac mitochondrial polymerase dysfunction alters nuclear DNA methylation. Furthermore, aging causes a robust change in cardiac DNA methylation that is partially associated with mitochondrial polymerase dysfunction. This study addresses how Y955C-mutated mitochondrial DNA polymerase g and aging affect cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation.
2016-05-06 | GSE72888 | GEO
Project description:Cardiomyopathy (CM) is an intrinsic weakening of the myocardium with contractile dysfunction and congestive heart failure (CHF). CHF has been postulated to result from decreased mitochondrial energy production and oxidative stress. The effects of decreased mitochondrial oxygen consumption can also accelerate with aging, with the mitochondrial theory of aging forming the basis of this knowledge. We previously showed DNA methylation changes in human hearts with CM. This was associated with mitochondrial DNA depletion, being another molecular marker of CM. We examined the relationship between mitochondrial dysfunction and cardiac epigenetic DNA methylation changes in both young and old mice. We used genetically engineered C57Bl/6 mice transgenic for a cardiac-specific mutant of the mitochondrial polymerase (termed Y955C). Y955C mice undergo left ventricular hypertrophy (LVH) at a young age (~94 days old), and LVH decompensated to CHF at old age (~255 days old). In Y955C hearts, 95 differentially expressed genes were found, while 4,452 genes were differentially expressed in aged hearts. Moreover, cardiac DNA methylation patterns differed between Y955C (4,506 peaks with 68.5% hypomethylation) and aged hearts (73,286 peaks with 80.2% hypomethylated). Correlatively, of the 95 Y955C-dependent differentially expressed genes, 30 genes (31.6%) also displayed differential DNA methylation; in the 4,452 age dependent differentially expressed genes, 342 gene (7.7%) displayed associated DNA methylation changes. Both Y955C and aging demonstrated significant enrichment of CACGTG-associated E-box motifs in differentially methylated regions. Cardiac mitochondrial polymerase dysfunction alters nuclear DNA methylation. Furthermore, aging causes a robust change in cardiac DNA methylation that is partially associated with mitochondrial polymerase dysfunction. This study addresses how Y955C-mutated mitochondrial DNA polymerase g and aging affect cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation.
2016-05-06 | GSE72889 | GEO
Project description:A comparison of epigenetic nuclear DNA methylation and gene expression changes between human dialated cardiomypathy left ventricle samples and non-failing cardiac left ventricule samples This study addresses how depletion of huaman cardiac left ventricle mitochondrial DNA and epigentic nuclear DNA methylation promote cardiac dysfunction in human dilated cardiomyopathy. Each sample was fluorescently labeled and hybridized to Roche Nimblegen 2.1M Deluxe Promoter Arrays and Expression arrays.
2013-06-05 | E-GEOD-43435 | biostudies-arrayexpress
Project description:A comparison of epigenetic nuclear DNA methylation and gene expression changes between human dialated cardiomypathy left ventricle samples and non-failing cardiac left ventricule samples This study addresses how depletion of huaman cardiac left ventricle mitochondrial DNA and epigentic nuclear DNA methylation promote cardiac dysfunction in human dilated cardiomyopathy.
2013-06-05 | GSE43435 | GEO
Project description:Aging is the progressive decline in organismal function that leads to an increased risk of multiple diseases and mortality. The molecular basis of this decline is unknown. Using quantitative PCR for mitochondrial mRNA from multiple tissues from the same animals, we found that the rate of change in mouse mitochondrial expression is tissue-specific, with cardiac expression declining early (8-10 months), adipose expression declining late (25-30 months), and no change in kidney or skin. In cardiac tissue, mitochondria-derived mRNA levels declined more slowly than nuclear encoded mRNAs, suggesting a potential dysregulation. These changes were independent of alteration in mitochondrial number, as measured by quantitative PCR of mitochondrial DNA and citrate synthase activity. We found no change in the variability between mitochondrial mRNA levels with age, suggesting that the changes are not due to random dysregulation at the level of gene expression. Caloric restriction (CR), a lifespan-extending intervention proposed to act through mitochondrial biogenesis, delayed the decline in both cardiac and adipose mitochondrial mRNA levels of F344 rats. CR caused an increase in citrate synthase activity but did not alter mitochondrial DNA content, indicating increased translation or reduced turnover of mitochondrial proteins. These results demonstrate that mitochondrial gene expression changes with age are not coupled to mitochondrial number, are likely to be regulated, and are governed by tissue-specific processes. These findings indicate that aging is neither a programmed organism-wide change orchestrated in a top-down fashion nor a product of random dysregulation of gene expression but that tissue-specific factors may independently control aging in different organ compartments. Keywords: aging Cardiac ventricle total RNA from 10 young (4-6 month) and 10 young (25-28 month) mice were compared.
2015-07-03 | E-GEOD-12480 | biostudies-arrayexpress
Project description:Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.
2020-02-17 | MSV000084961 | MassIVE
Project description:Mitochondrial dysfunction is implicated in aging and aging-related disorders, such as neurodegenerative diseases and stroke. To study the effects of progressive mitochondrial dysfunction, a homozygous knock-in mouse expressing a proof-reading deficient version of the nucleus-encoded catalytic subunit of mitochondrial DNA (mtDNA) polymerase (PolgA) has been developed. In the mtDNA mutator mouse the proofreading activity of PolgA has been abolished by a single amino acid change. PolgA is the catalytic subunit of the polymerase gamma, which is involved in replicating and proofreading the mitochondrial DNA. As a result, mtDNA mutator mice develop high levels of point mutations and linear deletions, which lead to several human-like phenotypes associated with aging, including reduced lifespan (42-44 weeks), weight loss, alopecia, anemia, kyphosis, osteoporosis, sarcopenia, loss of subcutaneous fat, and reduced fertility. We investigate the molecular mechanism through which exercise may improve the phenotype of the mtDNA mutator mouse, which is a model of premature aging induced by mitochondrial dysfunction. Remarkably, forced endurance exercise has been shown to rescue the progeroid aging phenotypes of the mtDNA mutator mice, and to induce systemic mitochondrial rejuvenation. Here, using voluntary, rather than forced exercise, we investigate the molecular mechanisms underlying such a dramatic improvement, and also assess the effect of exercise on brain tissues, such as cortex and striatum in our model. The complete proteome of key tissues (muscle, brain cortex, brain striatum) from exercising and sedentary mtDNA mutator mice as well as exercising and sedentary wild type mice is quantified using peptide high-resolution isoelectric focusing (HiRIEF) coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS) with an isobaric tag (TMT10plex) strategy.
2019-08-05 | PXD011741 | Pride
Project description:Low-LET radiation can cause cardiovascular dysfunctions at high-dose rates. For example, photons used in thoracic radiotherapy are known to cause acute cardiac tissue damage with elevated serum cardiac Troponin I level and long-term cardiac complications when delivered as fractionated exposures at high-dose rates. However, the effects of continuous low-dose rate radiation exposure on the heart, which simulate the space radiation environment, have not been well-studied. In this study, we aim to model low-LET space radiation-induced cardiovascular dysfunction using human induced pluripotent stem cell (iPSC)-derived engineered heart tissues (EHTs) exposed to protracted γ-ray irradiation. The investigation of pathophysiological changes in this model may provide insights and guide the development of countermeasures. As a proof-of-principle for the application of this model in drug development, we also tested the protective effect of a mitochondrial-specific antioxidant, MitoTempo, on irradiated EHTs.
2023-09-05 | GSE242108 | GEO