The effect of Tmem135 overexpression on the mouse heart
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE99522 | GEO | 2018/05/31
REPOSITORIES: GEO
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Project description:Mitochondria are highly dynamic organelles undergoing fusion, fission and degradation. Although mitochondria are known to be essential for cellular metabolism, it is not fully understood how mitochondrial dynamics affect cellular metabolism. We previously identified a mouse gene, transmembrane protein 135 (TMEM135) that plays a role in the regulation of mitochondrial dynamics. Mice with mutant Tmem135 (Tmem135FUN025/FUN025) show accelerated aging phenotypes and age-related pathologies in the retina including the retinal pigment epithelium (RPE). We also generated a transgenic mouse line globally overexpressing the Tmem135 gene (Tmem135 TG). In several tissues and cells that we studied such as the retina, heart and fibroblast cells, we observed that the Tmem135 mutation causes elongated mitochondria, while over-expression of Tmem135 results in fragmented mitochondria. These unique mouse models allow us to test how abnormal mitochondrial dynamics affect metabolic signatures of tissues and cells. In this study, we identified metabolic changes in primary RPE cell cultures as well as tissues isolated from Tmem135FUN025/FUN025 mice (fusion > fission) and Tmem135 TG mice (fusion < fission) using nuclear magnetic resonance (NMR) spectroscopy. Metabolomics analysis revealed a tissue-dependent response to alterations to Tmem135 whereby, significant metabolic changes were observed in heart in both mutant and TG mice as compared to WT while negligible effects were observed in cerebellum and hippocampus. We also observed changes in Tmem135FUN025/FUN025 and Tmem135 TG RPE cells associated with osmosis, glucose metabolism and phospholipid metabolism. Significant depletion of NAD+ was detected in both Tmem135FUN025/FUN025 and Tmem135 TG RPE cells, indicating that imbalance in mitochondrial dynamics to both directions lowers the cellular NAD+ level. Thus, we have identified metabolomic changes associated with imbalanced mitochondrial dynamics in heart tissue and RPE cells which can likely lead to functional abnormalities.
2021-02-12 | MTBLS1410 | MetaboLights
Project description:To compare the effects of biological sex (female/male) and age (4 mo./20 mo.) on C57BL/6J mouse hearts, we performed mRNA sequencing.
2022-09-20 | GSE202384 | GEO
Project description:Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. To explain this discrepancy between the ongoing heart failure and maintained ATP levels in MuRF1 Tg+ hearts, we compared the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts. Although mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, total CK activity was significantly inhibited. We conclude that MuRF1’s inhibition of CK activity leads to increased susceptibility to heart failure following TAC, demonstrating for the first time that MuRF1 regulates cardiac energetics in vivo. Keywords: Genetic modification, physiological manipulation. Three-condition experiment, MuRF1 Tg+ vs. WT mice. Biological replicates: 4 WT baseline, 3 MuRF1 Tg+ baseline, cardiac overpressure hypertrophy induced by trans-aortic banding at 1 week (3 WT, 3 MurF Tg) and 4 weeks (3 WT, 3 MurF Tg), hearts harvested. One replicate per array.
2009-06-03 | E-GEOD-11661 | biostudies-arrayexpress
Project description:Aims A kinase interacting protein 1 (AKIP1) stimulates physiological growth in cultured cardiomyocytes and attenuates ischemia / reperfusion (I/R) injury in ex vivo perfused hearts. We aimed to determine whether AKIP1 modulates the cardiac response to acute and chronic cardiac stress in vivo. Methods and results Transgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG) were created. AKIP1-TG mice and their wild type (WT) littermates displayed similar cardiac structure and function. Likewise, cardiac remodeling in response to transverse aortic constriction or permanent coronary artery ligation was identical in AKIP1-TG and WT littermates, as evidenced by serial cardiac magnetic resonance imaging and pressure-volume loop analysis. Histological indices of remodeling, including cardiomyocyte cross-sectional diameter, capillary density and left ventricular fibrosis were also similar in AKIP1-TG mice and WT littermates. When subjected to 45 minutes of ischemia followed by 24 hours of reperfusion, AKIP1-TG mice displayed a significant 2-fold reduction in myocardial infarct size and reductions in cardiac apoptosis. In contrast to previous reports, AKIP1 did not co-immunoprecipitate with or regulate the activity of the signaling molecules NF-κB, protein kinase A or AKT. AKIP1 was, however, enriched in cardiac mitochondria and co-immunoprecipitated with a key component of the mitochondrial permeability transition (MPT) pore, ATP-synthase. Finally, mitochondria isolated from AKIP1-TG hearts displayed markedly reduced calcium induced swelling, indicative of reduced MPT pore formation. Conclusions In contrast to in vitro studies, AKIP1 overexpression does not influence cardiac remodeling in response to chronic cardiac stress. AKIP1 does, however, reduce myocardial I/R injury through stabilization of the MPT pore. These findings suggest that AKIP1 deserves further investigation as a putative treatment target for cardioprotection from I/R injury during acute myocardial infarction.
2020-11-23 | GSE83472 | GEO
Project description:Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. To explain this discrepancy between the ongoing heart failure and maintained ATP levels in MuRF1 Tg+ hearts, we compared the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts. Although mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, total CK activity was significantly inhibited. We conclude that MuRF1’s inhibition of CK activity leads to increased susceptibility to heart failure following TAC, demonstrating for the first time that MuRF1 regulates cardiac energetics in vivo. Keywords: Genetic modification, physiological manipulation.
2009-06-03 | GSE11661 | GEO
Project description:The goal of this study is to compare the NGS-derived heart transcriptome profiling (RNA-seq) between kdrl GFP positive endothelial cells of 4-HT induced Tg(ubi:loxp-DsRed-stop-loxp-DN-xBrg1; kdrl:CreER; kdrl:eGFP) (DNK) and Tg(ubi:loxp-DsRed-stop-loxp-DN-xBrg1; kdrl:eGFP) (CtrlK) injured hearts.
2022-07-09 | GSE154193 | GEO
Project description:Aging impairs the mitochondrial electron transport chain (ETC), especially in interfibrillar mitochondria (IFM). Mitochondria are in close contact with the endoplasmic reticulum (ER). Induction of ER stress leads to ETC injury in adult heart mitochondria. We asked if ER stress contributes to the mitochondrial dysfunction during aging. Subsarcolemmal mitochondria (SSM) and IFM were isolated from 3, 18, and 24 mo. C57Bl/6 mouse hearts. ER stress progressively increased with age, especially in 24 mo. mice that manifest mitochondrial dysfunction. OXPHOS was decreased in 24 mo. IFM oxidizing complex I and complex IV substrates. Proteomic analysis showed that the content of multiple complex I subunits was decreased in IFM from 24 mo. hearts, but remained unchanged in in 18 mo. IFM without a decrease in OXPHOS. Feeding mice with 4-phenylbutyrate (4-PBA) for two weeks attenuated the ER stress and improved mitochondrial function in 24 mo. mice. These results indicate that ER stress contributes to the mitochondrial dysfunction in aged hearts. Attenuation of ER stress is a potential approach to improve mitochondrial function in aged hearts.
2020-07-23 | PXD018545 | Pride
Project description:Effect of overexpression of PKR1 in mice hearts on the cardiac transcriptome
2017-10-31 | GSE94603 | GEO
Project description:Effect of overexpression of PKR2 in mice hearts on the cardiac transcriptome.
2021-03-02 | GSE147674 | GEO
Project description:Despite some success of pharmacotherapies targeting primarily neurohormonal dysregulation, heart failure is a growing global pandemic with increasing burden. Treatments that improve the disease by reversing heart failure at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators of gene expression, acting through complex biological networks, and playing thereby essential roles in disease progression. Adverse structural remodelling of the left ventricle due to myocardial infarction (MI) is a common pathological feature leading to heart failure. We previously demonstrated increased cardiomyocyte expression of the miR-212/132 family during pathological cardiac conditions. Transgenic mice overexpressing the miR-212/132 cluster (miR-212/132-TG) develop pathological cardiac remodelling and die prematurely from progressive HF. Using both knockout and antisense strategies, we have shown miR-132 to be both necessary and sufficient to drive the pathological growth of cardiomyocytes in a murine model of left ventricular pressure overload. Based on the findings, we proposed that miR-132 may serve as a therapeutic target in heart failure therapy. Here we provide novel mechanistic insight and translational evidence for the therapeutic efficacy in small and large animal models (n=135) of heart failure. We demonstrate strong PK/PD relationship, dose-dependent efficacy and high clinical potential of a novel optimized synthetic locked nucleic acid phosphorothioate backbone antisense oligonucleotide inhibitor of miR-132 (antimiR-132) as a next-generation heart failure therapeutic.
2020-01-09 | PXD015337 | Pride