MuRF1 regulation of Fenofibrate’s induction of spontaneous cardiac hypertrophy in vivo.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE68480 | GEO | 2016/03/01
SECONDARY ACCESSION(S): PRJNA282879
REPOSITORIES: GEO
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Project description:MuRF1 -/- w/ Fenofibrate treatment leads to the reduction of proteolytic and fibrolytic enzymes, increasing hypertrophy Four strain-matched groups of 3-8 week old mice were investigated: 1) MuRF1 -/- Fenofibrate feed; 2) MuRF1 -/- chow feed; 3) MuRF1 +/+ Fenofibrate feed; 4) MuRF1 +/+ chow feed at two time points: 1) 3 weeks; 2) 8 Weeks Biological replicates: Two to three per condition. Hearts harvested. One replicate per array.
2016-03-01 | E-GEOD-68480 | biostudies-arrayexpress
Project description:Muscle ring finger (MuRF) proteins have been implicated in the transmission of mechanical forces to nuclear cell signaling pathways through their association with the sarcomere. We recently reported that MuRF1, but not MuRF2, regulated pathologic cardiac hypertrophy in vivo. This was surprising since MuRF1 and MuRF2 interact redundantly with sarcomeric proteins in yeast two hybrid studies, and form both homo- and hetero-dimers with each other. To determine if MuRF1 and MuRF2 were functionally redundant during development, we created mice lacking either 3 or 4 of the MuRF1 and MuRF2 alleles and compared them functionally. Surprisingly, only mice missing all four MuRF1 and MuRF2 alleles (MuRF1-/-//MuRF2-/-) developed a spontaneous hypertrophic cardiomyopathy - mice that were null for one of the genes, but heterozygous for the other (i.e. MuRF1-/-//MuRF2+/- or MuRF1+/-//MuRF2-/-) were phenotypically identical to wild type mice. Electron microscopy of the hearts of MuRF1-/-//MuRF2-/-(MuRF1/MuRF2 DN) mice identified altered Z disc and M line architecture, and a distinct swelling of mitochondria. MuRF1-/-//MuRF2-/- mouse hearts displayed increased expression of genes associated with fetal cardiac metabolism, including smooth muscle actin and b myosin heavy chain, suggesting that the cardiac hypertrophy seen in these mice was associated with a reversion to a fetal gene program. Despite our prediction that we would also see an increase in glucose compared to fatty acid oxidation (another trait of fetal cardiac metabolism) we saw that MuRF1-/-//MuRF2-/- heart homogenates oxidized significantly less glucose compared to controls, suggesting an important role for MuRF1 and MuRF2 in the regulation of glucose metabolism in vivo. This study identifies a previously unreported redundancy in the function of MuRF proteins in normal cardiac development. Keywords: Genetic modification. Four strain-matched groups of 12 week old mice were investigated: 1) MuRF1 -/- MuRF2 -/-; 2) MuRF1 +/+ MuRF2 +/+; 3) MuRF1 -/- MuRF2 +/-; 4) MuRF1 +/- MuRF2 -/-. Biological replicates: 4 WT, 4 MuRF1 -/- // MuRF2 -/-, 4 MuRF1 +/- //MuRF2 -/-, 4 MuRF1 -/- // MuRF2 +/-. Hearts harvested. One replicate per array.
2013-04-01 | E-GEOD-14512 | biostudies-arrayexpress
Project description:Muscle ring finger (MuRF) proteins have been implicated in the transmission of mechanical forces to nuclear cell signaling pathways through their association with the sarcomere. We recently reported that MuRF1, but not MuRF2, regulated pathologic cardiac hypertrophy in vivo. This was surprising since MuRF1 and MuRF2 interact redundantly with sarcomeric proteins in yeast two hybrid studies, and form both homo- and hetero-dimers with each other. To determine if MuRF1 and MuRF2 were functionally redundant during development, we created mice lacking either 3 or 4 of the MuRF1 and MuRF2 alleles and compared them functionally. Surprisingly, only mice missing all four MuRF1 and MuRF2 alleles (MuRF1-/-//MuRF2-/-) developed a spontaneous hypertrophic cardiomyopathy - mice that were null for one of the genes, but heterozygous for the other (i.e. MuRF1-/-//MuRF2+/- or MuRF1+/-//MuRF2-/-) were phenotypically identical to wild type mice. Electron microscopy of the hearts of MuRF1-/-//MuRF2-/-(MuRF1/MuRF2 DN) mice identified altered Z disc and M line architecture, and a distinct swelling of mitochondria. MuRF1-/-//MuRF2-/- mouse hearts displayed increased expression of genes associated with fetal cardiac metabolism, including smooth muscle actin and b myosin heavy chain, suggesting that the cardiac hypertrophy seen in these mice was associated with a reversion to a fetal gene program. Despite our prediction that we would also see an increase in glucose compared to fatty acid oxidation (another trait of fetal cardiac metabolism) we saw that MuRF1-/-//MuRF2-/- heart homogenates oxidized significantly less glucose compared to controls, suggesting an important role for MuRF1 and MuRF2 in the regulation of glucose metabolism in vivo. This study identifies a previously unreported redundancy in the function of MuRF proteins in normal cardiac development. Keywords: Genetic modification.
2013-04-01 | GSE14512 | GEO
Project description:We previously identified a role for the muscle-specific ubiquitin ligase MuRF1 (Muscle Ring Finger-1) in cardiac ischemia-reperfusion (I/R) injury. We found that cardiomyocyte-specific (alphaMHC-) MuRF1 transgenic mice (MuRF1 Tg+) mice were significantly protected from I/R injury. As we discovered MuRF1’s regulation of other transcriptions factors, we sought to identify other ways in which MuRF1 was cardioprotective in I/R injury. In the present study, we first identified the regulation of MuRF1 expression by qPCR in a porcine model of I/R injury. MuRF1 mRNA significantly increased within 90 minutes of I/R injury. We next assayed MuRF1 Tg+ ventricular tissue after I/R reperfusion injury by microarray (44K transcripts) to identify how MuRF1 regulates the transcriptome. We identified 71 significantly altered genes having a >1.5-fold (p<0.01) in MuRF1 Tg+ and wildtype hearts challenged with I/R injury (or sham operation). Functional annotation of the top upregulated genes found enrichment for myogenesis, cell adhesion, and nucleic acid metabolism. TRANSFAC analysis of MuRF1 Tg+ significant genes identified enrichment for genes (30-53%) with promoter regions recognized by the transcription factors MAZ, PIT1, VMW65, and BACH2. The transcription factor MAZ binds muscle creatine kinase (MCK) promoter in skeletal and cardiac myocytes, known most for its regulation of myogenin and MEF2C in cardiomyocytes. While the role of PIT1 and BACH2 in adult cardiomyocytes is not clear, VMW65 is a powerful transactivator with functions in chromatin remodeling. In neonatal cardiomycoyte I/R injury, VMW65 associates with HIF1alpha to upregulate cardioprotective VEGF, Glut-1, Glut-4, HSP70, and iNOS expression. These findings elucidate the MuRF1-specific regulation of genes in cardiac I/R injury that are associated with cardioprotection and may represent multiple additional direct or indirect mechanisms that MuRF1 regulates cardiomyocyte signaling.
2019-01-05 | GSE108940 | 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: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:Thyroid hormone (TH) is recognized for its role in cellular metabolism and growth and participates in homeostasis of the heart. T3 activates pro-survival pathways including Akt and mTOR. Treatment with T3 after myocardial infarction is cardioprotective and promotes elements of physiological hypertrophic response after cardiac injury. Although T3 is known to benefit the heart, very little about its regulation at the molecular level has been described to date. The ubiquitin proteasome system (UPS) regulates nuclear hormone receptors such as estrogen, progesterone, androgen, and glucocorticoid receptors by both degradatory and non-degradatory mechanisms. However, how the UPS regulates T3-mediated activity is not well understood. In this study, we aim to determine the role of the muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) in regulating T3-induced cardiomyocyte growth. An increase in MuRF1 expression inhibits T3-induced physiological cardiac hypertrophy, whereas a decrease in MuRF1 expression enhances T3's activity both in vitro and in cardiomyocytes in vivo MuRF1 interacts directly with TRα to inhibit its activity by posttranslational ubiquitination in a non-canonical manner. We then demonstrated that a nuclear localization apparatus that regulates/inhibits nuclear receptors by sequestering them within a subcompartment of the nucleus was necessary for MuRF1 to inhibit T3 activity. This work implicates a novel mechanism that enhances the beneficial T3 activity specifically within the heart, thereby offering a potential target to enhance cardiac T3 activity in an organ-specific manner.
| S-EPMC5453669 | biostudies-literature
Project description:MuRF1 is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Tibialis anterior (TA) muscles were transfected with an untagged MuRF1 plasmid or control plasmid for 14 days. A total of 963 ubiquitination sites, corresponding to 250 proteins, were quantified from the TA muscle. Statistical analysis revealed that the overexpression of MuRF1 resulted in significant upregulation of 153 ubiquitination sites on 45 proteins and significant downregulation of 16 sites on 11 proteins. Substrates of MuRF1 include contractile and metabolic proteins, deubiquitinases, p62, and VCP. Moreover, MuRF1-mediated ubiquitination leads to destabilization and breakdown of the sarcomere and reveals a role for MuRF1 in the regulation of additional proteolytic pathways in skeletal muscle.
2021-07-07 | PXD023872 | Pride
Project description:Purpose: The physiological cardiac hypertrophy is an adaptive condition that does not associate with myocyte cell death while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. Alpha-2 macroglobulin (α-2M) an acute phase protein induces cardiac hypertrophy via the ERK1,2 and PI3K/Akt signaling. This study is aimed at exploring the miRNome of α-2M induced hypertrophied cardiomyocytes and to understand the role of miRNAs in determination of pathological and physiological hypertrophy. Methods: Hypertrophy was induced in H9c2 cardiomyoblasts using alpha-2 macroglobulin. The induction of hypertrophy is confirmed by microscopy and gene expression studies. Subsequently, the total RNA was isolated and small RNA sequencing was executed in Illumina HiSeq 2000. Results: Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy. Among the differentially expressed candidates, miR-99 family (miR-99a, miR-99b and miR-100) showed significant downregulation upon α-2M treatment while isoproterenol treatment (pathological hypertrophy) upregulated their expression. The binding site for Egr1 transcription factor was identified in the promoter region of miR-99 family, and interestingly all miRNAs with Egr1 binding site proven by ChIP-Seq were downregulated during physiological hypertrophy Conclusions: The results proved Egr-1 mediated regulation of miR-99 family determines the uniqueness of pathological and physiological hypertrophy. Upregulated miR-99 expression during pathological hypertrophy suggests that it can be a valuable diagnostic marker and potential therapeutic target for cardiac hypertrophy and heart failure. Small RNA profiles of control and hypertrophied cardiomyocyte H9c2 cells were generated by deep sequencing using Illumina HiSeq 2000
2015-11-01 | E-GEOD-73597 | biostudies-arrayexpress
Project description:The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator-activated receptor alpha (PPARα) for nuclear export via mono-ubiquitination. Since MuRF1-/- mice have an estimated fivefold increase in PPARα activity, we sought to determine how challenge with the PPARα agonist fenofibrate, a PPARα ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1+/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle α-actin mRNA. In addition to pathological hypertrophy, MuRF1-/- mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1-/- genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <-4 log fold change; P ≤ .0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARα, cardiac hypertrophy, and hemostasis.
| S-EPMC4754579 | biostudies-literature