Metabolic and Transcriptional Alterations in the Early Stages of Cardiac Fuel Switch Hint at Novel mTOR-mediated Regulation of Hypertrophy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE103375 | GEO | 2018/04/27
REPOSITORIES: GEO
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Project description:1. Background- Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids (FA) to fatty acyl-CoAs. Cardiac-specific ACSL1 knockout results in a shift towards glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of FA oxidation on cardiac metabolism and function. 2. Methods and Results- Compared to WT hearts, global cardiac transcriptional analysis revealed differential expression of 245 genes in Acsl1H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 139 genes whose expression was uniquely changed upon short-term cardiac inactivation of ACSL1. In particular, partial ACSL1 ablation led to the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified 65 metabolites altered in hearts displaying partially reduced ACSL activity, whereas rapamycin treatment normalized the cardiac metabolomic fingerprint. Chronic mTOR inhibition via rapamycin treatment revealed novel mTORC1 targets involved in fibrosis, amino acid catabolism, and mitochondrial transport and metabolism. 3. Conclusions- Short-term cardiac-specific ACSL1 inactivation (Acsl1H-/-) resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, leading to the identification of novel mTORC1 targets that regulate cardiac hypertrophy development, and suggesting heart-specific mTOR signaling that occurs during the early stages of substrate switching. Moreover, the rate of increased glucose use correlated negatively with hypertrophy development, strongly suggesting that hearts do not become hypertrophied if they can compensate or switch faster from FA to glucose use.
2018-04-27 | GSE103376 | GEO
Project description:1. Background- Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids (FA) to fatty acyl-CoAs. Cardiac-specific ACSL1 knockout results in a shift towards glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of FA oxidation on cardiac metabolism and function. 2. Methods and Results- Compared to WT hearts, global cardiac transcriptional analysis revealed differential expression of 245 genes in Acsl1H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 139 genes whose expression was uniquely changed upon short-term cardiac inactivation of ACSL1. In particular, partial ACSL1 ablation led to the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified 65 metabolites altered in hearts displaying partially reduced ACSL activity, whereas rapamycin treatment normalized the cardiac metabolomic fingerprint. Chronic mTOR inhibition via rapamycin treatment revealed novel mTORC1 targets involved in fibrosis, amino acid catabolism, and mitochondrial transport and metabolism. 3. Conclusions- Short-term cardiac-specific ACSL1 inactivation (Acsl1H-/-) resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, leading to the identification of novel mTORC1 targets that regulate cardiac hypertrophy development, and suggesting heart-specific mTOR signaling that occurs during the early stages of substrate switching. Moreover, the rate of increased glucose use correlated negatively with hypertrophy development, strongly suggesting that hearts do not become hypertrophied if they can compensate or switch faster from FA to glucose use.
2018-04-27 | GSE103863 | GEO
Project description:Metabolic and Transcriptional Alterations in the Early Stages of Cardiac Fuel Switch Hint at Novel mTOR-mediated Regulation of Hypertrophy
| PRJNA401094 | ENA
Project description:Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage. The β-cells are not able to control glucose uptake and they are therefore left vulnerable for endogenous toxicity from metabolites produced in excess amounts upon increased glucose availability. In order to handle excess fuel, the β-cells possess specific metabolic pathways, but little is known about these pathways. We present a study of β-cell metabolism under increased fuel pressure using a stable isotope resolved NMR approach to investigate early metabolic events leading up to β-cell dysfunction. The approach is based on a recently described combination of 13C metabolomics combined with signal enhanced NMR via dissolution dynamic nuclear polarization (dDNP). Glucose-responsive INS-1 β-cells were incubated with increasing concentrations of [U-13C] glucose under conditions where GSIS was not affected (2-8 h). We find that pyruvate and DHAP were the metabolites that responded most strongly to increasing fuel pressure. The two major divergence pathways for fuel excess, the glycerolipid/fatty acid metabolism and the polyol pathway, were found not only to operate at unchanged rate but also with similar quantity.
| S-EPMC7508987 | biostudies-literature
Project description:Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. We previously developed two transgenic mouse models that carry FHC associated mutations in alpha-tropomyosin (TM): FHC alpha-TM175 mice show patchy areas of mild ventricular disorganization and limited hypertrophy; whereas FHC alpha-TM180 mice exhibit severe hypertrophy and fibrosis and die within 6 months. To obtain a better understanding of the molecular mechanisms associated with the early onset of cardiac hypertrophy, we conducted a detailed comparative analysis of gene expression in 2.5-month-old control and FHC alpha-TM175 and alpha-TM180 ventricular tissue. Results show that 754 genes (from a total of 22,600) were differentially expressed between the NTG and the FHC hearts. There are 178 differentially regulated genes between NTG and the FHC alpha-TM175 hearts, 388 genes are differentially expressed between NTG and FHC alpha-TM180 hearts, and 266 genes are differentially expressed between FHC alpha-TM175 and FHC alpha-TM180 hearts. Genes that exhibit the largest increase in expression belong to the "secreted/extracellular matrix" category, and those with the most significant decrease in expression are associated with "metabolic enzymes." Keywords: Cardiac hypertrophy, Tropomyosin, Mutation, Transgenic mouse, Microarray
2006-04-18 | GSE4678 | GEO
Project description:Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy.
| S-EPMC4123302 | biostudies-literature
Project description:Basal autophagy is tightly regulated by transcriptional and epigenetic factors to maintain cellular homeostasis. Dysregulation of cardiac autophagy is associated with heart diseases, including cardiac hypertrophy, but the mechanism governing cardiac autophagy is rarely identified. To analyze the in vivo function of miR-199a in cardiac autophagy and cardiac hypertrophy, we generated cardiac-specific miR-199a transgenic mice and showed that overexpression of miR-199a was sufficient to inhibit cardiomyocyte autophagy and induce cardiac hypertrophy in vivo. miR-199a impaired cardiomyocyte autophagy in a cell-autonomous manner by targeting glycogen synthase kinase 3? (GSK3?)/mammalian target of rapamycin (mTOR) complex signaling. Overexpression of autophagy related gene 5 (Atg5) attenuated the hypertrophic effects of miR-199a overexpression on cardiomyocytes, and activation of autophagy using rapamycin was sufficient to restore cardiac autophagy and decrease cardiac hypertrophy in miR-199a transgenic mice. These results reveal a novel role of miR-199a as a key regulator of cardiac autophagy, suggesting that targeting miRNAs controlling autophagy as a potential therapeutic strategy for cardiac disease.
| S-EPMC5520159 | biostudies-literature
Project description:RationaleTRPM4 is a non-selective Ca2+-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the Trpm4 gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as ß-adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear.ObjectivesWe aimed to investigate the role of the TRPM4 channel on whole cardiac function with a Trpm4 gene knock-out mouse (Trpm4-/-) model.Methods and resultsMorpho-functional analysis revealed left ventricular (LV) eccentric hypertrophy in Trpm4-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks) when compared to Trpm4+/+ littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in Trpm4-/- mice were smaller than Trpm4+/+with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the Trpm4-/-neonatal stage, suggesting hyperplasia. Adult Trpm4-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. Trpm4-/-mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, Trpm4-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca2+ or K+ currents involved in the repolarizing phase.ConclusionsTRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular electrical activity which impact heart development.
| S-EPMC4274076 | biostudies-literature
Project description:Perhexiline is a potent anti-anginal drug used for treatment of refractory angina and other forms of heart disease. It provides an oxygen sparing effect in the myocardium by creating a switch from fatty acid to glucose metabolism through partial inhibition of carnitine palmitoyltransferase 1 and 2. However, the precise molecular mechanisms underlying the cardioprotective effects elicited by perhexiline are not fully understood. The present study employed a combined proteomics, metabolomics and computational approach to characterise changes in murine hearts upon treatment with perhexiline. According to results based on difference in-gel electrophoresis, the most profound change in the cardiac proteome related to the activation of the pyruvate dehydrogenase complex. Metabolomic analysis by high-resolution nuclear magnetic resonance spectroscopy showed lower levels of total creatine and taurine in hearts of perhexiline-treated mice. Creatine and taurine levels were also significantly correlated in a cross-correlation analysis of all metabolites. Computational modelling suggested that far from inducing a simple shift from fatty acid to glucose oxidation, perhexiline may cause complex rebalancing of carbon and nucleotide phosphate fluxes, fuelled by increased lactate and amino acid uptake, to increase metabolic flexibility and to maintain cardiac output. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".
| S-EPMC3573230 | biostudies-literature
Project description:The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age-dependent degeneration. Over the life span, the RPE develops an expanded endo-lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity. The functional consequences of hyperactive mTORC1 in the RPE are unclear. In the current study, we used integrated high-resolution metabolomic and genomic approaches to examine mice with RPE-specific deletion of the tuberous sclerosis 1 (Tsc1) gene which encodes an upstream suppressor of mTORC1. Our data show that RPE cells with constitutively high mTORC1 activity were reprogramed to be hyperactive in glucose and lipid metabolism. Lipolysis was suppressed, mitochondrial carnitine shuttle was inhibited, while genes involved in fatty acid (FA) biosynthesis were upregulated. The metabolic changes occurred prior to structural changes of RPE and retinal degeneration. These findings have revealed cellular events and intrinsic mechanisms that contribute to lipid accumulation in the RPE cells during aging and age-related degeneration.
| S-EPMC7811279 | biostudies-literature