Post-prandial cardiac hypertrophy is sustained by mechanics, epigenetic, and metabolic reprogramming in pythons [RNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Python regius
PROVIDER: GSE273554 | GEO | 2024/08/04
REPOSITORIES: GEO
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Project description:Constricting pythons, known for their ability to consume infrequent, massive meals, exhibit rapid and reversible cardiac hypertrophy following feeding. Our primary goal was to investigate how python hearts achieve this adaptive response after feeding. Isolated myofibrils increased force after feeding without changes in sarcomere ultrastructure and without increasing energy cost. Ca2+ transients were prolonged after feeding with no changes in myofibril Ca2+ sensitivity. Feeding reduced titin-based tension, resulting in decreased cardiac tissue stiffness. Feeding also reduced the activity of sirtuins, a metabolically-linked class of histone deacetylases, and increased chromatin accessibility. A transcription factor enrichment analysis on transposase-accessible chromatin with sequencing (ATAC-Seq) revealed the prominent role of transcription factors YY1 and NRF1 in post-feeding cardiac adaptation. Gene expression was also changed in favor of translation and metabolism. Finally, metabolomics analysis and ATP production assay demonstrated that cardiac adaptation after feeding not only increased energy demand but also energy production. These findings have broader implications for our understanding of cardiac adaptation across species and hold promise for the development of innovative approaches to address cardiovascular diseases.
2024-08-04 | GSE273555 | GEO
Project description:C57BL/6J mice were subjected to night restricted feeding (ZT12-ZT24) and livers were isolated immediate before (ZT10) and after feeding (ZT14). Combined RNA-seq, DNase-seq and H3K27Ac ChIP-seq identified hundreds of genes and enhancers regulated by acute feeding. Importantly, this feeding regulated transcriptional program follows similar rhythmic expression patterns as the intrinsic circadian transcriptional programs. ChIP-seq showed that feeding repressed enhancers were occupied by both GR and FOXO1 and occupancy of these factors were suppressed by feeding correlating with increased insulin levels and reduced corticosterone levels. Interestingly, despite considerable genome-wide overlap between GR and FOXO1, injection of dexamethasone (dex) or insulin receptor antagonist (S961) immediately before feeding, demonstrated that the glucocorticoid and insulin receptor pathways control distinct transcriptional programs. And strikingly, only combined dex and S961 treatment reversed feeding induced changes to most of the hepatic transcriptome. These corticosteroid and insulin regulated transcriptional programs are dysregulated in diet-induced obese animals.
2018-11-01 | GSE119713 | GEO
Project description:AMP-activated protein 1 kinase (AMPK), a phylogenetically conserved serine/threonine kinase regarded as a key cellular energy sensor, exists in eukaryotes as a heterotrimer comprising a catalytic α and regulatory β and γ subunits. In humans, activating mutations in the gene encoding the γ2 subunit of AMPK (PRKAG2) display a cardiac phenotype of left ventricular hypertrophy (LVH), conduction system disease, ventricular pre-excitation and increased cardiomyocyte glycogen accumulation. While existing transgenic models have elucidated the pathogenesis of several aspects of the disease5-7, the slow heart rate (sinus bradycardia) – a prominent feature of the disease – remains poorly understood. Here, using gene-targeting to generate mice which recapitulate this bradycardia, we demonstrate that γ2 AMPK activation perturbs fundamental mechanisms that determine sinoatrial pacemaker cell function. Reduction in the sarcolemmal hyperpolarization activated (“funny”) current (If) and damping of ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ releases (LCRs)12,13 contribute to reduced sinoatrial cell spontaneous activity and, ultimately, to a lower heart rate. Pharmacological activation of AMPK reversibly reduces the beating rate of murine pluripotent stem cell-derived induced sinoatrial bodies. In contrast, using a mouse knock-out of γ2 AMPK, which exhibits an increased heart rate, we demonstrate a role for γ2 AMPK in physiological heart rate regulation, including an indispensable role in the bradycardic adaptation to endurance exercise. Through regulating the cardiac pacemaker and thereby heart rate, γ2 AMPK by virtue of its energy-sensing role, is a key physiological determinant of overall cardiac energy homeostasis.
2017-09-30 | GSE73047 | GEO
Project description:: The adult heart develops hypertrophy to reduce ventricular wall stress and maintain cardiac function in response to an increased workload. Although pathological hypertrophy generally progresses to heart failure, physiological hypertrophy may be cardioprotective. Cardiac-specific overexpression of the lipid-droplet protein perilipin 5 (Plin5) promotes cardiac hypertrophy, but it is unclear if this response is beneficial. We analyzed human RNA-sequencing data from the left ventricle and showed that cardiac PLIN5 expression correlates with upregulation of cardiac contraction-related processes. To investigate how elevated cardiac Plin5 levels affect cardiac contractility, we generated mice with cardiac-specific overexpression of Plin5 (MHC-Plin5 mice). These mice displayed increased left ventricular mass and cardiomyocyte size but preserved heart function. Quantitative proteomics identified sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) as a Plin5-interacting protein. Phosphorylation of phospholamban, the master regulator of SERCA2, was increased in MHC-Plin5 versus wild-type cardiomyocytes. Live imaging showed increases in intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function in MHC-Plin5 versus wild-type cardiomyocytes. These results identify a role for Plin5 in improving cardiac contractility through enhanced Ca2+ signaling.
2023-01-20 | PXD035121 | Pride
Project description:Mitochondrial Ca2+ (mCa2+) plays an important role in regulating cardiac metabolism and physiology. However, its contribution to metabolic and functional defects in the hearts of type 2 diabetic mice (T2D) is not well understood. Ca2+ is imported into mitochondria by the mitochondrial calcium uniporter complex (MCUC) which is a highly selective multimeric Ca2+ ion channel composed of pore-forming, scaffold, and regulatory subunits. Here, we describe new mechanisms involving the MCUC inhibitory subunit MCUb and its role in determining cardiac dysfunction by linking cardiac mitochondrial metabolism and contractile function. Hearts from T2D mice were analyzed 5 months following a single streptozotocin (STZ) injection (75 mg/kg) and high fat diet (HFD) feeding, and compared to control hearts from mice fed normal chow. Transcriptional and proteomic profiling were employed to characterize these hearts. Regulation of MCUb gene expression was investigated using a recombinant mutant inactive Cas9 (dCas9)-based gene promoter pull down approach coupled with mass spectrometry (MS). A dominant negative MCUb (MCUb W246R/V251E=dnMCUb) was engineered. dnMCUb was biochemically characterized in vitro, tested in neonatal cardiac myocytes exposed to culture media mimicking the diabetic milieu, and expressed in type 2 diabetic mice for 1 month. The impact of dnMCUb on the cardiac physiology was then investigated using omics as well as functional approaches aimed to highlight metabolic and contractile features. RNA-seq and proteomics analysis revealed that T2D hearts relied almost exclusively on fatty acid oxidative metabolism. In parallel we found a significant increase in MCUb mRNA and protein in T2D hearts, which was associated with decreased mCa2+ import rates. MS analysis of proteins co-precipitated with dCas9 revealed the presence of NCOR2 in control but not in T2D MCUb gene promoters. Downregulation of NCOR2 in isolated cardiac myocytes from control mice recapitulated the increase in MCUb gene expression. The dnMCUb mutant increased MCUC Ca2+ affinity by improving the architecture of the complex. Furthermore, when dnMCUb was introduced to cardiac myocytes and T2D mice we observed increased mitochondrial glucose oxidation, mitochondrial ATP production, and enhanced cardiac function. These were linked to the complete restoration of phospholamban (PLN) phosphorylation via Protein Kinase A (PKA) as revealed by both MS analysis of the phosphoproteome and studies dedicated on PLN only followed by PKA pharmacological inhibition. We detail a new pathological axis in which T2D induces global metabolic adaptations and inflexibility in part due to impaired mCa2+ transport into the mitochondrial matrix, resulting from MCUb overexpression. Moreover, we describe a mCa2+-dependent regulation of cytosolic Ca2+ (cCa2+) trafficking in which mCa2+ regulates the activity of SERCA2a via PKA-dependent phosphorylation of PLN.
2022-12-15 | GSE145294 | GEO
Project description:Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value. Here, we report that the transcription factor Zinc finger E-box-binding homeobox2 (ZEB2) is induced by Hypoxia-inducible factor 1-alpha (HIF1a) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+-handling and contractility during ischemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed ZEB2 in cardiomyocytes to be necessary and sufficient to protect the heart against ischemia-induced diastolic dysfunction and structural remodeling. Moreover, RNA sequencing (RNA-seq) of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban (PLN) at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signaling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodeling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with antimiR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy. Together, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF.
2024-12-19 | GSE236827 | GEO
Project description:The cardiomyocyte-specific deletion of Ddx5 in mice resulted in heart failure characterized by diminished cardiac function, enlarged heart chambers, and heightened fibrosis. Proteomic analysis unveiled the involvement of DDX5 in RNA splicing within cardiomyocytes. Our study identified DDX5 as a regulator of the abnormal splicing of CamkIIδ, preventing the generation of CaMKIIδA. This isoform activates LTCC through serine phosphorylation of Cacna1c, disrupting Ca2+ homeostasis. Consistently, DDX5-depleted cardiomyocytes exhibited elevated intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content.
2024-12-02 | GSE248444 | GEO
Project description:The cardiomyocyte-specific deletion of Ddx5 in mice resulted in heart failure characterized by diminished cardiac function, enlarged heart chambers, and heightened fibrosis. Proteomic analysis unveiled the involvement of DDX5 in RNA splicing within cardiomyocytes. Our study identified DDX5 as a regulator of the abnormal splicing of CamkIIδ, preventing the generation of CaMKIIδA. This isoform activates LTCC through serine phosphorylation of Cacna1c, disrupting Ca2+ homeostasis. Consistently, DDX5-depleted cardiomyocytes exhibited elevated intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content.
2024-12-02 | GSE248443 | GEO
Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.
2024-07-15 | PXD053037 | Pride
Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.
2024-07-15 | PXD053051 | Pride