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Project description:Loss of fatty acid oxidation in mitochondria promotes epigenetic control of cardiomyocyte maturation status
| PRJNA723273 | ENA
Project description:Sepsis-induced cardiac injury (SIC) is one of the most common complications in the intensive care unit (ICU) with high morbidity and mortality. Mitochondrial dysfunction is one of the main reasons for SIC, and Interleukin-13 (IL-13) is a master regulator of mitochondria biogenesis. The aim of the present study was to investigate the role of IL-13 in SIC and explore the underlying mechanism. It was found that reactive oxygen species (ROS) production and apoptosis were significantly increased in lipopolysaccharide (LPS)-stimulated primary cardiomyocytes, which was accompanied with obvious mitochondria dysfunction. The results of RNA-sequencing (RNA-seq), mitochondrial membrane potential, fatty acid uptake and oxidation rate suggested that treatment with IL-13 could restore the function and morphology of mitochondria, indicating that it played an important role in protecting septic cardiomyocytes. These findings demonstrated that IL-13 alleviated sepsis-induced cardiac inflammation and apoptosis by improving mitochondrial fatty acid uptake and oxidation, suggesting that IL-13 may prove to be a potential promising target for SIC treatment.
| S-EPMC8484794 | biostudies-literature
Project description:Cardiomyocyte proliferation accounts for the increase of cardiac muscle during fetal mammalian heart development. Shortly after birth, cardiomyocyte transits from hyperplasia to hypertrophic growth. Here, we have investigated the role of fatty acid β-oxidation in cardiomyocyte proliferation and hypertrophic growth during early postnatal life in mice. A transient wave of increased cell cycle activity of cardiomyocyte was observed between postnatal day 3 and 5, that proceeded as cardiomyocyte hypertrophic growth and maturation. Assessment of cardiomyocyte metabolism in neonatal mouse heart revealed a myocardial metabolic shift from glycolysis to fatty acid β-oxidation that coincided with the burst of cardiomyocyte cell cycle reactivation and hypertrophic growth. Inhibition of fatty acid β-oxidation metabolism in infant mouse heart delayed cardiomyocyte cell cycle exit, hypertrophic growth and maturation. By contrast, pharmacologic and genetic activation of PPARα, a major regulator of cardiac fatty acid metabolism, induced fatty acid β-oxidation and initially promoted cardiomyocyte proliferation rate in infant mice. As the cell cycle proceeded, activation of PPARα-mediated fatty acid β-oxidation promoted cardiomyocytes hypertrophic growth and maturation, which led to cell cycle exit. As a consequence, activation of PPARα-mediated fatty acid β-oxidation did not alter the total number of cardiomyocytes in infant mice. These findings indicate a unique role of fatty acid β-oxidation in regulating cardiomyocyte proliferation and hypertrophic growth in infant mice.
| S-EPMC6440456 | biostudies-literature
Project description:AimsHuman pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature foetal to an adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and oxidative phosphorylation (OXPHOS) among others. Lysine demethylase 5 (KDM5) specifically demethylates H3K4me1/2/3 and has emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function. The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation.Methods and resultsKDM5A, B, and C proteins were mainly expressed in the early post-natal stages, and their expressions were progressively downregulated in the post-natal CMs and were absent in adult hearts and CMs. In contrast, KDM5 proteins were persistently expressed in the iPSC-CMs up to 60 days after the induction of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor, induced differential expression of 2372 genes, including upregulation of genes involved in fatty acid oxidation (FAO), OXPHOS, and myogenesis in the iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the cleavage under targets and release using nuclease assay showed enriched of the H3K4me3 peaks at the promoter regions of genes encoding FAO, OXPHOS, and sarcomere proteins. Consistent with the chromatin and gene expression data, KDM5 inhibition increased the expression of multiple sarcomere proteins and enhanced myofibrillar organization. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene and increased its RNA and protein levels. Knockdown of ESRRA in KDM5-C70-treated iPSC-CM suppressed expression of a subset of the KDM5 targets. In conjunction with changes in gene expression, KDM5 inhibition increased oxygen consumption rate and contractility in iPSC-CMs.ConclusionKDM5 inhibition enhances maturation of iPSC-CMs by epigenetically upregulating the expressions of OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.
| S-EPMC11074792 | biostudies-literature
Project description:The healthy adult heart primarily relies on fatty acid oxidation (FAO) for energy production but instantaneously adapts its substrate preference in response to physiological or pathological challenges. Accurate FAO measurements are crucial to investigate early metabolic (mal)adaptations. While measurements in intact cardiomyocytes offer greater physiological relevance, current FAO protocols mainly employ cell-free systems and/or require expensive equipment. Here, we present an easy-to-use, inexpensive, and sensitive method to measure, compare and modulate FAO in various cardiomyocyte models. Basal FAO was 2-fold higher in fresh versus cultured adult rat cardiomyocytes (aRCM), while OXPHOS protein levels were maintained. Basal FAO was higher in cultured (3-fold) and fresh (8-fold) aRCM, versus widely used neonatal rat cardiomyocytes (nRCM) and mouse HL1 cardiomyocytes. Moreover, we utilized chemical and pharmacological treatments in order to modulate the FAO flux at different cellular signalling levels. Our data indicate that caution should be taken when studying metabolism in nRCM and HL1 cell models, as these display significantly lower FAO than aRCM. Accurate FAO measurement in cultured aRCM opens new avenues for studying the complex cardiomyocyte metabolic responses to mechanical, nutritional, pharmacological, and genetic manipulations.
| S-EPMC5784119 | biostudies-literature
Project description:Rationale: Human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature fetal to adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and OXPHOS among others. Lysine demethylase 5 (KDM5) specifically demethylate H3K4me1/2/3 and have emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function.Objectives: The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation.Methods and Results: KDM5A, B, and C proteins were mainly expressed in the early post-natal stages and their expressions were progressively downregulated in the postnatal cardiomyocytes and were absent in adult hearts and CMs. In contrast, KDM5 proteins were persistently expressed in the iPSC-CMs up to 60 days after the induction of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor, induced differential expression of 2,372 genes, including upregulation of genes involved in fatty acid oxidation (FAO), OXPHOS, and myogenesis in the iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assay showed enriched of the H3K4me3 peaks at the promoter regions of genes encoding FAO, OXPHOS, and sarcomere proteins. Consistent with the chromatin and gene expression data, KDM5 inhibition increased expression of multiple sarcomere proteins and enhanced myofibrillar organization. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene and increased its RNA and protein levels. Knockdown of ESRRA in KDM5-C70-treated iPSC-CM suppressed expression of a subset of the KDM5 targets. In conjunction with changes in the gene expression, KDM5 inhibition increased oxygen consumption rate and contractility in iPSC-CMs.
2023-12-15 | GSE250210 | GEO
Project description:Rationale: Human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature fetal to adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and OXPHOS among others. Lysine demethylase 5 (KDM5) specifically demethylate H3K4me1/2/3 and have emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function.Objectives: The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation.Methods and Results: KDM5A, B, and C proteins were mainly expressed in the early post-natal stages and their expressions were progressively downregulated in the postnatal cardiomyocytes and were absent in adult hearts and CMs. In contrast, KDM5 proteins were persistently expressed in the iPSC-CMs up to 60 days after the induction of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor, induced differential expression of 2,372 genes, including upregulation of genes involved in fatty acid oxidation (FAO), OXPHOS, and myogenesis in the iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assay showed enriched of the H3K4me3 peaks at the promoter regions of genes encoding FAO, OXPHOS, and sarcomere proteins. Consistent with the chromatin and gene expression data, KDM5 inhibition increased expression of multiple sarcomere proteins and enhanced myofibrillar organization. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene and increased its RNA and protein levels. Knockdown of ESRRA in KDM5-C70-treated iPSC-CM suppressed expression of a subset of the KDM5 targets. In conjunction with changes in the gene expression, KDM5 inhibition increased oxygen consumption rate and contractility in iPSC-CMs.
2023-12-15 | GSE250208 | GEO
Project description:Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC.
| S-EPMC11199980 | biostudies-literature
Project description:Nonalcoholic steatohepatitis (NASH) is a rapidly growing cause of chronic liver damage, cirrhosis, and hepatocellular carcinoma. How fatty liver pathogenesis is subject to epigenetic regulation is unknown. We hypothesized that chromatin remodeling is important for the pathogenesis of fatty liver disease. AT-rich interactive domain-containing protein 1A (ARID1A), a DNA-binding component of the SWItch/sucrose nonfermentable adenosine triphosphate-dependent chromatin-remodeling complex, contributes to nucleosome repositioning and access by transcriptional regulators. Liver-specific deletion of Arid1a (Arid1a liver knockout [LKO]) caused the development of age-dependent fatty liver disease in mice. Transcriptome analysis revealed up-regulation of lipogenesis and down-regulation of fatty acid oxidation genes. As evidence of direct regulation, ARID1A demonstrated direct binding to the promoters of many of these differentially regulated genes. Additionally, Arid1a LKO mice were more susceptible to high-fat diet-induced liver steatosis and fibrosis. We deleted Pten in combination with Arid1a to synergistically drive fatty liver progression. Inhibition of lipogenesis using CAT-2003, a potent sterol regulatory element-binding protein inhibitor, mediated improvements in markers of fatty liver disease progression in this Arid1a/Pten double knockout model. Conclusion: ARID1A plays a role in the epigenetic regulation of hepatic lipid homeostasis, and its suppression contributes to fatty liver pathogenesis. Combined Arid1a and Pten deletion shows accelerated fatty liver disease progression and is a useful mouse model for studying therapeutic strategies for NASH.
| S-EPMC6461494 | biostudies-literature
Project description:ObjectiveAbnormal lipid metabolism in mammalian tissues can be highly deleterious, leading to organ failure. Carnitine Palmitoyltransferase 2 (CPT2) deficiency is an inherited metabolic disorder affecting the liver, heart, and skeletal muscle due to impaired mitochondrial oxidation of long-chain fatty acids (mLCFAO) for energy production.MethodsHowever, the basis of tissue damage in mLCFAO disorders is not fully understood. Mice lacking CPT2 in skeletal muscle (Cpt2Sk-/-) were generated to investigate the nexus between mFAO deficiency and myopathy.ResultsCompared to controls, ex-vivo contractile force was reduced by 70% in Cpt2Sk-/- oxidative soleus muscle despite the preserved capacity to couple ATP synthesis to mitochondrial respiration on alternative substrates to long-chain fatty acids. Increased mitochondrial biogenesis, lipid accumulation, and the downregulation of 80% of dystrophin-related and contraction-related proteins severely compromised the structure and function of Cpt2Sk-/- soleus. CPT2 deficiency affected oxidative muscles more than glycolytic ones. Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake. In agreement, Cpt2Sk-/- soleus had decreased calcium uptake and significant accumulation of palmitoyl-carnitine, suggesting that LCACs and calcium dyshomeostasis are linked in skeletal muscle.ConclusionsOur data demonstrate that loss of CPT2 and mLCFAO compromise muscle structure and function due to excessive mitochondrial biogenesis, downregulation of the contractile proteome, and disruption of calcium homeostasis.
| S-EPMC11408158 | biostudies-literature