Cardiomyocyte Pdk4 response is associated with metabolic maladaptation in aging
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ABSTRACT:
PROVIDER: PRJNA879068 | ENA |
REPOSITORIES: ENA
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Project description:Pyruvate Dehydrogenase Kinase 4 (Pdk4) is a pyruvate dehydrogenase inhibiton gene that strongly regulates metabolism. We studied the expression of Pdk4 in the young and aged mouse heart in both healthy conditions and after ischemic insult.
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Project description:We identified PDK4 as a gene with adaptive transcriptional response to chemical stress. Although PDK4 is an energy resource regulator induced by starvation, expression of other fasting-inducible genes was unaffected, indicating additional physiological role of PDK4 for liver adaptation to the chemical stress. We used microarrays to determine genes with altered transcriptional level by PDK4 overexpression. Mice were infected with Ad-control (empty adenovirus vector) or Ad-PDK4 (PDK4 overexpressing adenovirus vector) at a dose of 10^9 PFU/mouse by tail vein injection. 3 days after the infection, mice were sacrificed for RNA preparation from the liver. Ad-control infected = 4, Ad-PDK4 infected = 3. Specimens from mice of each group were pooled, and 10 ug RNA from each pool was used for cRNA synthesis.
2010-12-25 | E-GEOD-22534 | biostudies-arrayexpress
Project description:We identified PDK4 as a gene with adaptive transcriptional response to chemical stress. Although PDK4 is an energy resource regulator induced by starvation, expression of other fasting-inducible genes was unaffected, indicating additional physiological role of PDK4 for liver adaptation to the chemical stress. We used microarrays to determine genes with altered transcriptional level by PDK4 overexpression.
2010-12-25 | GSE22534 | GEO
Project description:Prostate cancer has a broad spectrum of clinical behavior, hence biomarkers are urgently needed for risk stratification. We previously described the protective effect of signal transducer and activator of transcription 3 (STAT3) in a prostate cancer mouse model. We now show the importance of STAT3-regulated metabolic functions and explain their influence on aggressive prostate cancer. By utilizing a gene co-expression network in addition to laser microdissected proteomics from human and murine FFPE samples, we established a workflow that facilitates the discovery of new biomarkers. We thereby identified the protective effect of pyruvate dehydrogenase kinase 4 (PDK4) in prostate cancer. PDK4 is a key regulator of the citrate cycle and low PDK4 is significantly associated with disease recurrence.
2020-04-22 | PXD014251 | Pride
Project description:As a critical hallmark of senescent cells, the senescence-associated secretory phenotype (SASP) develops over the course of chronological aging and in diverse age-related conditions, and is a key driver of chronic inflammation and age-associated phenotypes. For years, the identification, characterization and pharmacological targeting of senescent cells have gained substantial attention in the field of aging and age-related pathologies. Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy regulation, and drives the metabolic reprogramming of mammalian cells towards a Warburg-like effect. Upregulation of PDK4 is responsible for enhanced production of lactate in the tissue microenvironment of aged organisms, potentially causing chronic inflammation and contributing to accelerated aging. Targeting PDK4 holds the potential to prevent lactate accumulation, minimize tissue damage and postpone senescence-associated systemic aging. Here we profiled the genome-wide expression of cells (mainly fibroblasts) in mouse pulmonary alveolus, with the assistance of laser capture microdissection (LCM) of primary lung tissues. Animals were allowed to naturally age, or subject to treatment by PDK4-IN (an anthraquinone derivative, PDK4 inhibitor). These data may provide a baseline to further determine the effects of lactate reduction by PDK4-specific targeting on cellular senescence, tissue homeostasis, and explore the wide implications of PDK4 expression in organismal aging and age-related morbidity.
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Project description:Corticosteroids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and are routinely prescribed to breast cancer patients undergoing chemotherapy treatment to alleviate side effects. Triple negative breast cancers (TNBCs) account for 15-20% of diagnoses and lack expression of estrogen and progesterone receptors as well as amplified HER2, but often express high GR levels. GR is a mediator of TNBC progression to advanced metastatic disease, however the mechanisms underpinning this transition to more aggressive behavior remain elusive. We previously showed that tissue/cellular stress (hypoxia, chemotherapies) as well as factors in the tumor microenvironment (TGFβ, HGF) activate p38 MAPK, which phosphorylates GR on Ser134. In the absence of ligand, p-Ser134-GR further upregulates genes important for responses to cellular stress, including key components of the p38 MAPK pathway. Herein, we show that GR Ser134 is required for TNBC metastatic colonization to the lung. To understand the mechanisms of p-Ser134-GR action in the presence of GR agonists, we examined glucocorticoid-driven transcriptomes in CRISPR (knock-in) models of TNBC cells expressing wild-type or phospho-mutant (S134A) GR. We identified dexamethasone- and p-Ser134-GR-dependent regulation of specific gene sets controlling TNBC migration (NEDD9, CSF1, RUNX3) and metabolic adaptation (PDK4, PGK1, PFKFB4). TNBC cells harboring S134A GR displayed metabolic reprogramming that was phenocopied by PDK4 knockdown. PDK4 knockdown or chemical inhibition also blocked cancer cell migration. Our results reveal a convergence of GR agonists (i.e., host stress) with cellular stress signaling whereby pSer134-GR critically regulates TNBC metabolism, an exploitable target for the treatment of this deadly disease.
2023-09-12 | GSE221355 | GEO
Project description:Aging is the predominant cause of morbidity and mortality in industrialized countries, yet the molecular mechanisms driving aging and especially the contribution by the microbiome remain unclear. We combined multi-omics with metabolic modeling to comprehensively characterize host–microbiome interactions during aging in mice. Our findings reveal a complex dependency of host metabolism on known and novel microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These microbial changes coincided with increased inflammaging as well as a corresponding downregulation of key host pathways, predicted by our model to be microbiome-dependent, that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate microbiome–host interactions that potentially influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.
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Project description:Aging increases the risk for failure of many metabolically-stressed organs and exacerbates liver degeneration related to obesity and diabetes. We used snRNA-seq to identify the effect of metabolic disease (MASLD) on biological aging of hepatocyte.
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Project description:Activation of CD4+ T cells requires metabolic reprograming to sustain demands of cellular building blocks and ATP. Pyruvate dehydrogenase kinase (PDK) is an enzyme regulating pyruvate dehydrogenase complex subunit alpha 1 (PDHE1-alpha), which converts pyruvate to acetyl-CoA. Gene expression analysis of TCR-stimulated CD4+ T cells with PDK4 deletion exhibited the reduced calcium signaling and aerobic glycolysis pathway.
2022-11-01 | GSE161653 | GEO