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ABSTRACT:
PROVIDER: PRJNA593900 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondrial Substrate Utilization Regulates Cardiomyocyte Cell Cycle Progression
| PRJNA593899 | ENA
Project description:The role of peroxisome proliferator-activated receptor M-NM-4 (PPARM-NM-4) activation on global gene expression and mitochondrial fuel utilization were investigated in human myotubes. Only 21 genes were up-regulated and 3 genes were down-regulated after activation by the PPARM-NM-4 agonist GW501516. Pathway analysis showed up-regulated mitochondrial fatty acid oxidation, TCA cycle and cholesterol biosynthesis. GW501516 increased oleic acid oxidation and mitochondrial oxidative capacity by 2-fold. Glucose uptake and oxidation were reduced, but total substrate oxidation was not affected, indicating a fuel switch from glucose to fatty acid. Cholesterol biosynthesis was increased, but lipid biosynthesis and mitochondrial content were not affected. This study confirmed that the principal effect of PPARM-NM-4 activation was to increase mitochondrial fatty acid oxidative capacity. Our results further suggest that PPARM-NM-4 activation reduced glucose utilization through a switch in mitochondrial substrate preference by up-regulating pyruvate dehydrogenase kinase isozyme 4 and genes involved in lipid metabolism and fatty acid oxidation. Keywords: Expression profiling by array Human myotubes from four donors were exposed to a PPARM-NM-4 agonist or control for 96 h after which gene expression was profiled.
2014-05-23 | E-GEOD-40789 | biostudies-arrayexpress
Project description:Insulin signaling regulates cardiac substrate utilization and is implicated in physiological adapations of the heart. While extensively investigated in several metabolic organs using phosphoproteomic strategies, the signaling response elicited in cardiac tissue in general, and specifically in the spezialized cardiomyocyte cells, has not yet been investigated to the same extend.
2024-08-10 | PXD050545 | Pride
Project description:The role of peroxisome proliferator-activated receptor δ (PPARδ) activation on global gene expression and mitochondrial fuel utilization were investigated in human myotubes. Only 21 genes were up-regulated and 3 genes were down-regulated after activation by the PPARδ agonist GW501516. Pathway analysis showed up-regulated mitochondrial fatty acid oxidation, TCA cycle and cholesterol biosynthesis. GW501516 increased oleic acid oxidation and mitochondrial oxidative capacity by 2-fold. Glucose uptake and oxidation were reduced, but total substrate oxidation was not affected, indicating a fuel switch from glucose to fatty acid. Cholesterol biosynthesis was increased, but lipid biosynthesis and mitochondrial content were not affected. This study confirmed that the principal effect of PPARδ activation was to increase mitochondrial fatty acid oxidative capacity. Our results further suggest that PPARδ activation reduced glucose utilization through a switch in mitochondrial substrate preference by up-regulating pyruvate dehydrogenase kinase isozyme 4 and genes involved in lipid metabolism and fatty acid oxidation. Keywords: Expression profiling by array
2014-05-23 | GSE40789 | GEO
Project description:Cardiac glucose delivery and utilization are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetic patients. The loss of mitochondrial substrate flexibility in regulating cellular and cardiac function is actively under investigation.
2020-10-05 | GSE123975 | GEO
Project description:Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. We have discovered that an alternative mitochondrial complex II (CII) assembly, designated here as CIIlow, serves as a check-point for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CIIlow leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings uncover a new core complex inside mitochondria that provides homeostatic control of cellular metabolism to reflect availability of energy, with SDHA being its central molecule.
2018-04-16 | GSE108938 | GEO
Project description:Cardiac-specific Glut1 transgenic (Glut1-TG) mice exhibited higher glucose uptake and utilization compared with wild type mice. Cardiac pathological hypertrophy is accompanied by a switch of substrate metabolism from fatty acid oxidation to glucose use, resulting in a fetal like metabolic profile. However, the role of increasing glucose utilization in regulating cardiomyocyte growth is poorly understood. In order to identify novel pathways that is regulated by glucose, we performed microarray analyses using hearts from Glut1-TG and WT mice. The microarray analyses revealed that many genes that are involved in branched-chain amino acids (BCAAs) were downregulated in Glut1-TG mice.
2018-05-14 | GSE110766 | GEO
Project description:The Ser/Thr protein phosphatase 2A (PP2A) regulates the dephosphorylation of many phosphoproteins. Substrate recognition are mediated by B regulatory subunits. Here, we report the identification of a substrate conserved motif [RK]-V-x-x-[VI]-R in FAM122A, an inhibitor of B55α/PP2A. This motif is necessary for FAM122A binding to B55α, and computational structure prediction suggests the motif, which is helical, blocks substrate docking to the same site. In this model, FAM122A also spatially constrains substrate access by occluding the catalytic subunit. Consistently, FAM122A functions as a competitive inhibitor as it prevents substrate binding and dephosphorylation of CDK substrates by B55α/PP2A in cell lysates. FAM122A deficiency in human cell lines reduces the proliferation rate, cell cycle progression, and hinders G1/S and intra-S phase cell cycle checkpoints. FAM122A-KO in HEK293 cells attenuates CHK1 and CHK2 activation in response to replication stress. Overall, these data strongly suggest that FAM122A is a short helical motif (SHeM)-dependent, substrate-competitive inhibitor of B55α/PP2A that suppresses multiple functions of B55α in the DNA damage response and in timely progression through the cell cycle interphase
2024-08-10 | PXD052836 | Pride
Project description:Heart muscle cells, cardiomyocytes, are highly differentiated cells that usually do not proliferate . During the non-proliferative state, extracellular signals control cardiomyocyte contractile function. However, during development and regeneration, cardiomyocytes enter the cell cycle and divide. It is unknown how cardiomyocytes modify their intracellular signaling to direct the cell cycle program. Here, we show that the nuclear lamina protein Lamin B2 (Lmnb2) regulates cardiomyocyte cell cycle activity using a gatekeeper mechanism. We identified Lmnb2 as a candidate for regulating intracellular signaling with deep transcriptional profiling of single cardiomyocytes. Lmnb2 was sufficient and necessary for cardiomyocyte cycling in the presence of serum. Lmnb2 increased the nucleoporin NUP98 and permeability of the nuclear membrane for phosphorylated ERK1/2. In vivo, the Lmnb2 gene was required for cardiomyocyte cell cycle activity during development. Increasing the expression of Lmnb2 in neonatal mice promoted cardiomyocyte M-phase and cytokinesis. LmnB2 gene transfer in neonatal mice that received a myocardial injury increased cardiomyocyte division and myocardial function in the injury border zone, indicating that the regenerated cardiomyocytes were functionally integrated. We propose a gatekeeper function of Lmnb2 that can be targeted to increase cardiomyocyte regeneration without the administration of exogenous growth factors.
2020-02-28 | GSE108360 | GEO