Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure
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ABSTRACT:
PROVIDER: PRJNA1118272 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29235821.fastq.gz | Fastqsanger.gz | |||
| SRR29235822.fastq.gz | Fastqsanger.gz | |||
| SRR29235823.fastq.gz | Fastqsanger.gz | |||
| SRR29235824.fastq.gz | Fastqsanger.gz | |||
| SRR29235825.fastq.gz | Fastqsanger.gz |
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Project description:Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown. Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of 13C-glucose. Cardiac glycogen was measured biochemically and by transmission electron microscopy. Cardiac glucose uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the heart failure in CS-Mpc2-/- mice. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed either low-fat or ketogenic diet. Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, suggesting their heart failure is not caused by energetic stress. These hearts displayed increased enrichment from 13C-glucose and increased glycolytic metabolite pool sizes. 13C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ~6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of the priming enzyme glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet. Conclusions: Our results indicate that loss of MPC in the heart increases glycolytic metabolism and ultimately glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is dramatically reduced by consumption of a ketogenic diet.
2024-06-03 | GSE268694 | GEO
Project description:Glycogenin is considered essential for glycogen synthesis as it acts as a primer for the initiation of the polysaccharide. In this study, we challenge this notion and demonstrate that glycogen can be synthesized in vivo in the absence of glycogenin. Glycogenin-deficient mice (Gyg KO) accumulate high amounts of the polysaccharide in skeletal and cardiac striated muscles. This glycogen shows no covalently bound protein, thereby indicating that no protein primer is essential for glycogen synthesis. Gyg KO mice show lower resting energy expenditure and lesser resistance when subjected to endurance exercise than control animals, which can be attributed to a switch of oxidative myofibers toward glycolytic metabolism. This switch is caused by the over-accumulation of glycogen, since mice overexpressing glycogen synthase specifically in skeletal muscle show a similar metabolic alteration. These results may explain the muscular defects of GSD XV patients, who show high glycogen accumulation in striated muscles.
2017-07-06 | PXD006377 | Pride
Project description:The cold shock response of B. subtilis was defined after 0.5 hr and 2 hr cold shock using RNA sequencing. We identified novel RNAs (including non-coding RNAs) that play a role during growth at low temperatures. Deletion of the cold induced protein YplP results in a cold sensitive phenotype, and a comparative RNA sequencing analysis suggests that YplP induces pftAB expression after prolonged incubation at low temperatures, thereby optimizing pyruvate transport under cold shock conditions.
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Project description:We applied time-course transcriptomics and genetics to identify sigma factors, metabolic processes and adhesins that drive biofilm formation. These analyses revealed that extracellular pyruvate induces biofilm formation in the presence of DOC. In the absence of DOC, pyruvate supplementation was sufficient to induce biofilm formation in a process that was dependent on pyruvate transport by the membrane protein CstA.
2021-05-04 | GSE165116 | GEO
Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi RNA-Seq analysis was used to characterize hepatic diet-associated gene expression changes between wild-type and PTG KO mice. Mice were maintained on a normal chow diet or a high-fat diet as indicated. 2-3 biological replicates per genotype/diet.
2014-06-13 | E-GEOD-45319 | biostudies-arrayexpress
Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi
2014-06-13 | GSE45319 | GEO
Project description:C. trachomatis possess a cryptic 7.5 kb plasmid of unknown function. Here we describe a comprehensive molecular and biological characterization of the naturally occurring plasmidless human Chlamydia trachomatis strain L2 (25667R). We found that despite minimal chromosomal polymorphisms the LGV L2 (25667R) strain was indistinguishable from the L2 (434) plasmid positive strain in its in vitro infectivity characteristics such as growth kinetics, plaquing efficiency, and plaque size. The primary in vitro phenotypic differences between L2 (434) and L2 (25667R) were the accumulation of glycogen granules in the inclusion matrix and the lack of the typical intra-inclusion Brownian-like movement characteristic of C. trachomatis strains. Conversely, we observed a marked difference between the two strains in their ability to colonize and infect the female mouse genital tract. The ID50 of the L2 (25667R) plasmidless strain was 500 fold greater (1.XX x 10X IFU) than the L2 (434) plasmid bearing strain (1. XX x 10X IFU). Transcriptome analysis of the two strains clearly demonstrated a decrease in transcript levels of a subset of chromosomal genes for the L2 (25667R) strain. Among those genes was glgA which encodes for glycogen synthase; a finding consistent with the failure of the L2 (25667R) strain to accumulate glycogen granules. Collectively, these findings support an important role for the plasmid in in vivo infectivity and suggest that this virulence characteristic might be controlled by the plasmids ability to regulate the expression of specific chromosomal genes. These results also support an important role for the plasmid in the pathogenesis of human infection and disease. Keywords: strain comparison C. trachomatis strain L2-25667R compared to strain L2-434
2010-05-06 | E-GEOD-10199 | biostudies-arrayexpress
Project description:Glycogen is the largest soluble cytosolic macromolecule and considered as the principal storage form of glucose. Cancer cells generally increase their glucose consumption and rewire their metabolism towards aerobic glycolysis to promote growth. Here we report that glycogen accumulation is a key initiating oncogenic event and essential for malignant transformation. RNA-sequencing analysis reveals that G6PC, an enzyme catalyzing the last step of glycogenolysis, is frequently downregulated to augment glucose storage in pro-tumor cells. Accumulated glycogen undergoes liquid-liquid phase separation undergoes liquid-liquid phase separation, which results in the assembly of the laforin-Mst1/2 complex and consequently traps Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme PYGL deficiency in both human and mice result in glycogen storage disease with enlarged liver size and cancer development, phenocopying Hippo deficiency. Consistently, elimination of glycogen accumulation abrogates liver enlargement and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that glycogen not only provides nutrition and energy to the cells but also functions as a key initiating oncogenic metabolite, which physically blocks Hippo signaling through glycogen phase separation to augment pro-tumor cell initiation and progression.
2021-10-06 | GSE148933 | GEO
Project description:C. trachomatis possess a cryptic 7.5 kb plasmid of unknown function. Here we describe a comprehensive molecular and biological characterization of the naturally occurring plasmidless human Chlamydia trachomatis strain L2 (25667R). We found that despite minimal chromosomal polymorphisms the LGV L2 (25667R) strain was indistinguishable from the L2 (434) plasmid positive strain in its in vitro infectivity characteristics such as growth kinetics, plaquing efficiency, and plaque size. The primary in vitro phenotypic differences between L2 (434) and L2 (25667R) were the accumulation of glycogen granules in the inclusion matrix and the lack of the typical intra-inclusion Brownian-like movement characteristic of C. trachomatis strains. Conversely, we observed a marked difference between the two strains in their ability to colonize and infect the female mouse genital tract. The ID50 of the L2 (25667R) plasmidless strain was 500 fold greater (1.XX x 10X IFU) than the L2 (434) plasmid bearing strain (1. XX x 10X IFU). Transcriptome analysis of the two strains clearly demonstrated a decrease in transcript levels of a subset of chromosomal genes for the L2 (25667R) strain. Among those genes was glgA which encodes for glycogen synthase; a finding consistent with the failure of the L2 (25667R) strain to accumulate glycogen granules. Collectively, these findings support an important role for the plasmid in in vivo infectivity and suggest that this virulence characteristic might be controlled by the plasmids ability to regulate the expression of specific chromosomal genes. These results also support an important role for the plasmid in the pathogenesis of human infection and disease. Keywords: strain comparison
2009-01-15 | GSE10199 | GEO
Project description:BACKGROUND: Correlating in vitro mitochondrial data to outcomes in vivo remains a challenge and improving methods to assess mitochondrial function in vivo would both guide safer candidate selection and support the growing number of discovery programmes targeting mitochondria for pharmacological intervention. OBJECTIVES: The aim was to assess the toxicity profile of a compound with complex III electron transport chain inhibitory activity (GSK932121A) in order to identify markers and mechanisms of mitochondrial perturbation in vivo. METHODS:Crl:CD(SD) rats were dosed IP with GSK932121A for up to 5 hours depending upon the severity of observed clinical signs. Respirometry, microscopy, lactate/pyruvate and transcriptomics profiling were used to aid identification of a mode of action and this data was compared with functional data in isolated mitochondria. RESULTS AND DISCUSSION: GSK932121A administered in vivo caused hypothermia and a metabolic shift in energy production provoking an increased lactate/pyruvate ratio, microvesicular steatosis and glycogen depletion; alongside gene expression changes indicative of a fasted state. Our data improves current understanding of the toxicological consequences of drug induced respiratory chain inhibition and guides endpoint selection for future investigative safety studies with mitochondrially active molecules. 50mg/kg GSK932121A treated rat livers (n=10) were used to assess differential gene expression when compared with 0mg.kg GSK932121A Vehicle Control (n=12). Two samples were excluded from the 50mg/kg group due to low plasma exposure to GSK932121A
2015-01-29 | E-GEOD-65374 | biostudies-arrayexpress