Impaired cardiac branched-chain amino acid metabolism in a novel model of diabetic cardiomyopathy
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ABSTRACT:
PROVIDER: PRJNA1115897 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29155165_1.fastq.gz | Fastqsanger.gz | |||
| SRR29155165_2.fastq.gz | Fastqsanger.gz | |||
| SRR29155166_1.fastq.gz | Fastqsanger.gz | |||
| SRR29155166_2.fastq.gz | Fastqsanger.gz | |||
| SRR29155167_1.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic alterations occur in the heart of patients with type 2 diabetes mellitus (T2DM). However, the relationships between branched-chain amino acid (BCAA) metabolism and the pathophysiology of diabetic cardiomyopathy (DbCM) remain unclear. Here, we sought to establish a novel model of DbCM and reveal its metabolic alterations, especially focusing on BCAA metabolism. Using adipocyte-specific 3′-phosphoinositide–dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice as a new model of DbCM, we demonstrated that cardiac BCAA catabolic enzymes were down-regulated in these mice, leading to the accumulation of BCAAs in the heart. Mechanistically, the accumulation of the BCAA leucine could cause cardiac hypertrophy via the activation of mammalian target of rapamycin complex 1 (mTORC1). A-PDK1KO mice mimic the cardiac phenotypes and metabolic alterations seen in human DbCM and exhibit impaired BCAA metabolism in the heart. This model may contribute to a better understanding of DbCM pathophysiology and the development of novel therapies for it.
2025-04-23 | GSE268260 | GEO
Project description:Postoperative insulin resistance refers to the phenomenon that the body’s glucose uptake stimulated by insulin is reduced due to stress effects such as trauma or the inhibitory effect of insulin on liver glucose output is weakened after surgery.
There is a clear link between postoperative insulin resistance and poor perioperative prognosis. Therefore, exploring interventions to reduce postoperative stress insulin resistance, stabilize postoperative blood glucose, and reduce postoperative complications are clinical problems that need to be solved urgently. In recent years, research on branched-chain amino acids and metabolic diseases has become a hot spot. Studies have found that in the rat model, preoperatively given a high branched-chain amino acid diet can inhibit postoperative insulin resistance and stabilize blood glucose levels. This research plan is to try to add branched-chain amino acids before surgery to observe the occurrence of postoperative insulin resistance in patients.
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Project description:Branched‐chain amino acid (BCAA) metabolism is a central hub for energy production and regulation of numerous physiological processes. Controversially, both increased and decreased levels of BCAAs are associated with longevity. Using genetics and multi‐omics analyses in Caenorhabditis elegans, we identified adaptive regulation of the ubiquitin‐proteasome system (UPS) in response to defective BCAA catabolic reactions after the initial transamination step. Worms with impaired BCAA metabolism show a slower turnover of a GFP‐based proteasome substrate, which is suppressed by loss‐of‐function of the first BCAA catabolic enzyme, the branched‐chain aminotransferase BCAT‐1. The exogenous supply of BCAA‐derived carboxylic acids, which are known to accumulate in the body fluid of patients with BCAA metabolic disorders, is sufficient to regulate the UPS. The link between BCAA intermediates and UPS function presented here sheds light on the unexplained role of BCAAs in the aging process and opens future possibilities for therapeutic interventions.
2022-09-22 | GSE185451 | GEO
Project description:Branched Chain Amino Acids (BCAA) Modulate Metabolic Inflammation
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Project description:Background: Cells regulate protein synthesis in response to fluctuating nutrient availability through mechanisms that affect both translation initiation and elongation. Branched-chain amino acids, leucine, isoleucine, and valine, are essential nutrients. However, how their depletion affects translation remains largely unclear. Here, we investigate the immediate effects of single, double, and triple branched-chain amino acid deprivation on translational dynamics in NIH3T3 cells using RNA-seq and ribosome profiling. Results: All starvation conditions increased ribosome dwell times, with pronounced stalling at all valine codons during valine and triple starvation, whereas leucine and isoleucine starvation produced milder, codon-specific effects. Notably, stalling under isoleucine deprivation largely decreased under triple starvation. Positional enrichment of valine codons near the 5' end and downstream isoleucine codons potentially contributes to these patterns, suggesting a possible elongation bottleneck that influences translational responses under branched-chain amino acid starvation. The presence of multiple valine stalling sites was associated with decreased protein levels. Finally, codon-specific dwell time changes correlated strongly with patterns of tRNA isoacceptor charging. Conclusions: Together, these findings suggest that differential ribosome stalling under branched-chain amino acid starvation reflects a balance between amino acid supply, tRNA charging dynamics, codon position, and stress-response signaling.
2025-09-02 | GSE291652 | GEO
Project description:Background Cells regulate protein synthesis in response to fluctuating nutrient availability through mechanisms that affect both translation initiation and elongation. Branched-chain amino acids, leucine, isoleucine, and valine, are essential nutrients. However, how their depletion affects translation remains largely unclear. Here, we investigate the immediate effects of single, double, and triple branched-chain amino acid deprivation on translational dynamics in NIH3T3 cells using RNA-seq and ribosome profiling. Results All starvation conditions increased ribosome dwell times, with pronounced stalling at all valine codons during valine and triple starvation, whereas leucine and isoleucine starvation produced milder, codon-specific effects. Notably, stalling under isoleucine deprivation largely decreased under triple starvation. Positional enrichment of valine codons near the 5′ end and downstream isoleucine codons potentially contributes to these patterns, suggesting a possible elongation bottleneck that influences translational responses under branched-chain amino acid starvation. The presence of multiple valine stalling sites was associated with decreased protein levels. Finally, codon-specific dwell time changes correlated strongly with patterns of tRNA isoacceptor charging. Conclusions Together, these findings suggest that differential ribosome stalling under branched-chain amino acid starvation reflects a balance between amino acid supply, tRNA charging dynamics, codon position, and stress-response signaling.
2025-09-02 | GSE291653 | GEO
Project description:Branched-chain amino acids (BCAAs) metabolism is dysregulated in diabetic retinopathy. Retina Müller cells maintain various metabolic processes and immune homeostasis. Here, we found that branched-chain aminotransferase 1 (BCAT1), which catalyzes the first step of BCAAs metabolism, was predominantly expressed in retina Müller cells. Under diabetic conditions, BCAT1 showed increased enzymatic activity in Müller cells, which drove the remodeling of BCAAs catabolism, and upregulated the expression of inflammatory genes such as interleukin 6 (IL6) and tumor necrosis factor-α (TNF-α). Mechanistically, BCAT1 activity was negatively regulated by Polo-like kinase 4 (PLK4) via phosphorylation at threonine 333. Increased BCAT1 activity further reduced α-ketoglutarate (α-KG) levels, a critical substrate for histone demethylation, resulting in higher H3K4me3 levels at inflammatory gene promoters, and further upregulated inflammation genes. Treatment with chemical BCAT inhibitor significantly reduced inflammatory gene expression and vascular leakage in diabetic retinas in vivo. These findings reveal a crucial role of BCAT1 in metabolic remodeling and inflammatory regulation, which indicates that BCAT1 could be used as a target for diabetic retinopathy.
2025-06-25 | GSE282215 | GEO
Project description:Impaired Branched-Chain Amino Acid Catabolism is Associated with Chemotherapy-Induced Heart Failure and Rescued by Metformin
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Project description:To study the role of branched-chain amino acid metabolism in neural stem cells we generated two primary neural stem cell culture lines in which on was deleted for the Ppm1k gene using floxed cells and adenovirus delviered cre-recombinase.
2023-04-06 | GSE205603 | GEO
Project description:Development, growth and adult survival are coordinated with available metabolic resources. The insulin/IGF and TOR signaling pathways relay nutritional status, thereby ascertaining that the organism responds appropriately to environmental conditions. MicroRNAs are short (21-23 nt) regulatory RNAs that confer specificity on the RNA-induced silencing complex (RISC) to inhibit a given set of mRNA targets. We profiled changes in miRNA expression during adult life in Drosophila melanogaster and determined that miR-277 is down-regulated with age. This miRNA controls branched-chain amino acid (BCAA) catabolism and the activity of the TOR kinase, a central growth regulator. Metabolite analysis suggests that the mechanistic basis may be an accumulation of BCKAs, rather than BCAAs, thus avoiding potentially detrimental consequences of increased branched chain amino acid levels on e.g. translational fidelity. Constitutive miR-277 expression as well as transgenic inhibition with a miRNA sponge construct shortens lifespan. Furthermore, constitutive miR-277 expression is synthetically lethal with reduced insulin signaling. Thus, optimal metabolic adaptation requires tuning of cellular BCAA catabolism by miR-277 to be concordant with systemic growth signaling.
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