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Excessive Branched Chain Amino Acid Accumulation Creates an Unfavourable Myocardial Milieu that Inhibits the Cardioprotective Effects of Implanted Mesenchymal Stem Cells in Ischemic Heart Injury

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE183028 | GEO | 2021/09/02

REPOSITORIES: GEO

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Excessive Branched Chain Amino Acid Accumulation Creates an Unfavourable Myocardial Milieu that Inhibits the Cardioprotective Effects of Implanted Mesenchymal Stem Cells in Ischemic Heart Injury [CUT&Tag]

Project description:Myocardial infarction (MI) causes cardiac metabolic reprogramming and results in robust changes in intramyocardial metabolite composition, but little is known about how these metabolic changes influence the fate of implanted stem cells. We found that excessive branched chain amino acid (BCAA) accumulation, a metabolic signature of the post-infarcted heart, created an unfavorable milieu inhibiting the retention and cardioprotection of intramyocardially-delivered mesenchymal stem cells (MSCs). BCAA at pathological levels sensitized MSCs to the acquisition of a injured phenotype by suppressing the histone H3K9 trimethylation (H3K9me3) modification. Furthermore, a novel mTORC1/DUX4/KDM4E axis was identified as the cause of the H3K9me3 loss and adverse phenotype acquisition induced by BCAA. Enhancing BCAA catabolism in MSCs via genetic or pharmacological approaches improved their adaptation to the extracellular BCAA milieu and strengthened their cardioprotective efficacy. These findings reveal a critical role of myocardial metabolic reprogramming in regulating the fate and cardioprotection of implanted MSCs after MI.

2021-09-02 | GSE183027 | GEO

2021-09-02 | GSE183025 | GEO

Excessive Branched Chain Amino Acid Accumulation Creates an Unfavourable Myocardial Milieu that Inhibits the Cardioprotective Effects of Implanted Mesenchymal Stem Cells in Ischemic Heart Injury

Project description:Excessive Branched Chain Amino Acid Accumulation Creates an Unfavourable Myocardial Milieu that Inhibits the Cardioprotective Effects of Implanted Mesenchymal Stem Cells in Ischemic Heart Injury

| PRJNA758887 | ENA

| PRJNA758891 | ENA

| PRJNA758890 | ENA

Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction.

Project description:Mesenchymal stem cells (MSCs) delivered into the post-ischemic heart milieu have a low survival and retention rate, thus restricting the cardioreparative efficacy of MSC-based therapy. Chronic ischemia results in metabolic reprogramming in the heart, but little is known about how these metabolic changes influence implanted MSCs. Here, we found that excessive branched-chain amino acid (BCAA) accumulation, a metabolic signature seen in the post-ischemic heart, was disadvantageous to the retention and cardioprotection of intramyocardially injected MSCs. Discovery-driven experiments revealed that BCAA at pathological levels sensitized MSCs to stress-induced cell death and premature senescence via accelerating the loss of histone 3 lysine 9 trimethylation (H3K9me3). A novel mTORC1/DUX4/KDM4E axis was identified as the cause of BCAA-induced H3K9me3 loss and adverse phenotype acquisition. Enhancing BCAA catabolic capability in MSCs via genetic/pharmacological approaches greatly improved their adaptation to the high BCAA milieu and strengthened their cardioprotective efficacy. We conclude that aberrant BCAA accumulation is detrimental to implanted MSCs via a previously unknown metabolite-signaling-epigenetic mechanism, emphasizing that the metabolic changes of the post-ischemic heart crucially influence the fate of implanted MSCs and their therapeutic benefits.

| S-EPMC9163108 | biostudies-literature

Association between Excessive Dietary Branched-Chain Amino Acids Intake and Hypertension Risk in Chinese Population.

Project description:The dietary intake of branched-chain amino acids (BCAAs) has been reported to be associated with both elevated blood pressure (BP) and hypertension risk, while published findings were inconsistent, and the causality has never been well disclosed. We performed this prospective study aiming to find out the relationship between dietary BCAAs intake and hypertension risk in the Chinese population. A total of 8491 participants (40,285 person-years) were selected. The levels of dietary BCAAs intake were estimated using the 24-h Food Frequency Questionnaire. Associations of both BP values and hypertension risk with per standard deviation increase of BCAAs were estimated using linear and COX regression analysis, respectively. The hazard ratios and 95% confidence interval were given. Restricted cubic spline analysis (RCS) was used to estimate the nonlinearity. Both systolic and diastolic BP values at the end points of follow-up were positively associated with dietary BCAAs intake. Positive associations between BCAAs intake and hypertension risk were shown in both men and women. By performing a RCS analysis, the nonlinear relationship between BCAAs intake and hypertension was shown. As the intake levels of Ile, Leu, and Val, respectively, exceeded 2.49 g/day, 4.91 g/day, and 2.88 g/day in men (2.16 g/day, 3.84 g/day, and 2.56 g/day in women), the hypertension risk increased. Our findings could provide some concrete evidence in the primary prevention of hypertension based on dietary interventions.

| S-EPMC9268479 | biostudies-literature

Reprograming of Proteasomal Degradation by Branched Chain Amino Acid Metabolism

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

Altered branched-chain amino acid metabolism due to boron deficiency

Project description:The importance of boron (B) for living organisms is a puzzling matter. Despite the long established essential micronutrient role of B for vascular plants, only recent research gave insights on the mechanisms of its uptake, transport and direct participation in cell-wall formation. Despite that its precise role in plant metabolism remains elusive. In an attempt to clarify the role of B in plant metabolism the gene expression profile of a persistent response to B suppression was evaluated. For that purpose, the transcriptional profile of Arabidopsis thaliana subjected to 2 days of B deficiency was analyzed and the genes that kept responding 4 days after B deficiency were selected. The gene expression profile of Arabidopsis plants submitted to Ca deficiency was also evaluated and this data cross-compared with the 2 days transcriptional profile obtained under B deficiency.

2015-12-25 | GSE67768 | GEO

Disorders of branched chain amino acid metabolism.

Project description:The three essential branched-chain amino acids (BCAAs), leucine, isoleucine and valine, share the first enzymatic steps in their metabolic pathways, including a reversible transamination followed by an irreversible oxidative decarboxylation to coenzyme-A derivatives. The respective oxidative pathways subsequently diverge and at the final steps yield acetyl- and/or propionyl-CoA that enter the Krebs cycle. Many disorders in these pathways are diagnosed through expanded newborn screening by tandem mass spectrometry. Maple syrup urine disease (MSUD) is the only disorder of the group that is associated with elevated body fluid levels of the BCAAs. Due to the irreversible oxidative decarboxylation step distal enzymatic blocks in the pathways do not result in the accumulation of amino acids, but rather to CoA-activated small carboxylic acids identified by gas chromatography mass spectrometry analysis of urine and are therefore classified as organic acidurias. Disorders in these pathways can present with a neonatal onset severe-, or chronic intermittent- or progressive forms. Metabolic instability and increased morbidity and mortality are shared between inborn errors in the BCAA pathways, while treatment options remain limited, comprised mainly of dietary management and in some cases solid organ transplantation.

| S-EPMC5685199 | biostudies-literature

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