Abstract 86: Catabolic Remodeling of Branched Chain Amino Acids in Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Haipeng Sun ◽  
Meiyi Zhou ◽  
Chen Gao ◽  
Kristine Olson ◽  
Ji-Youn Youn ◽  
...  
Keyword(s):  
Heart Failure ◽  
Amino Acids ◽  
Regulatory Protein ◽  
Pressure Overload ◽  
Branched Chain Amino Acids ◽  
Atp Production ◽  
Genetic Ablation ◽  
Catabolic Genes ◽  
Metabolic Remodeling ◽  
Branched Chain

Metabolic remodeling is an integral part of heart failure. Although glucose and fatty acids metabolism have been extensively studied, little is known about the role of amino acids homeostasis in heart physiology and pathology. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids for both protein synthesis and cellular signaling. Elevated levels of BCAAs have been linked with heart failure. However, the underlying regulatory mechanism and functional significance of abnormal BCAA catabolism in heart failure have not been established. We found that genes involved in BCAA catabolism, including a key regulatory protein PP2Cm, are significantly down-regulated at mRNA as well as protein level in pressure-overload induced failing heart in mice. Furthermore, the concentrations of BCAA catabolic products branched-chain keto acids (BCKAs) are also elevated in heart tissues of post TAC mice. Interestingly, the down-regulation of BCAA catabolic genes mimics a similar expression pattern observed in fetal heart, suggesting that decreased BCAA catabolic activity is part of the metabolic remodeling in pathologically stressed heart from an adult to a fetal-like state. Genetic ablation of PP2Cm in mouse leads to defect in BCAA catabolism and accumulation of BCAAs and BCKAs in cardiac tissue and serum. PP2Cm deficient mice had lower cardiac contractility and higher susceptibility to develop heart failure under pressure overload. In addition, BCKAs treatment to isolated mitochondria resulted in lower oxygen consumption rate and ATP production. PP2Cm deficiency as well as BCKAs treatment induced oxidative stress in cardiomyocyte and antioxidant treatment ameliorated the development of heart failure in PP2Cm deficient animals. Together, these data indicated that BCAA catabolic remodeling is likely an integrated component of metabolic remodeling during heart failure. More importantly, mis-regulation of BCAA catabolism in heart promoted heart failure progression, involving direct impact on mitochondrial function and redox homeostasis in cardiomyocytes.

Abstract 357: Branched-Chain Amino Acid Metabolic Reprogramming in Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Haipeng Sun ◽  
Kristine Olson ◽  
Meiyi Zhou ◽  
Domenick Prosdocimo ◽  
Chen Gao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Amino Acid ◽  
Building Blocks ◽  
Metabolic Reprogramming ◽  
Genetic Ablation ◽  
Failing Heart ◽  
Catabolic Genes ◽  
Metabolic Remodeling ◽  
Heart Failure Progression ◽  
Branched Chain

Metabolic remodeling is an integral part of heart failure. Current studies are largely focusing on glucose and fatty acid metabolism, while little is known about the changes in amino acid homeostasis during heart failing process. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, serve as not only essential building blocks for protein synthesis, but also important energy source and signaling molecules that have significant effects on cell growth and function. In this study, we demonstrated that the BCAA catabolic intermediate branched-chain keto acid (BCKA) accumulated in both mouse and human failing heart. BCAA catabolic genes were selectively and significantly down-regulated at both mRNA and protein levels in failing heart in mice, mimicking a similar expression pattern observed in neonatal heart. Using both in vitro and in vivo models, we established that BCAA catabolic genes were regulated by Krüppel-like factor 15 (KLF15), a key transcriptional regulator for glucose, fat, and amino acid nutrient homeostasis, suggesting that the KLF15-mediated BCAA catabolic regulation is part of the metabolic remodeling during heart failure. Genetic ablation of PP2Cm, a key regulator of BCAA catabolism, led to a significant impairment of BCAA catabolic activities and accumulation of BCKA in cardiac tissue. Importantly, PP2Cm deficiency accelerated heart failure under pressure overload. PP2Cm deficiency or elevated BCKA induced oxidative stress in cardiomyocytes and impairment of oxygen consumption and ATP production of mitochondria. Antioxidant treatment ameliorated the heart failure progression in PP2Cm deficient animals. Taken together, our data established for the first time that BCAA catabolic reprogramming is an integral component of metabolic remodeling during heart failure, and this remodeling can significantly contribute to heart failure progression.

scholarly journals Impact of Melatonin and Branched-Chain Amino Acids Cosupplementation on Quality of Life, Fatigue, and Nutritional Status in Cachectic Heart Failure Patients: A Randomized Controlled Trial

2019 ◽  
pp. 155982761987404 ◽  
Author(s):  
Hamed Jafari-Vayghan ◽  
Jalal Moludi ◽  
Sevda Saleh-Ghadimi ◽  
Elgar Enamzadeh ◽  
Mir Hossein Seyed-Mohammadzad ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Heart Failure ◽  
Amino Acids ◽  
Placebo Group ◽  
Nutritional Status ◽  
Branched Chain Amino Acids ◽  
Significant Difference ◽  
Branched Chain ◽  
The Impact

Background: Cardiac cachexia (CC) adversely affects the lifestyle of heart failure (HF) patients. The current study examined the impact of melatonin cosupplementation and branched-chain amino acids (BCAAs) on quality of life (QoL), fatigue, and nutritional status in cachectic HF patients. Methods: In this trial, 84 CC patients were randomized to melatonin, BCAAs, or coadministration (both) as intervention groups and a control group over 8 weeks. At baseline and postintervention, QoL, fatigue, and nutritional status were assessed. Results: After intervention, improvement in the overall and physical dimensions of QoL and appetite score were found to be statistically significant in the BCAAs (P < .001) and the melatonin+BCAAs (P < .001) groups compared with the placebo group. The emotional dimension score was significantly lower in the BCAAs group compared with the placebo group (P = .001). There was a statistically significant improvement in fatigue severity in all 3 intervention groups compared with the placebo group. The nutrition risk index (NRI) score increased significantly only in the melatonin group (P = .015), and there was no significant difference between the other groups (P = .804). Conclusions: Cosupplementation with BCAAs and melatonin improved QoL, fatigue status, and appetite in cachectic HF patients but did not affect NRI.

Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

2020 ◽  
Vol 36 (3) ◽  
Author(s):  
Lee‐Ling Lim ◽  
Eric S.H. Lau ◽  
Erik Fung ◽  
Heung‐Man Lee ◽  
Ronald C.W. Ma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Hong Kong ◽  
Branched Chain Amino Acids ◽  
Incident Heart Failure ◽  
Branched Chain ◽  
Diabetes Register

Significance of Branched-Chain Amino Acids in Lean Patients With Heart Failure

2016 ◽  
Vol 22 (9) ◽  
pp. S218 ◽  
Author(s):  
Takayuki Namba ◽  
Toyokazu Kimura ◽  
Shunpei Horii ◽  
Risako Yasuda ◽  
Takumi Toya ◽  
...  
Keyword(s):  
Heart Failure ◽  
Amino Acids ◽  
Branched Chain Amino Acids ◽  
Patients With Heart Failure ◽  
Branched Chain

scholarly journals The Effect of Branched Chain Amino Acids on Skeletal Muscle Mitochondrial Function in Young and Elderly Adults

2010 ◽  
Vol 95 (2) ◽  
pp. 894-902 ◽  
Author(s):  
Laura L. Tatpati ◽  
Brian A. Irving ◽  
Andrea Tom ◽  
Maureen L. Bigelow ◽  
Katherine Klaus ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Mitochondrial Function ◽  
Complex I ◽  
The Elderly ◽  
Branched Chain Amino Acids ◽  
Saline Infusion ◽  
Elderly Adults ◽  
Atp Production ◽  
Branched Chain

Abstract Context: A reduction in maximal mitochondrial ATP production rate (MAPR) and mitochondrial DNA (mtDNA) abundance occurs with age in association with muscle weakness and reduced endurance in elderly people. Branched chain amino acids (BCAA) have been extensively used to improve physical performance. Objective: The objective was to determine whether an 8-h infusion of BCAA enhances MAPR equally in healthy young and elderly adults. Methods: Using a crossover study design, we compared the effect BCAA vs. saline infusion in 12 young (23.0 ± 0.8 yr) and 12 elderly (70.7 ± 1.1 yr) participants matched for sex and body mass index. Skeletal muscle MAPR and mtDNA abundance were measured in muscle biopsy samples obtained before and at the end of the 8-h infusion. Results: In young participants, MAPR with the substrates glutamate plus malate (supplying electrons to complex I) and succinate plus rotenone (complex II) increased in response to BCAA infusion, relative to a decline in MAPR in response to the saline infusion. In contrast, MAPR was unaffected by BCAA infusion in the elderly participants. Moreover, mtDNA abundance was lower in the elderly compared with the young participants but was unaffected by the BCAA infusion. Insulin and C-peptide concentrations declined over time during the saline infusion, but these declines were prevented by the BCAA infusion. Conclusions: BCAA increased skeletal muscle MAPR in the young participants in comparison with saline, but this effect was not seen in the elderly participants indicating, that unlike in the young, BCAA does not increase muscle mitochondrial function in the elderly.

The Branched-Chain Amino Acids Level at Discharge is a Useful Prognostic Biomarker in Patients with Acute Heart Failure

2015 ◽  
Vol 21 (10) ◽  
pp. S173
Author(s):  
Hiroaki Hiraiwa ◽  
Takahiro Okumura ◽  
Toru Kondo ◽  
Soichiro Aoki ◽  
Rinya Kato ◽  
...  
Keyword(s):  
Heart Failure ◽  
Amino Acids ◽  
Acute Heart Failure ◽  
Prognostic Biomarker ◽  
Branched Chain Amino Acids ◽  
Branched Chain

scholarly journals Modulation of the Sensitivity of FimB Recombination to Branched-Chain Amino Acids and Alanine in Escherichia coli K-12

2005 ◽  
Vol 187 (18) ◽  
pp. 6273-6280 ◽  
Author(s):  
Maryam Lahooti ◽  
Paula L. Roesch ◽  
Ian C. Blomfield
Keyword(s):  
Escherichia Coli ◽  
Amino Acids ◽  
Invertible Element ◽  
Regulatory Protein ◽  
Regulatory Elements ◽  
Branched Chain Amino Acids ◽  
Integration Host Factor ◽  
Control Element ◽  
Branched Chain ◽  
K 12

ABSTRACT Phase variation of type 1 fimbriae of Escherichia coli requires the site-specific recombination of a short invertible element. Inversion is catalyzed by FimB (switching in either direction) or FimE (inversion mainly from on to off) and is influenced by auxiliary factors integration host factor (IHF) and leucine-responsive regulatory protein (Lrp). These proteins bind to sites (IHF site II and Lrp sites 1 and 2) within the invertible element to stimulate recombination, presumably by bending the DNA to enhance synapses. Interaction of Lrp with a third site (site 3) cooperatively with sites 1 and 2 (termed complex 1) impedes recombination. Inversion is stimulated by the branched-chain amino acids (particularly leucine) and alanine, and according to a current model, the amino acids promote the selective loss of Lrp from site 3 (complex 2). Here we show that the central portion of the fim invertible element, situated between Lrp site 3 and IHF site II, is dispensable for FimB recombination but that this region is also required for full amino acid stimulation of inversion. Further work reveals that the region is likely to contain multiple regulatory elements. Lrp site 3 is shown to bind the regulatory protein with low affinity, and a mutation that enhances binding to this element is found both to diminish the stimulatory effects of IVLA on FimB recombination and to inhibit recombination in the absence of the amino acids. The results obtained emphasize the importance of Lrp site 3 as a control element but also highlight the complexity of the regulatory system that affects this site.

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