Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease.

BACKGROUND: Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease. METHODS: The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D. RESULTS: The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile Q5 versus Q1, 1.196 [95% CI, 1.109-1.289] and 1.226 [95% CI, 1.160-1.296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26-0.64) and CHD (0.48 [95% CI, 0.29-0.67]) with an absolute effect significantly larger compared with the effect of glycine (-0.06 [95% CI, -0.1 to -0.03] and -0.08 [95% CI, -0.11 to -0.05], respectively) or tBCAAs (0.22 [95% CI, 0.09-0.34] and 0.12 [95% CI, 0.01-0.24], respectively). CONCLUSIONS: The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.

Branched-chain amino acids plus vitamin D supplementation promote increased muscle strength following lumbar surgery for lumbar spinal stenosis: a randomized trial.

BACKGROUND CONTEXT: Adequate nutrition is essential to address the surgical stress response and mitigate loss of muscle mass, strength, and functionality in older adults with lumbar spinal stenosis (LSS). However, it is unknown whether amino acids and/or vitamin D are beneficial in older adults following lumbar surgery for LSS. PURPOSE: To evaluate whether branched-chain amino acids (BCAA) plus vitamin D supplementation could attenuate the loss of muscle mass and strength, accelerate the return of functional mobility, and improve clinical outcomes following lumbar surgery for LSS. STUDY DESIGN/SETTING: A single-center, single-blind randomized controlled trial. PATIENT SAMPLE: Eighty patients who received lumbar surgery for LSS. OUTCOME MEASURES: The primary outcome was the Zurich claudication questionnaire (ZCQ), and secondary outcomes included knee muscle strength, muscle mass measured by bioelectrical impedance analysis, gait speed and a timed up-and-go test (TUG) at 12 weeks postoperatively. Follow-up assessment was performed for the ZCQ at 52 weeks postoperatively. METHODS: Patients ingested the supplementation (BCAA group: BCAA plus vitamin D, Nonamino acid group: nonamino acid) twice daily for 3 weeks from the day after surgery, and received two hours of postoperative inpatient rehabilitation 5 times a week. RESULTS: No significant differences were observed in the mean changes on the ZCQ between the two groups at 12 weeks and 52 weeks. At 2 weeks postoperatively, the nonamino acid group showed significant deterioration compared with the BCAA group for strengths of knee extensor and knee flexor (p < .01). At 12 weeks, the BCAA group showed significant improvements in knee extensor strength and knee flexor strength compared with the nonamino acid group (p <.01). There were no significant differences in mean changes of muscle mass, maximum gait speed, and TUG at 12 weeks between two groups. CONCLUSIONS: BCAA plus vitamin D supplementation did not improve LSS-related clinical outcomes after lumbar surgery for LSS, even though muscle strength increased. Future studies should focus on long-term outcomes for muscle mass and physical function, including development of sarcopenia and frailty.

Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure.

BACKGROUND: Hydrogen sulfide (H2S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H2S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload-induced heart failure. METHODS: Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency. RESULTS: Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H2S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction. CONCLUSIONS: Our data suggest that 3-MST derived mitochondrial H2S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.

Role of branched-chain amino acids in the development and progression of nonalcoholic fatty liver disease / 临床肝胆病杂志

Nonalcoholic fatty liver disease is a common chronic liver disease with the risk of progression to nonalcoholic hepatitis, liver fibrosis, and hepatocellular carcinoma. Nonalcoholic fatty liver disease has various pathogeneses, among which abnormal metabolism of branched-chain amino acids can induce oxidative stress, autophagy, and mitochondrial dysfunction in hepatocytes and is the most important mechanism in the development and progression of nonalcoholic fatty liver disease. This article reviews related research advances and analyzes the possible role of abnormal metabolism of branched-chain amino acids in the development and progression of nonalcoholic fatty liver disease, in order to improve clinical awareness and diagnosis.

[Effect of oral administration of branched-chain amino acids supplementation on the mortality of patients with hepatocellular carcinoma: a meta-analysis].

Objective: To investigate the effect of oral administration of branched-chain amino acids (BCAA) supplementation on the mortality of patients with hepatocellular carcinoma (HCC) after treatment. Methods: Computer searching of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature Database was conducted to search for clinical controlled trials and randomized controlled trials (RCTs) on the effect of oral administration of BCAA on the mortality of patients with HCC. The retrieval time limit was from the time of the establishment of each database to December 30, 2019. Two researchers independently screened the literature and extracted the data. Another researcher assessed the risk of bias in the included studies and then used RevMan 5.3 software for meta-analysis. Results: A total of 14 studies were included with 1 179 patients. The overall results showed that oral administration of BCAA had no significant effect on the mortality of HCC patients at 1 year after treatment (RR=0.85, 95%CI:0.68-1.06, P=0.16), while the mortalities of patients at 3 years (RR=0.73, 95%CI: 0.61-0.88, P=0.000 7) and 5 years (RR=0.57, 95%CI:0.34-0.96, P=0.03) after treatment were significantly lower than those of the control group. The subgroup analysis showed that for radiofrequency ablation (RFA) patients, there was no significant difference in 1-year mortality between the BCAA group and the control group (RR=0.96, 95%CI:0.14-6.5, P=0.97), while 3-year mortality was significantly reduced (RR=0.59, 95%CI:0.43-0.81, P=0.001); for hepatectomy patients, there was no significant differences in 1 -and 3-year mortality between the two groups (RR=0.90, 95%CI:0.44-1.88, P=0.79; RR=0.97, 95%CI:0.71-1.33, P=0.85, respectively). In addition, as for albumin levels, BCAA supplementation significantly increased albumin levels without considering the treatment of HCC (SD=0.45, 95%CI: 0.29-0.90; P=0.000 1), but had no significant effect on hepatectomy patients (SD=0, 95%CI: -0.41-0.41, P=0.99). Conclusion: BCAA supplementation might improve liver reserve function and long-term prognosis of HCC patients, which was related to the surgical method. Supplementing BCAA reduced the long-term mortality of RFA patients, but had no significant effect on hepatectomy patients.

Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets.

BACKGROUND: Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine, and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with the risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown. METHODS: The activity of human platelets from healthy subjects before and after ingestion of BCAAs was measured. Protein phosphatase 2Cm specifically dephosphorylates branched-chain α-keto acid dehydrogenase and thereby activates BCAA catabolism. Protein phosphatase 2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. RESULTS: We found that ingestion of BCAAs significantly promoted human platelet activity (n=5; P<0.001) and arterial thrombosis formation in mice (n=9; P<0.05). We also found that the valine catabolite α-ketoisovaleric acid and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/α-ketoisovaleric acid catabolic pathway plays a major role in BCAA-facilitated platelet activation. Protein phosphatase 2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5; P<0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbß3-mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or Chinese hamster ovary cells expressing integrin αIIbß3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbß3-mediated BCAA-facilitated platelet activation and thrombosis formation. In addition, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from patients with type 2 diabetes mellitus are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity in ob/ob mice (n=4; P<0.05). CONCLUSIONS: BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome-associated thrombophilia.

Free carnitine and branched chain amino acids are not good biomarkers in Huntington's disease / Carnitina livre e aminoácidos de cadeia ramificada não são bons biomarcadores na doença de Huntington

ABSTRACT Background: Huntington's disease (HD), caused by an expanded CAG repeat at HTT, has no treatment, and biomarkers are needed for future clinical trials. Objective: The objective of this study was to verify if free carnitine and branched chain amino acids levels behave as potential biomarkers in HD. Methods: Symptomatic and asymptomatic HD carriers and controls were recruited. Age, sex, body mass index (BMI), age of onset, disease duration, UHDRS scores, and expanded CAG tract were obtained; valine, leucine, isoleucine, and free carnitine were measured. Baseline and longitudinal analysis were performed. Results: Seventy-four symptomatic carriers, 20 asymptomatic carriers, and 22 non-carriers were included. At baseline, valine levels were reduced in symptomatic and asymptomatic HD carriers when compared to non-carriers. No difference in free carnitine or isoleucine+leucine levels were observed between groups. BMI of symptomatic individuals was lower than those of non-carriers. Valine levels correlated with BMI. Follow-up evaluation was performed in 43 symptomatic individuals. UHDRS total motor score increased 4.8 points/year on average. No significant reductions in BMI or valine were observed, whereas free carnitine and isoleucine+leucine levels increased. Conclusions: Although valine levels were lower in HD carriers and were related to BMI losses observed in pre-symptomatic individuals, none of these metabolites seem to be biomarkers for HD.

RESUMO Introdução: A doença de Huntington (DH), causada por uma repetição CAG expandida no HTT, não possui tratamento e biomarcadores são necessários para futuros ensaios clínicos. Objetivo: Nosso objetivo foi verificar se os níveis de carnitina livre e aminoácidos de cadeia ramificada se comportam como potenciais biomarcadores na DH. Métodos: Portadores sintomáticos e assintomáticos e controles foram recrutados. Idade, sexo, índice de massa corporal (IMC), idade de início, duração da doença, escores UHDRS e trato CAG expandido foram obtidos; valina, leucina, isoleucina e carnitina livre foram medidas. Foram realizadas análises basal e longitudinal. Resultados: Setenta e quatro portadores sintomáticos, 20 portadores assintomáticos e 22 não portadores foram incluídos. No início do estudo, os níveis de valina estavam reduzidos em portadores de DH sintomáticos e assintomáticos quando comparados aos não portadores. Não foram observadas diferenças nos níveis de carnitina livre ou isoleucina + leucina entre os grupos. O IMC dos indivíduos sintomáticos foi menor que o dos não portadores. Níveis de valina correlacionaram-se com o IMC. Avaliação de acompanhamento foi realizada em 43 indivíduos sintomáticos. A pontuação do escore motor total da UHDRS aumentou 4,8 pontos/ano em média. Não foram observadas reduções significativas no IMC ou na valina, enquanto os níveis de carnitina livre e isoleucina+leucina aumentaram. Conclusões: Embora os níveis de valina tenham sido menores nos portadores de DH e estivessem relacionados às perdas de IMC observadas em indivíduos pré-sintomáticos, nenhum desses metabólitos parece ser biomarcador para a DH.

Isolated branched-chain amino acid intake and muscle protein synthesis in humans: a biochemical review / Consumo isolado de aminoácidos de cadeia ramificada e síntese de proteína muscular em humanos: uma revisão bioquímica

ABSTRACT Alongside a proper diet, ergogenic aids with potential direct and/or indirect physical performance enhancing effects are sought after for improved adaptation to physical training. Nutritional ergogenics include diet composition changes and/or dietary supplementation. Branched-chain amino acids valine, leucine and isoleucine are widely popular among products with ergogenic claims. Their major marketing appeal derives from allegations that branched-chain amino acids intake combined with resistance physical exercise stimulates muscle protein synthesis. Evidence supporting the efficacy of branched-chain amino acids alone for muscle hypertrophy in humans is somewhat equivocal. This brief review describes physiological and biochemical mechanisms underpinning the effects of complete protein source and branched-chain amino acid intake on skeletal muscle growth in the postabsorptive and post-exercise state. Evidence in favor of or against potential anabolic effects of isolated branched-chain amino acid intake on muscle protein synthesis in humans is also examined.

RESUMO No treinamento físico, buscam-se, além de uma dieta adequada, recursos ergogênicos que possam maximizar direta e/ou indiretamente o desempenho físico. Entre as categorias de recursos ergogênicos, o nutricional compreende a modulação da composição dietética e/ou uso de suplementação. A comercialização dos suplementos de aminoácidos de cadeia ramificada valina, leucina e isoleucina possui muita popularidade entre aqueles com alegação ergogênica. O principal marketing está na afirmação de que o consumo isolado de aminoácidos de cadeia ramificada associado ao exercício físico resistido estimula a síntese de proteína muscular. As evidências da eficácia da ingestão isolada de aminoácidos de cadeia ramificada para a hipertrofia muscular em humanos parecem equivocadas. Nesta breve revisão, apresentamos a compreensão fisiológica e bioquímica de como a ingestão de uma fonte completa de proteína e de aminoácidos de cadeia ramificada afeta o crescimento do músculo esquelético no estado pós-absortivo e pós-exercício. Mostramos também as evidências que suportam ou não a afirmação dos potenciais efeitos anabólicos na síntese de proteína muscular dos aminoácidos de cadeia ramificada quando consumidos isoladamente em humanos.

Extended Duration Nocturnal Hemodialysis and Changes in Plasma Metabolite Profiles.

BACKGROUND AND OBJECTIVES: In-center, extended duration nocturnal hemodialysis has been associated with variable clinical benefits, but the effect of extended duration hemodialysis on many established uremic solutes and other components of the metabolome is unknown. We determined the magnitude of change in metabolite profiles for patients on extended duration nocturnal hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a 52-week prospective, observational study, we followed 33 patients receiving conventional thrice weekly hemodialysis who converted to nocturnal hemodialysis (7-8 hours per session, three times per week). A separate group of 20 patients who remained on conventional hemodialysis (3-4 hours per session, three times per week) served as a control group. For both groups, we applied liquid chromatography-mass spectrometry-based metabolite profiling on stored plasma samples collected from all participants at baseline and after 1 year. We examined longitudinal changes in 164 metabolites among those who remained on conventional hemodialysis and those who converted to nocturnal hemodialysis using Wilcoxon rank sum tests adjusted for multiple comparisons (false discovery rate <0.05). RESULTS: On average, the nocturnal group had 9.6 hours more dialysis per week than the conventional group. Among 164 metabolites, none changed significantly from baseline to study end in the conventional group. Twenty-nine metabolites changed in the nocturnal group, 21 of which increased from baseline to study end (including all branched-chain amino acids). Eight metabolites decreased after conversion to nocturnal dialysis, including l-carnitine and acetylcarnitine. By contrast, several established uremic retention solutes, including p-cresol sulfate, indoxyl sulfate, and trimethylamine N-oxide, did not change with extended dialysis. CONCLUSIONS: Across a wide array of metabolites examined, extended duration hemodialysis was associated with modest changes in the plasma metabolome, with most differences relating to metabolite increases, despite increased dialysis time. Few metabolites showed reduction with more dialysis, and no change in several established uremic toxins was observed.

Metabolism change of gastric cancer in L-leucine/L-valine imbalance / 中国现代普通外科进展

Objective: To observe the effect of imbalanced BCAA on metabolism of gastric cancer cell line 800-7901 in Vitro. Methods: L-Valine(L-Val) of MEM culture medium Were restricted to serial levels of 1/2, 1/4, 1/8 or 1/16 concentration of normal With increased L-Leucine(L-Leu) concentration to 1 fold, 2 folds cc 4 folds respectively. Gastric poor differentiated cancer cell line 800-7901 and fetal liver cell were cultured in these culture media. Morphologic character of two cell lines were observed everyday. Total protein mounts were recorded on the 3nd day and 5th day of incubation. Consuming volume of L-Val , L-Les and glucose of 800-7901 were detected respectively. Results :Restricted L-Val to less than 1/8 concentration retard 300-7901 cell's growth, reduced protein volume of SGC-7901. 300-7901 cell required more glucose when L-Val supply was subtracted. At same restricted level of L-Val, increasing L-Val to 4 times increased their glucose utilization. Few effect en fetal liver cell growth was found Con-elusion: Increasing L-Leu and restricting L-Val supply can inhibit growth of cancer cell. Gastric cancer uptake high mount of L-Val for both protein synthesis end energy supply through gluconeogenesis.