Oral Branched-chain Amino Acids Research Articles

Research progress on albumin therapy for hepatic encephalopathy

Hepatic encephalopathy (HE) is one of the severe complications of decompensated stage cirrhosis that causes cerebral dysfunction due to hepatic insufficiency and/or portosystemic shunts, and it usually manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. The pathogenesis of HE is complex, although ammonia toxicity, oxidative stress, inflammation, intestinal dysbiosis, and others among them mainly play an important role. The treatment for HE lacks specific drugs, and the current available drugs include non-absorbable disaccharides (lactulose), antibiotics (rifaximin), and other therapies (oral branched-chain amino acids, intravenous injection of L-ornithine-L-aspartic acid, probiotics). Recent research has shown that human albumin is a safe and effective treatment for HE, improving not only cognitive function but also enhancing patients' quality of life.

Head Injury Treatment With Healthy and Advanced Dietary Supplements: A Pilot Randomized Controlled Trial of the Tolerability, Safety, and Efficacy of Branched Chain Amino Acids in the Treatment of Concussion in Adolescents and Young Adults.

Concussion is a common injury in the adolescent and young adult populations. Although branched chain amino acid (BCAA) supplementation has shown improvements in neurocognitive and sleep function in pre-clinical animal models of mild-to-moderate traumatic brain injury (TBI), to date, no studies have been performed evaluating the efficacy of BCAAs in concussed adolescents and young adults. The goal of this pilot trial was to determine the efficacy, tolerability, and safety of varied doses of oral BCAA supplementation in a group of concussed adolescents and young adults. The study was conducted as a pilot, double-blind, randomized controlled trial of participants ages 11-34 presenting with concussion to outpatient clinics (sports medicine and primary care), urgent care, and emergency departments of a tertiary care pediatric children's hospital and an urban tertiary care adult hospital, between June 24, 2014 and December 5, 2020. Participants were randomized to one of five study arms (placebo and 15 g, 30 g, 45 g, and 54 g BCAA treatment daily) and followed for 21 days after enrollment. Outcome measures included daily computerized neurocognitive tests (processing speed, the a priori primary outcome; and attention, visual learning, and working memory), symptom score, physical and cognitive activity, sleep/wake alterations, treatment compliance, and adverse events. In total, 42 participants were randomized, 38 of whom provided analyzable data. We found no difference in our primary outcome of processing speed between the arms; however, there was a significant reduction in total symptom score (decrease of 4.4 points on a 0-54 scale for every 500 g of study drug consumed, p value for trend = 0.0036, [uncorrected]) and return to physical activity (increase of 0.503 points on a 0-5 scale for every 500 g of study drug consumed, p value for trend = 0.005 [uncorrected]). There were no serious adverse events. Eight of 38 participants reported a mild (not interfering with daily activity) or moderate (limitation of daily activity) adverse event; there were no differences in adverse events by arm, with only two reported mild adverse events (both gastrointestinal) in the highest (45 g and 54 g) BCAA arms. Although limited by slow enrollment, small sample size, and missing data, this study provides the first demonstration of efficacy, as well as safety and tolerability, of BCAAs in concussed adolescents and young adults; specifically, a dose-response effect in reducing concussion symptoms and a return to baseline physical activity in those treated with higher total doses of BCAAs. These findings provide important preliminary data to inform a larger trial of BCAA therapy to expedite concussion recovery.

The Preventive Effect of Exercise and Oral Branched-Chain Amino Acid Supplementation on Obesity-Induced Brain Changes in Ldlr-/-.Leiden Mice.

Exercise and dietary interventions are promising approaches to tackle obesity and its obesogenic effects on the brain. We investigated the impact of exercise and possible synergistic effects of exercise and branched-chain amino acids (BCAA) supplementation on the brain and behavior in high-fat-diet (HFD)-induced obese Ldlr-/-.Leiden mice. Baseline measurements were performed in chow-fed Ldlr-/-.Leiden mice to assess metabolic risk factors, cognition, and brain structure using magnetic resonance imaging. Thereafter, a subgroup was sacrificed, serving as a healthy reference. The remaining mice were fed an HFD and divided into three groups: (i) no exercise, (ii) exercise, or (iii) exercise and dietary BCAA. Mice were followed for 6 months and aforementioned tests were repeated. We found that exercise alone changed cerebral blood flow, attenuated white matter loss, and reduced neuroinflammation compared to non-exercising HFD-fed mice. Contrarily, no favorable effects of exercise on the brain were found in combination with BCAA, and neuroinflammation was increased. However, cognition was slightly improved in exercising mice on BCAA. Moreover, BCAA and exercise increased the percentage of epididymal white adipose tissue and muscle weight, decreased body weight and fasting insulin levels, improved the circadian rhythm, and transiently improved grip strength. In conclusion, BCAA should be supplemented with caution, although beneficial effects on metabolism, behavior, and cognition were observed.

New Evidence of Oral Branched-Chain Amino Acid Supplementation on the Prognosis of Patients With Advanced Liver Disease.

Oral branched-chain amino acids (BCAAs) might benefit patients with advanced liver disease. We assess its effects on prognosis compared with control from the meta-analysis. Study end points were development of hepatic encephalopathy (HE), hepatocellular carcinoma (HCC), mortality, and overall liver-related events (LREs). Risk ratios (RRs) and hazard ratios (HRs) were calculated using random effects model and heterogeneity using I 2 statistic. Twenty-eight studies were included in this meta-analysis; 1,578 and 1,727 patients in oral BCAAs and control groups, respectively. From studies using RRs as outcome measures, oral BCAAs were better in preventing HE and LRE than controls, with RRs 0.684 (95% confidence interval [CI] 0.497-0.941; P = 0.019) and 0.788 (95% CI 0.585-0.810; P < 0.001), respectively. Oral BCAAs had marginal effect on preventing HCC compared with control, with RR 0.791 (95% CI 0.619-1.011; P = 0.061); no significant difference in mortality was detected. From studies using HRs as outcome measures, oral BCAAs were superior to control in preventing LRE with adjusted HR 0.497 (95% CI 0.321-0.770; P = 0.002). In subgroups undergoing HCC resection, oral BCAAs had beneficial effect in preventing HE (RR 0.716, 95% CI 0.514-0.996; P = 0.047) and LRE (RR 0.716, 95% CI 0.595-0.860; P < 0.001). Oral BCAAs could afford clinical benefits in reducing HE and LRE risks, especially among patients undergoing HCC resection.

Oral Branched-Chain Amino Acids Supplementation in Athletes: A Systematic Review.

Branched-chain amino acids (BCAAs) are oxidized in the muscle and result in stimulating anabolic signals—which in return may optimize performance, body composition and recovery. Meanwhile, among athletes, the evidence about BCAA supplementation is not clear. The aim of this study was to review the effects of BCAAs in athletic populations. The research was conducted in three databases: Web of Science (all databases), PubMed and Scopus. The inclusion criteria involved participants classified both as athletes and people who train regularly, and who were orally supplemented with BCAAs. The risk of bias was individually assessed for each study using the revised Cochrane risk of bias tool for randomized trials (RoB 2.0). From the 2298 records found, 24 studies met the inclusion criteria. Although BCAAs tended to activate anabolic signals, the benefits on performance and body composition were negligible. On the other hand, studies that included resistance participants showed that BCAAs attenuated muscle soreness after exercise, while in endurance sports the findings were inconsistent. The protocols of BCAA supplements differed considerably between studies. Moreover, most of the studies did not report the total protein intake across the day and, consequently, the benefits of BCAAs should be interpreted with caution.

Oral Branched Chain Amino Acids on Strength Antagonism Athletes

Oral Branched Chain Amino Acids on Strength Antagonism Athletes

Angiotensin Receptor Blockers Potentiate the Protective Effect of Branched-Chain Amino Acids on Skeletal Muscle Atrophy in Cirrhotic Rats.

This study investigated the combined effect of the angiotensin II (AT-II) receptor blocker losartan and branched-chain amino acids (BCAAs) on skeletal muscle atrophy in rats with cirrhosis and steatohepatitis. Fischer 344 rats are fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and treated with oral losartan (30mg kg-1 day-1 ) and/or BCAAs (Aminoleban EN, 2500mg kg-1 day-1 ). Treatment with losartan and BCAAs attenuated hepatic inflammation and fibrosis and improved skeletal muscle atrophy and strength in CDAA-fed rats. Both agents reduced intramuscular myostatin and pro-inflammatory cytokine levels, resulting in inhibition of the ubiquitin-proteasome system (UPS) through interference with the SMAD and nuclear factor-kappa B pathways, respectively. Losartan also augmented the BCAA-mediated increase of skeletal muscle mass by promoting insulin growth factor-I production and mitochondrial biogenesis. Moreover, losartan decreased the intramuscular expression of transcription factor EB (TFEB), a transcriptional inducer of E3 ubiquitin ligase regulated by AT-II. In vitro assays illustrated that losartan promoted mitochondrial biogenesis and reduced TFEB expression in AT-II-stimulated rat myocytes, thereby potentiating the inhibitory effects of BCAAs on the UPS and caspase-3 cleavage. These results indicate that this regimen could serve as a novel treatment for patients with sarcopenia and liver cirrhosis.

Glycine increases fat-free mass in malnourished haemodialysis patients: a randomized double-blind crossover trial.

BackgroundProtein energy wasting is associated with negative outcome in patients under chronic haemodialysis (HD). Branched‐chain amino acids (BCAAs) may increase the muscle mass. This post hoc analysis of a controlled double‐blind randomized crossover study assessed the impact of BCAAs on nutritional status, physical function, and quality of life.MethodsWe included 36 chronic HD patient features of protein energy wasting as plasma albumin <38 g/L, and dietary intakes <30 kcal/kg/day and <1 g protein/kg/day. Patients received either oral BCAA (2 × 7 g/day) or glycine (2 × 7 g/day) for 4 months (Period 1), followed by a washout period of 1 month, and then received the opposite supplement (Period 2). The outcomes were lean body mass measured by dual‐energy X‐ray absorptiometry, fat‐free mass index measured by bioelectrical impedance, resting energy expenditure, dietary intake and appetite rating, physical activity and function, quality of life, and blood parameters. Analyses were performed by multiple mixed linear regressions including type of supplementation, months, period, sex, and age as fixed effects and subjects as random intercepts.ResultsTwenty‐seven patients (61.2 ± 13.7 years, 41% women) were compliant to the supplementations (consumption >80% of packs) and completed the study. BCAA did not affect lean body mass index and body weight, but significantly decreased fat‐free mass index, as compared with glycine (coeff −0.27, 95% confidence interval −0.43 to −0.10, P = 0.002, respectively). BCAA and glycine intake had no effect on the other clinical parameters, blood chemistry tests, or plasma amino acids.ConclusionsBranched‐chain amino acid did not improve lean body mass as compared with glycine. Unexpectedly, glycine improved fat‐free mass index in HD patients, as compared with BCAA. Whether long‐term supplementation with glycine improves the clinical outcome remains to be demonstrated.

Current Practice of Branched Chain Amino Acids Administration in Patients with Liver Cirrhosis: A Physician Survey

Introduction: Protein Energy Malnutrition (PEM) is prevalent in about 65-90% of patients with liver disorders. PEM is usually associated with poor quality of life, high risk of complications, morbidity and mortality, and longer duration of hospital stays. PEM is also associated with decreased skeletal muscle mass and reduced levels of serum albumin and Branched Chain Amino Acids (BCAAs). Therefore, BCAAs are recommended as nutritional therapy in various liver disorders. Aim: To understand the current practice of BCAA use in patients with liver cirrhosis in India. Materials and Methods: A cross-sectional, questionnaire-based survey was conducted pan India involving 100 gastroenterologists over a period of four months from September 2019 to December 2019. Each physician participated in the survey after verbal consent. Ample time was given for completion of the questionnaires. Results: Out of 83 participating physicians, nearly 3/4th considered liver cirrhosis as the most common Gastrointestinal (GI) disorder where nutrition is important in patient management. Malnutrition was commonly observed in patients with cirrhosis by nearly over 80% physicians and was most common in patients with decompensated cirrhosis. Weight loss and loss of appetite can be early signs of sarcopenia as these were common profiles observed in patients with malnutrition. Total 51.8% physicians considered BCAA administration in all Child-Pugh class patients. The practice of BCAA treatment with regards to its dose and duration highly varied for patients with cirrhosis, Hepatic Encephalopathy (HE), and Liver Transplantation (LT). Proteins from vegetarian source (50.6%) and BCAA supplementation (96.4%) were considered as major treatments for HE patients. Majority of the physicians reported that BCAA administration improved quality of life (52.4%), reduced HE episodes (49.4%), improved muscle mass (50%), and reduced hospitalisation rates (49.4%) in 20-40% of their patients. In all, 92.8% of physicians suggested that early administration of oral BCAA can prolong the waiting period for LT. Conclusion: Branched Chain Amino Acids (BCAA) is an integral part of nutritional management in patients with liver cirrhosis in India. Further studies are required to guide the decision on dose and duration of BCAA treatment in the management of cirrhosis.

Effects of branched-chain amino acids on postoperative tumor recurrence in patients undergoing curative resection for hepatocellular carcinoma: A randomized clinical trial.

No effective postoperative adjuvant therapies have been established for patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate the effect of oral administration of branched-chain amino acids (BCAA) on the recurrence-free survival (RFS) after hepatic resection in HCC patients. In this randomized clinical trial, HCC patients undergoing curative resections were randomly assigned in a 1:1 ratio to the BCAA group or surgery-alone group. The BCAA group received BCAA (Livact® ) for up to 4years. The primary endpoint was RFS. The secondary endpoint was overall survival (OS). Multivariate analysis was performed to detect the clinical characteristics significantly associated with RFS. Between January 2010 and October 2014, 156 patients (75 in BCAA group and 81 in surgery-alone group) were enrolled in the study. Of these, two patients were excluded from the efficacy analysis. Comparison of the survival curves by the log rank test demonstrated no significant difference in the RFS (P=.579) or OS (P=.268) between the BCAA and the control group. Multivariate analysis revealed that the RFS was significantly associated with age and number of tumors. A beneficial effect of BCAA on the RFS was found in patients younger than 72years old with a HbA1c level of<6.4%. Oral BCAA supplementation could not reduce the risk of recurrence after hepatic resection in HCC patients; however, the results suggested that BCAA supplementation may be beneficial for selected patients who were younger and had mildly impaired glucose tolerance.

Regular exercise and branched-chain amino acids prevent ischemic acute kidney injury-related muscle wasting in mice.

Acute kidney injury (AKI) causes glucose and protein metabolism abnormalities that result in muscle wasting, thereby affecting the long‐term prognosis of critical illness survivors. Here, we examined whether early intervention with treadmill exercise and branched‐chain amino acids (BCAA) can prevent AKI‐related muscle wasting and reduced physical performance in mice. Unilateral 15 min ischemia‐reperfusion injury was induced in contralateral nephrectomized mice, and muscle histological and physiological changes were assessed and compared with those of pair‐fed control mice, since AKI causes severe anorexia. Mice exercised for 30 min each day and received oral BCAA for 7 days after AKI insult. By day 7, ischemic AKI significantly decreased wet weight, myofiber cross‐sectional area, and central mitochondrial volume density of the anterior tibialis muscle, and significantly reduced maximal exercise time. Regular exercise and BCAA prevented AKI‐related muscle wasting and low physical performance by suppressing myostatin and atrogin‐1 mRNA upregulation, and restoring reduced phosphorylated Akt and PGC‐1α mRNA expression in the muscle. Ischemic AKI induces muscle wasting by accelerating muscle protein degradation and reducing protein synthesis; however, we found that regular exercise and BCAA prevented AKI‐related muscle wasting without worsening kidney damage, suggesting that early rehabilitation with nutritional support could prevent AKI‐related muscle wasting.

Effects of Branched-Chain Amino Acid (BCAA) Supplementation on the Progression of Advanced Liver Disease: A Korean Nationwide, Multicenter, Prospective, Observational, Cohort Study.

Background and Aims: Clinical evidence for the benefits of branched-chain amino acids (BCAAs) is lacking in advanced liver disease. We evaluated the potential benefits of long-term oral BCAA supplementation in patients with advanced liver disease. Methods: Liver cirrhosis patients with Child–Pugh (CP) scores from 8 to 10 were prospectively recruited from 13 medical centers. Patients supplemented with 12.45 g of daily BCAA granules over 6 months, and patients consuming a regular diet were assigned to the BCAA and control groups, respectively. The effects of BCAA supplementation were evaluated using the model for end-stage liver disease (MELD) score, CP score, serum albumin, serum bilirubin, incidence of cirrhosis-related events, and event-free survival for 24 months. Results: A total of 124 patients was analyzed: 63 in the BCAA group and 61 in the control group. The MELD score (p = 0.009) and CP score (p = 0.011) significantly improved in the BCAA group compared to the control group over time. However, the levels of serum albumin and bilirubin in the BCAA group did not improve during the study period. The cumulative event-free survival was significantly improved in the BCAA group compared to the control group (HR = 0.389, 95% CI = 0.221–0.684, p < 0.001). Conclusion: Long-term supplementation with oral BCAAs can potentially improve liver function and reduce major complications of cirrhosis in patients with advanced liver disease.

The impact of personalized nutritional support on postoperative outcome within the enhanced recovery after surgery (ERAS) program for liver resections: results from the NutriCatt protocol.

Malnutrition in liver surgery is correlated with higher postoperative complications and longer length of hospital stay (LOHS), the same items that ERAS programs try to optimize. However, to date, standardized dietary protocols have not been defined within ERAS programs. Aim of this study was to evaluate the impact on LOHS and postoperative complications, of a personalized nutritional protocol (NutriCatt) with diet and oral branched-chain amino acid (BCAA) supplementation, adopted within the ERAS program. 1960 consecutive liver resections were performed from January 2000 to September 2018. perihilar cholangiocarcinoma, simultaneous colorectal and liver resections. Four groups for analysis: resections before 2009 (1st period); from 2009 to 2016 (2nd period, including laparoscopic resections); between 2016 and September 2017 (ERAS); after September 2017 (ERAS + NutriCatt). LOHS declined (p < 0.0001), from a median of 10days (1st period) to 8, 7 and 6 in 2nd period, ERAS and ERAS + NutriCatt groups, respectively. At multivariable analysis for risk of LOHS > 8days, the 2nd period, ERAS and ERAS + NutriCatt groups showed a protective effect. These results were confirmed for both minor and major resections. LOHS was significantly lower in ERAS + Nutricatt group than in ERAS group, without increasing risk of postoperative complications, although the rate of laparoscopic resections was similar in these two groups and complexity of liver resections was significantly higher in the last period. Adoption of a personalized nutritional protocol with BCAA supplementation within the ERAS program for liver resections was a safe and effective approach that may impact on reducing the LOHS.

Effects of Oral Branched-Chain Amino Acids (BCAAs) Intake on Muscular and Central Fatigue During an Incremental Exercise.

The aim of this study was to investigate the effects of oral branched-chain amino acids (BCAAs) intake on muscular (creatine kinase and myoglobin) and central (serotonin) fatigue during an incremental exercise protocol and to determine the time to exhaustion. Sixteen male long-distance runners (25.7 ± 2.0 yrs) performed two trials, 14 days apart. Using a double-blind, placebo-controlled, randomised crossover design, participants ingested either 20 g of BCAAs (BCAA trial) or a placebo 1 hour prior to performing an incremental exercise session on a treadmill. The starting speed was 8 km/h and this was increased by 1 km/h every 5 minutes until volitional exhaustion. Blood analysis indicated that plasma levels of serotonin were lower in the BCAA trial (259.3 ± 13.5 ng/ml) than the placebo trial (289.1 ± 14.5 ng/ml) (p < 0.05). There was a similar pattern of results for free fatty acid (p < 0.05). The creatine kinase level was higher in the BCAA trial (346.1 ± 33.7 U/L) than the placebo trial (307.3 ± 30.2 U/L). No significant difference between trials was observed regarding the level of myoglobin (p = 0.139). Time to exhaustion was longer in the BCAA trial (50.4 ± 2.3 min) than the placebo trial (46.6 ± 3.2 min). In conclusion, oral intake of 20 g of BCAAs 1 hour prior to an incremental treadmill exercise session increased time to exhaustion, probably due to the reduction in serotonin concentration. As myoglobin levels were within the normal range in both trials, we conclude that the participants did not reach muscular fatigue.

Evaluation of the Progressivity Parameters of Chronic Kidney Disease after Branched-Chain Amino Acid Supplementation in Children

Chronic Kidney Disease (CKD) is not an uncommon issuein children. Chronic kidney disease is the abnormality ofstructure or function of the kidney that occurs for more than three months. The presence of a longitudinal decline inGlomerulus Filtration Rate (GFR), proteinuria, and hypertension Are the characteristics of CKD. One of the recommendationsof nutritional supplementation as the prevention of CKD is by the administration of oral Branched-Chain Amino Acid (BCAA).To date, there has been no research to analyze the effects of the BCAA on children with stage 2-4CKD. This study aimed toanalyze the effect of BCAA in inhibiting the progressivity of stage 2-4 CKD in children and improving nutritional status.Astudy with randomized pre-post test controlled trial design was performed in the Outpatient Clinic of Pediatric Nephrologyin Dr. Soetomo Hospital with stage 2-4CKD. The subjects were divided into two groups, such as the BCAA and placebo, andwere monitored for eight weeks to be evaluated the GFR, albumin, proteinuria, blood pressure, and nutritional status.Sixteen children with stage 2-4 CKD dominated by 71.4% of male patients were enrolled in this study. The mean age was 12.5(SD 2.90) years. Approximately 50% (p=0.767) stage 2 chronic kidney, 50% (p=1.000) moderate malnutrition, and 64.28%(p=1.000) short stature were found, with nephrotic syndrome as the most common underlying cause of CKD (p=0.149). InBCAA group, decrease of GFR -5.08±7.13 (p=0.055), increase of serum albumin 0.20±0.23 (p=0.062), decrease of deltasystole -11.57±15.08 (p=0.565) and diastole -4.85±16.25 (p=0.708), weight loss -0.07±1.01 (p=0.828), an increase of height0.14±0.24 (p=0.771), and a decrease in BMI -0.03±0.74 (p=0.389) were reported. It was concluded that branched-chainamino acid (leucine, isoleucine, and valine) supplementation did not provide a significant effect to inhibit progressivity ofstage 2-4CKD in children and improvement of nutritional status.

Clinical audit on management of hepatic encephalopathy in children admitted to Gastroenterology and Hepatology Unit of Assiut University Children Hospital

Introduction Hepatic encephalopathy (HE) is an important metabolic disturbance in children. It is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, after exclusion of brain disease. Patients and methods A clinical audit on management of HE was applied according to the guideline protocol used in Gastroenterology and Hepatology Unit of Assiut University Children Hospital. The study included 52 children with HE who were admitted to Gastroenterology and Hepatology Unit over 1-year period from the 1st of March 2016 to the 28th of February 2017. Results Detailed history intake was recorded in most cases, except history of drug intake, which was not recorded in 23.15% of cases; history of reversal of sleep rhythm, which was not recorded in 17.3% of cases; and history of behavioral changes, which was not recorded in 9.6% of cases. Data of examination were recorded in most cases, except for fetor hepaticus, which was recorded in 42.3% of cases; asterixis, which was recorded in 36.5% of cases; and neurological examination, which was recorded in 91.2% of cases. Basic and mandatory investigations in the diagnosis of HE were done. The standard treatment of HE has been applied except admission to the ICU and prophylactic endotracheal intubation were not applied. Moreover, oral branched-chain amino acids and rifaximin were not given. Conclusion The international guidelines for the management of HE have been followed by the Gastroenterology and Hepatology Unit of Assiut University Children Hospital in most treatment lines and that some of the default is owing to poor-resource setting and lack of medication.

Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation.

Rationale: Myocardial vulnerability to ischemia/reperfusion (I/R) injury is strictly regulated by energy substrate metabolism. Branched chain amino acids (BCAA), consisting of valine, leucine and isoleucine, are a group of essential amino acids that are highly oxidized in the heart. Elevated levels of BCAA have been implicated in the development of cardiovascular diseases; however, the role of BCAA in I/R process is not fully understood. The present study aims to determine how BCAA influence myocardial energy substrate metabolism and to further clarify the pathophysiological significance during cardiac I/R injury.Methods: Parameters of glucose and fatty acid metabolism were measured by seahorse metabolic flux analyzer in adult mouse cardiac myocytes with or without BCAA incubation. Chronic accumulation of BCAA was induced in mice receiving oral BCAA administration. A genetic mouse model with defective BCAA catabolism was also utilized. Mice were subjected to MI/R and the injury was assessed extensively at the whole-heart, cardiomyocyte, and molecular levels.Results: We confirmed that chronic accumulation of BCAA enhanced glycolysis and fatty acid oxidation (FAO) but suppressed glucose oxidation in adult mouse ventricular cardiomyocytes. Oral gavage of BCAA enhanced FAO in cardiac tissues, exacerbated lipid peroxidation toxicity and worsened myocardial vulnerability to I/R injury. Etomoxir, a specific inhibitor of FAO, rescued the deleterious effects of BCAA on I/R injury. Mechanistically, valine, leucine and their corresponding branched chain α-keto acid (BCKA) derivatives, but not isoleucine and its BCKA derivative, transcriptionally upregulated peroxisome proliferation-activated receptor alpha (PPAR-α). BCAA/BCKA induced PPAR-α upregulation through the general control nonderepresible-2 (GCN2)/ activating transcription factor-6 (ATF6) pathway. Finally, in a genetic mouse model with BCAA catabolic defects, chronic accumulation of BCAA increased FAO in myocardial tissues and sensitized the heart to I/R injury, which could be reversed by adenovirus-mediated PPAR-α silencing.Conclusions: We identify BCAA as an important nutrition regulator of myocardial fatty acid metabolism through transcriptional upregulation of PPAR-α. Chronic accumulation of BCAA, caused by either dietary or genetic factors, renders the heart vulnerable to I/R injury via exacerbating lipid peroxidation toxicity. These data support the notion that BCAA lowering methods might be potentially effective cardioprotective strategies, especially among patients with diseases characterized by elevated levels of BCAA, such as obesity and diabetes.

Effect of Oral Branched-Chain Amino Acids and Glutamine Supplementation on Skeletal Muscle Atrophy After Total Gastrectomy in Rat Model

BackgroundSarcopenia is closely related to short-term outcomes of surgery and long-term prognosis. After gastrectomy, a decrease in muscle strength occurs because of insufficient nutrient intake and disturbed digestive function. Branched-chain amino acids (BCAAs) and glutamine (Gln) play vital roles in the signaling pathways regulating protein synthesis and protein degradation. In this study, we investigated the effects of BCAA and Gln supplementation alone or in combination on skeletal muscle atrophy after total gastrectomy in a rat model. MethodsMale Wistar rats were divided into five groups: (1) sham operation (n = 8); (2) total gastrectomized rats (TG [control group], n = 16); (3) TG with BCAA (TG-B, n = 16); (4) TG with Gln (TG-G, n = 16); and (5) TG with BCAA and Gln (TG-BG, n = 16). In all groups, body weight, muscle weight, and marker for muscle metabolism were examined. ResultsWeight gain was significantly greater in the TG-BG group (130.5%) than in the TG group (108.1%) at 15 wk (P < 0.05). The gastrocnemius muscle weight was significantly higher for TG-BG (2.84 g) than for TG (2.44 g) at 15 wk (P < 0.05). Western blotting indicated that atrogin-1 and MuRF1 levels were lower in the TG-BG group than in the TG group but were not suppressed in the TG-B or TG-G group. ConclusionsIn a rodent sarcopenia model induced by TG, the administration of BCAA in combination with Gln more effectively inhibited muscle atrophy than the administration of BCAA or Gln alone.

Dietary branched-chain amino acids intake exhibited a different relationship with type 2 diabetes and obesity risk: a meta-analysis.

To assess whether oral branched-chain amino acids (BCAA) supplementation exerts influence on circulating BCAA and the significance of dietary BCAA in type 2 diabetes and obesity risk. We searched PUBMED, EMBASE and Cochrane library through June 2018 to retrieve and screen published reports for inclusion in the meta-analysis after methodological assessment. Heterogeneity of studies was evaluated using I2 statistics, while sensitivity analysis and funnel plot were used to evaluate the potential effect of individual studies on the overall estimates and publication bias, respectively, using RevMan 5.3. Eight articles on randomized clinical trial of oral BCAA supplementation, and seven articles on dietary BCAA intake and type 2 diabetes/obesity risks were eligible for inclusion in our meta-analyses. Mean difference and 95% confidence interval (CI) of circulating leucine was 39.65 (3.54, 75.76) µmol/L, P = 0.03 post-BCAA supplementation. Also, OR and 95% CI for higher total BCAA intake and metabolic disorder risks were, 1.32 (1.14, 1.53), P = 0.0003-type 2 diabetes and 0.62 (0.47, 0.82), P = 0.0008-obesity. Oral BCAA supplementation exerts modest influence on circulating leucine profile and higher total BCAA intake is positively and contra-positively associated with type 2 diabetes and obesity risk, respectively.

The Prevalence and Implication of Zinc Deficiency in Patients With Chronic Liver Disease.

BackgroundPatients with liver cirrhosis often exhibit zinc deficiency. Although zinc is involved in many bioactivities, many aspects of clinical implications of zinc deficiency in liver cirrhosis remain unclear. We aimed to reveal the prevalence and implications of zinc deficiency in liver cirrhosis by assessing associations with parameters such as clinical symptoms and laboratory data.MethodsIn 235 cirrhosis patients enrolled at multiple medical institutions in 2009, we assessed how blood zinc levels were associated with their clinical symptoms, patients characteristics, and liver function test results.ResultsBlood zinc levels were most strongly correlated with blood albumin levels among the study parameters (r = 0.587, P < 0.0001). When blood albumin levels were ≤ 3.5 g/dL, blood zinc levels were < 70 μg/dL in 88% of patients. Additionally, significant correlations were observed with age (r = -0.253, P = 0.0014), aspartate aminotransferase levels (r = -0.254, P = 0.0020), total bilirubin levels (r = -0.222, P = 0.0053), prothrombin time (r = -0.255, P = 0.0029), branched-chain amino acid to tyrosine ratio (r = 0.357, P < 0.0001), Child-Pugh score (r = 0.469, P < 0.0001), ammonia levels (r = -0.246, P = 0.0028), and total cholesterol levels (r = 0.314, P < 0.0001). Blood zinc levels were significantly lower in patients with edema/ascites (P < 0.0001), those with hepatic encephalopathy (P = 0.0215), those receiving oral diuretics (P = 0.0045), and those receiving oral branched-chain amino acids (P < 0.0001) than in those without these conditions.ConclusionsZinc deficiency is prevalent in cirrhosis patients, whereas nitrogen metabolic disorders, particularly hypoalbuminemia, can be an indicator of zinc deficiency. Thus, cirrhosis patients exhibiting a nitrogen metabolic disorder should be examined for the presence of zinc deficiency.