Branched-chain Amino Acid Supplementation Research Articles

Management of minimal and overt hepatic encephalopathy with branched-chain amino acids: a review of the evidence.

Hepatic encephalopathy (HE) is a challenging complication of liver disease that is associated with substantial morbidity and mortality. Branched-chain amino acid (BCAA) supplementation in the management of HE is a debated topic. This narrative review aims to provide an up-to-date review of the topic and includes studies featuring patients with hepatocellular carcinoma. A review of the literature was performed using the online databases MEDLINE and EMBASE for studies between 2002 and December 2022. Keywords 'branched-chain amino acids', 'liver cirrhosis' and 'hepatic encephalopathy' were used. Studies were assessed for inclusion and exclusion criteria. Of 1045 citations, 8 studies met the inclusion criteria. The main outcomes reported for HE was changed in minimal HE (MHE) (n = 4) and/or incidence of overt HE (OHE) (n = 7). Two of the 4 studies reporting on MHE had improvement in psychometric testing in the BCAA group, but there was no change in the incidence of OHE in any of the 7 papers in the BCAA group. There were few adverse effects of BCAA supplementation. This review found weak evidence for BCAA supplementation for MHE, and no evidence for BCAAs for OHE. However, given the relative paucity and methodological heterogeneity of the current research, there is scope for future studies to examine the effects of varying timing, dosage, and frequency of BCAAs on outcomes such as HE. Importantly, research is also needed to examine BCAAs in conjunction with standard therapies for HE such as rifaximin and/or lactulose.

WED-321 - Efficacy and safety of branched-chain amino acids supplementation on muscle cramps in patients with cirrhosis: a randomized double-blinded controlled trial

WED-321 - Efficacy and safety of branched-chain amino acids supplementation on muscle cramps in patients with cirrhosis: a randomized double-blinded controlled trial

Effect and feasibility of the combination of branched chain amino acid and exercise therapy on muscle mass and echo intensity of muscle in orthopedic patients in a convalescent rehabilitation hospital: A crossover trial.

This study examined the feasibility of nutritional support combined with exercise intervention for restoring muscle and physical functions in convalescent orthopedic patients. We used a crossover design in which nutritional support combined with exercise intervention was administered daily during the early (1 month) and late (1 month) cycles with a 1-week washout period. The exercise intervention was performed twice daily for 2 months in the early and late groups. The exercise intervention consisted of one set of muscle strength, stretching, and physical activity exercises for 20 min each. Nutritional interventions were administered immediately after the exercise. A 3.4 g of branched-chain amino acid supplements (BCAAs) or 1.2 g of starch was ingested. We measured the skeletal muscle mass and isometric muscle strength of the limbs and performed balance tests. After the crossover, the BCAA and Placebo groups were compared. The ratio of improvement in the echo intensity of the rectus femoris (RF) was significantly higher in the BCAA group. A comparison of the order of nutritional intervention showed a significant effect on the RF echo intensity in both groups only when BCAAs were administered. This study's results suggest that the proposed combined intervention improves muscle quality and mass in convalescent orthopedic patients.

Walking exercise through smartphone application plus branched-chain amino acid supplementation benefits skeletal muscle mass and strength in liver cirrhosis: A prospective control trial.

Whether a combination of exercise and branched-chain amino acid (BCAA) supplementation was more beneficial than those given alone in sarcopenia related to liver cirrhosis (LC) is unknown. Widely used smartphone applications provide continuous and easily expandable management of chronic liver disease (CLD). This study is to investigate the effects of unsupervised walking exercise using WeChat combined with BCAA supplementation on skeletal muscle mass and strength in LC. The 127 LC patients of Child-Pugh A/B were assigned to group A (BCAA supplements, n=42), group B (walking exercise, n=43) and group C (walking exercise plus BCAA supplements, n=42). Laboratory data, average daily steps, serum BCAA, skeletal muscle mass index (SMI) and grip strength were analyzed pre- and 3 months after interventions. Of the 124 patients who completed interventions, albumin and daily steps were significantly increased in all groups (p=0.0001). Post-intervention BCAA were significantly elevated in group A (A vs B, p=0.001) and C (C vs B, p=0.012;). While post-intervention daily steps in group B (B vs A, p=0.0001) and C (C vs A, p=0.0001) were higher. Grip strength (C vs A, p=0.020; C vs B, p=0.036) and SMI (C vs A, p=0.035; C vs B, p=0.012) were increased in group C. Prevalence of sarcopenia was significantly decreased in group C (p=0.015). A combination of unsupervised walking exercise using smartphone applications and BCAA supplementation might be an effective and safe treatment for cirrhosis patients with Child-Pugh A/B to improve skeletal muscle mass and strength or to prevent progress of sarcopenia.

Branched chain amino acids in hepatic encephalopathy and sarcopenia in liver cirrhosis: Evidence and uncertainties.

Liver cirrhosis is commonly associated with nutritional alterations, reported in 20% of patients with compensated disease and over 60% of patients with decompensated cirrhosis. Nutritional disturbances are associated with a worse prognosis and increased risk of complication. Serum levels of branched-chain amino acids (BCAAs) are decreased in patients with liver cirrhosis. The imbalance of amino acids levels has been suggested to be associated with the development of complications, such as hepatic encephalopathy and sarcopenia, and to affect the clinical presentation and prognosis of these patients. Several studies investigated the efficacy of BCAAs supplementation as a therapeutic option in liver cirrhosis, but uncertainties remain about the real efficacy, the best route of administration, and dosage.

Branched-chain amino acids supplementation improves liver frailty index in frail compensated cirrhotic patients: a randomized controlled trial

BackgroundPhysical frailty is related with morbidity and mortality in patients with cirrhosis. Currently, there is no approved treatment of frailty in these patients. Here, we evaluated the efficacy of 16 weeks branched-chain amino acids (BCAA) supplementation on frailty in frail compensated cirrhotic patients.MethodsAfter a 4-week run-in period consisted of dietary and exercise counseling, compensated cirrhotic patients with frailty, defined by liver frailty index (LFI)≥4.5, were randomly assigned (1:1) to BCAA or control group. The BCAA group received twice daily BCAAs supplementation (210 kcal, protein 13.5 g, BCAA 2.03 g) for 16 weeks. The primary outcome was frailty reversion. The secondary outcomes were changes in biochemistries, body composition evaluated by bioelectrical impedance analysis, and quality of life (QoL).Results54 patients were prospectively enrolled (age 65.5 ± 9.9 years, 51.9% female, Child-Pugh A/B 68.5%/31.5%, MELD 10.3 ± 3.1). Baseline characteristics were similar between both groups. At week 16, BCAA group had a significant improvement in LFI (-0.36 ± 0.3 vs. -0.15 ± 0.28, P = 0.01), BMI (+ 0.51 ± 1.19 vs. -0.49 ± 1.89 kg/m2, P = 0.03), and serum albumin (+ 0.26 ± 0.27 vs. +0.06 ± 0.3 g/dl, P = 0.01). The proportion of frailty reversion at week 16 was significantly higher in BCAA group (36% vs. 0%, P < 0.001). Compared with baseline, BCAA group had a significant increase in skeletal muscle index (7.5 ± 1.6 to 7.8 ± 1.5 kg/m2, P = 0.03). Regarding the QoL, only the BCAA group had a significant improvement in all 4 domains of physical component score of the SF-36 questionnaire.ConclusionsA 16-week BCAA supplementation improved frailty in frail compensated cirrhotic patients. In addition, this intervention resulted in an improvement of muscle mass and physical domain of QoL in these patients.Trial registrationThis study was registered with Thai Clinical Trial Registry (TCTR20210928001; https://www.thaiclinicaltrials.org/#).

The effects of arginine and branched-chain amino acid supplementation to reduced-protein diet on intestinal health, cecal short-chain fatty acid profiles, and immune response in broiler chickens challenged with Eimeria spp.

We investigated the effects of supplementing arginine (Arg) and branched-chain amino acids (BCAA) in broilers fed reduced-protein diets and challenged with Eimeria spp. All birds were fed the same starter diet meeting Cobb 500 nutrient specifications from d 1 to 9. Four grower diets: positive control (PC) with 20.0% crude protein (CP); reduced-protein negative control (NC) with 17.5% CP; or NC supplemented with Arg or BCAA at 50% above recommendations (ARG or BCAA) were fed to the birds from d 9 to 28. Birds were allocated in a 2×4 factorial arrangement (4 diets, each with or without challenge), with 8 replicates per treatment. On d 14, the challenge groups were orally gavaged with mixed Eimeria spp. Intestinal permeability was higher (P < 0.05) in NC than PC, whereas the permeability of ARG and BCAA groups did not differ significantly from PC. On d 28, a significant interaction (P < 0.01) was observed in CD8+: CD4+ ratios in cecal tonsils (CT), Eimeria challenge increased the ratios in all groups except for the ARG group. On d 21, a significant interaction was found for CD4+CD25+ percentages in CT (P < 0.01) that Eimeria challenge increased the percentages only in PC and NC groups. On d 21 and 28, significant interactions (P < 0.01) were found for macrophage nitric oxide (NO) production. In nonchallenged birds, NO was higher in the ARG group than other groups, but in challenged birds, NO was higher in both ARG and BCAA groups. On d 21, a significant interaction was found for bile anticoccidial IgA concentrations (P < 0.05) that Eimeria challenge increased IgA only in NC and ARG groups. The results suggest that a reduced-protein diet exacerbates the impact of the Eimeria challenge on intestinal integrity, but this could be mitigated by Arg and BCAA supplementations. Arginine and BCAA supplementations in reduced-protein diets could be beneficial for broilers against Eimeria infection by enhancing the immune responses. The beneficial effects of Arg supplementation tended to be more pronounced compared to BCAA supplementation.

Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages

As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE−/− mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.

Community-based exercise and nutritional interventions to improve frailty syndrome among older adults: A quasi-experimental study

This study aimed to explore the efficacy of single and combined effects of exercise and branched-chain amino acid (BCAA) supplements on improving frailty and quality of life in older adults. In total, 120 study participants were allocated into a combined exercise-and-BCAA supplementation group, an exercise-only group, a BCAA supplementation-only group, and a control group. Results showed that Fried's frailty score significantly decreased in the combined exercise-and-BCAA supplementation group (β= -1.73, p<0.001), exercise-only group (β= -1.68, p<0.001), and BCAA supplementation-only group (β= -0.73, p=0.005) compared to the control group. Moreover, the combination of exercise and BCAA supplements and the exercise-only program produced significant improvements in frailty compared to the BCAA supplement-only group and control group (p<0.05). Exercise should be a critical approach for older adults to improve frailty. Healthcare professionals in geriatric care should incorporate exercise programs as frailty management and prevention for older adults.

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.

Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor response

Branched-chain amino acids (BCAAs) provide nutrient signals for cell survival and growth. How BCAAs affect CD8+ Tcell functions remains unexplored. Herein, we report that accumulation of BCAAs in CD8+ Tcells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm)-deficient mice leads to hyper-activity of CD8+ Tcells and enhanced anti-tumor immunity. CD8+ Tcells from PP2Cm-/- mice upregulate glucose transporter Glut1 expression in a FoxO1-dependent manner with more glucose uptake, as well as increased glycolysis and oxidative phosphorylation. Moreover, BCAA supplementation recapitulates CD8+ Tcell hyper-functions and synergizes with anti-PD-1, in line with a better prognosis in NSCLC patients containing high BCAAs when receiving anti-PD-1 therapy. Our finding thus reveals that accumulation of BCAAs promotes effector function and anti-tumor immunity of CD8+ Tcells through reprogramming glucose metabolism, making BCAAs alternative supplementary components to increase the clinical efficacy of anti-PD-1 immunotherapy against tumors.

The Effect of BCAA Supplementation in Aiding Muscle Soreness to Prevent Lateral Ligament Ankle Injuries in Basketball

Ankle injuries are very common in basketball, with 45% of basketball players experiencing at least one sprain at any point in their career and 53.7% of missed playtime is caused by ankle injuries. These injuries can be caused by overworking muscles and causing them to reach maximum tension and soreness. When this happens, the surrounding ligaments and tendons are more susceptible to injury since the muscles that they hold together are weaker and don't function at full strength. The purpose of the study is to understand if athletes will benefit from taking supplements of Branched Chain Amino Acid (BCAA), to prevent ankle injuries from high a vertical mobility sport like basketball, which includes vertical jumps, layups and re-bounds. Using a combination data collected from control group vs placebo group we proved that BCAA reduces muscle soreness. This is proved by lower soreness scores, and lower values of Creatine kinase (CK) in the blood by the control group that took BCAA. We then proved there is a direct linkage between soreness and muscle fatigue by referring to a study conducted on lateral muscle of Rabbits, which show muscle fatigue, cause soreness and resulting in lower energy production and instability in function, leading to Injury. Based on the study, we comprehensively conclude that BCAA can help reduce risk of ankle injury by reducing muscle soreness and fatigue in basketball players, thereby promoting stable lateral and ankle dorsiflexor muscles.

BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening.

There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

The Role of Branched-Chain Amino Acid Supplementation in Combination with Locoregional Treatments for Hepatocellular Carcinoma: Systematic Review and Meta-Analysis.

Branched-chain amino acid (BCAA) supplementation has been linked with favorable outcomes in patients undergoing surgical or palliative treatments for hepatocellular carcinoma (HCC). To date, there has been no systematic review investigating the value of BCAA supplementation in HCC patients undergoing locoregional therapies. A systematic search of the literature was performed across five databases/registries using a detailed search algorithm according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The search was conducted on March 23, 2022. Sixteen studies with a total of 1594 patients were analyzed. Most patients were male (64.6%) with a mean age of 68.2 ± 4.1 years, Child-Pugh score A (67.9%) and stage II disease (40.0%). Locoregional therapy consisted of radiofrequency ablation, transarterial chemoembolization or hepatic artery infusion chemotherapy. BCAA supplementation was in the form of BCAA granules or BCAA-enriched nutrient. Most studies reported improved albumin levels, non-protein respiratory quotient and quality of life in the BCAA group. Results pertaining to other outcomes including overall survival, recurrence rate, and Child-Pugh score were variable. Meta-analysis showed significantly higher levels of post-treatment serum albumin in the BCAA group (SMD = 0.54, 95% CI 0.20-0.87) but no significant differences in mortality rate (RR = 0.81, 95% CI: 0.65-1.02) and AST (SMD = -0.13, 95% CI: -0.43-0.18). BCAA supplementation is associated with higher post-treatment albumin levels. There are currently not sufficient data to support additional benefits. Further studies are needed to elucidate their value.

The effect of branched-chain amino acid supplementation on cancer treatment.

Background: Anticancer therapies are associated with significant adverse side effects and few treatments that alleviate symptoms exist. Branched-chain amino acids (BCAAs) have been investigated as an intervention for reducing anticancer therapy side effects, although a review of the literature results has yet to be published. Aim: The current review summarizes evidence surrounding this topic and suggests both support and caution in using BCAAs as a treatment for patients receiving anticancer therapies. Methods: In this review, two literature searches were completed. Google Scholar, PubMed, EBSCOhost, and Cochrane databases were searched using the terms "branched-chain amino acids and cancer" and "BCAA and cancer." Results: Two bodies of evidence emerged: One supporting beneficial effects and the other showing adverse outcomes of BCAA supplementation in patients with cancer. Evidence of benefit was a decrease in malnourishment and unintentional weight loss during and after chemotherapy. Potential harms included the idea cancer cells may utilize BCAAs as a source of energy for growth. Conclusions: Supplementation of BCAAs in individuals with cancer should be implemented cautiously. Those who are severely malnourished due to anticancer therapy may benefit the most. BCAA supplementation may also be provided once cancer has been destroyed from the individual's body to aid with recovery.

Branched-chain amino acid modulation of lipid metabolism, gluconeogenesis, and inflammation in a finishing pig model: targeting leucine and valine.

Branched-chain amino acids (BCAAs) play a regulatory role in adipogenesis and energy balance. Therefore, this study aimed to investigate the impact of BCAA supplements, especially leucine (Leu) and valine (Val) supplementation, on lipid metabolism and related disorders in a finishing pig model. The results demonstrated that Leu (1%) and Val decreased serum as well as hepatic lipid accumulation. Moreover, metabolomics and lipidomics analyses revealed that Leu and Val markedly downregulated the level of various lipid species in the liver. This outcome may be explained by Leu and Val promoting cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/hormone-sensitive triglyceride lipase (HSL) signaling pathways. Leu and Val altered the fatty acid composition in distinct adipose tissues and decreased the levels of inflammatory factors. Additionally, they significantly decreased back fat thickness, and the results of the fatty acid profiles demonstrated that Leu and Val significantly increased the levels of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) while decreasing those of saturated fatty acids (SFAs), especially in back fat and abdominal fat. Besides, Leu and Val restored glucose homeostasis by suppressing gluconeogenesis through the serine/threonine protein kinase (AKT)/transcription factor forkhead box O1 (FOXO1) signaling pathway in the liver and back fat. In summary, these results suggest that Leu and Val may serve as key regulators for modulating lipid metabolism and steatosis.

The Evaluation of Videos about Branched-Chain Amino Acids Supplements on YouTube™: A Multi-Approach Study

Branched-chain amino acids (BCAAs) are one of the most controversial ergogenic aids in terms of effectiveness and safety. This study aimed to evaluate the quality and reliability of BCAA supplements related to English videos on YouTube™ and to synthesize with the sentiment-emotion analysis of comments on videos. The content analysis of the information on videos was evaluated with the use of DISCERN, Journal of American Medical Association (JAMA) benchmark criteria, and Global Quality Score (GQS). In addition, word cloud and sentiment and emotional analysis of comments in videos were performed with the R package. As a result, the mean ± standard error values of DISCERN, JAMA, and GQS scores of all videos were 29.27 ± 1.97, 1.95 ± 0.12, and 2.13 ± 0.17, respectively. It was found that advertisement-free videos have a significantly higher DISCERN and GQS score than advertisement-included videos (p < 0.05). A moderately significant positive correlation was determined between DISCERN score of video content and the positive sentiment of video comments (rs: 0.400, p = 0.002). In conclusion, it was determined that BCAA-related YouTube™ videos have mostly very poor quality in terms of content and that videos with higher quality may receive positive comments from viewers according to the DISCERN instrument.

Role of Branched-Chain Amino Acids and Their Derivative β-Hydroxy-β-Methylbutyrate in Liver Cirrhosis.

Branched-chain amino acids (BCAA) supplementation is used to promote protein synthesis in different clinical conditions in which proteolysis is increased. In addition, lower plasma BCAA levels have been related to an increased risk of hepatic encephalopathy in liver cirrhosis. In this article we will review the role of supplementation with BCAAs and BCAA derivative β-hydroxy-β-methylbutyrate (HMB) in liver cirrhosis, focusing on nutritional and clinical effects. Evidence shows that BCAA supplementation slightly increases muscle mass and body mass index, with an upward trend in muscular strength and no change in fat mass. Moreover, BCAA supplementation improves symptoms of hepatic encephalopathy, and is indicated as second-line therapy. The evidence is more limited for BCAA derivatives. HMB supplementation appears to increase muscle mass in chronic diseases associated with cachexia, although this effect has not yet been clearly demonstrated in liver cirrhosis studies. To date, HMB supplementation has no clinical indication in liver cirrhosis.

Systematic review with meta-analysis: Branched-chain amino acid supplementation in liver disease.

Dietary supplementation with branched-chain amino acids (BCAA) is often used in cirrhotic patients to improve nutritional status. We wanted to explore the evidence for BCAA supplementation in chronic liver disease. We searched MEDLINE and EMBASE for studies with BCAA supplementation with the presence of a disease-control group (placebo or no intervention) using search terms 'liver cirrhosis', 'hepatocellular carcinoma', 'branched chain amino acids' and relevant synonyms. Risk of bias was assessed using ROBINS-I and RoB 2.0 tools. Meta-analyses were performed with a random-effects model. Results were reported following EQUATOR guidelines. Of 3378 studies screened by title and abstract, 54 were included (34 randomized controlled trials, 5 prospective case-control studies, 13 retrospective case-control studies: in total 2308 patients BCAA supplementation, 2876 disease-controls). Risk of bias was high/serious for almost all studies. According to meta-analyses, long-term (at least 6months) BCAA supplementation in cirrhotic patients significantly improved event-free survival (p=.008; RR .61 95% CI .42-.88) and tended to improve overall survival (p=.05; RR .58 95% CI .34-1.00). Two retrospective studies suggested the beneficial effects during sorafenib for hepatocellular carcinoma. Available studies reported no beneficial effects or contradictory results of BCAA after other specific therapeutic interventions (resection or radiological interventions for hepatocellular carcinoma, liver transplantation, paracentesis or variceal ligation). No convincing beneficial effects of BCAA supplementation on liver function, nutritional status or quality of life were found. No study reported serious side effects of BCAA. Prophylactic BCAA supplementation appears safe and might improve survival in cirrhotic patients.

Branched-chain amino acids promotes the repair of exercise-induced muscle damage via enhancing macrophage polarization.

The repair of exercise-induced muscle damage (EIMD) is closely related with inflammation. Branched-chain amino acids (BCAAs), as a nutritional supplement, promote EIMD repair; however, the underlying mechanism remains unclear. In vivo, Sprague-Dawley rats were subjected to Armstrong's eccentric exercise (a 120-min downhill run with a slope of -16° and a speed of 16mmin-1) to induce EIMD and BCAA supplement was administered by oral gavage. Protein expression of macrophages (CD68 and CD163) and myogenic regulatory factors (MYOD and MYOG) in gastrocnemius was analyzed. Inflammatory cytokines and creatine kinase (CK) levels in serum was also measured. In vitro, peritoneal macrophages from mice were incubated with lipopolysaccharide (LPS) or IL-4 with or without BCAAs in culture medium. For co-culture experiment, C2C12 cells were cultured with the conditioned medium from macrophages prestimulated with LPS or IL-4 in the presence or absence of BCAAs. The current study indicated BCAA supplementation enhanced the M1/M2 polarization of macrophages in skeletal muscle during EIMD repair, and BCAAs promoted M1 polarization through enhancing mTORC1-HIF1α-glycolysis pathway, and promoted M2 polarization independently of mTORC1. In addition, BCAA-promoted M1 macrophages further stimulated the proliferation of muscle satellite cells, whereas BCAA-promoted M2 macrophages stimulated their differentiation. Together, these results show macrophages mediate the BCAAs' beneficial impacts on EIMD repair via stimulating the proliferation and differentiation of muscle satellite cells, shedding light on the critical role of inflammation in EIMD repair and the potential nutritional strategies to ameliorate muscle damage.