Role of branched chain amino acids (BCAA) intake in preventing muscle proteolysis.
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Amino Acids↗
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Human brown fat metabolism associates with systemic branched-chain amino acids homeostasis.
Circulating branched-chain amino acids (BCAAs) are linked with insulin resistance, but the human tissues contributing to systemic BCAA homeostasis remain incompletely defined. Brown adipose tissue (BAT) is a metabolically active adipose depot associated with favourable insulin sensitivity, yet its role in BCAA metabolism in humans remains unclear. We tested whether human BAT metabolism is associated with circulating BCAA levels, BAT-resident BCAA-catabolic signatures, and longitudinal changes in systemic BCAA homeostasis. We studied 83 adults who underwent metabolic phenotyping, PET-CT assessment of cold-stimulated BAT metabolism, and serum metabolomic profiling at room temperature and during acute mild cold exposure. Supraclavicular BAT biopsies from 25 participants were analysed by transcriptomics and metabolomics, and 40 participants were re-examined for circulating BCAA profiles after approximately five years. Participants with high BAT metabolism had lower circulating BCAA levels than those with low BAT metabolism. Within BAT, metabolically active individuals exhibited lower relative BCAA abundance together with higher expression of genes involved in BCAA catabolism. These BAT BCAA-catabolic signatures aligned with thermogenic capacity and indices of systemic insulin sensitivity. In contrast, individuals with low BAT metabolism showed increases in circulating BCAAs over five years. Integrative analyses further linked circulating lipopolysaccharide, a marker of metabolic endotoxemia, with higher BAT BCAA and aminomalonate abundance, together with transcriptional patterns involving inflammatory and mitochondrial pathways. Together, these findings identify human BAT metabolism as a tissue phenotype linked to systemic BCAA homeostasis and extend the role of human BAT beyond thermogenesis, suggesting that BAT-associated BCAA handling may contribute to systemic metabolic health.
Humans↗
Infusion of the branched chain amino acids in postoperative patients. Anticatabolic properties.
Postinjury metabolism is characterized by breakdown of muscle protein as substrate for energy production and gluconeogenesis and by the resultant loss of lean body mass and weight loss. The branched chain amino acids (BCAAs) which are principally oxidized by the skeletal muscle have been implicated in recent in vitro and in vivo studies as having special anticatabolic and regulating effects in skeletal muscle. We studied the anticatabolic effects of the BCAAs in 35 patients undergoing operative injury of moderate severity. In a prospective randomized and blinded manner patients were infused for five days starting immediately after surgery with either 5% dextrose or 5% dextrose with an amino acid solution containing 22, 35 or 100% BCAAs. All patients survived and there were no major postoperative complications. Mean hospital stay was 17 days for patients receiving amino acids and 19 days for patients receiving 5% dextrose only (p = ns). All three groups receiving amino acid solutions were in nitrogen equilibrium or in a slight positive nitrogen balance, while the group receiving 5% dextrose only was in a mean negative nitrogen balance of 6.6 +/- 0.6 gN/day. The differences between the three groups receiving amino acids were slight and not significant. Weight loss was 2 +/- 0.7 kg in the 5% dextrose group, 1 +/- 0.7 kg in the 22% BCAAs group, 0.5 +/- 0.5 kg in the 35% BCAAs group and the 100% BCAAs group gained 0.4 +/- 1.8 kg. Blood chemistries in the different groups and during the study period remained within normal limits except for ammonia levels rising significantly in the 5% dextrose group and SGOT levels rising in the 22% and 35% BCAA groups. With mild variations the plasma amino acid patterns in all groups were similar to the normal pattern, even in the 100% BCAAs group receiving an unbalanced amino acid solution, suggesting the complete cessation of amino acid efflux from muscle, the muscle depending solely on the exogenous supply of BCAAs to satisfy its metabolic requirements. The results suggest that early nutritional suppport in the postoperative period will result in nitrogen equilibrium and that the infusion of the three BCAAs only in the postoperative state is as effective in preventing muscle catabolism as other more balanced amino acid solutions. In the postinjury state balanced amino acid solutions rich in BCAA may prove beneficial.
Adult↗
Tumor and host response to arginine and branched chain amino acid-enriched total parenteral nutrition. A study involving Walker 256 carcinosarcoma-bearing rats.
The metabolic effects of total parenteral nutrition (TPN) solutions containing different profiles of individual amino acids were investigated in the rats bearing Walker 256 carcinosarcoma. The rats were subcutaneously inoculated with 10(7) tumor cells and 6 days later were continuously infused intravenously for 8 days with three different TPN solutions. The experimental and control solutions were composed of high concentrations of branched chain amino acids (BCAA) and arginine (high Arg + BCAA TPN), high concentrations of BCAA (high BCAA TPN) and regular amino acids (regular TPN), respectively, and were isonitrogenous, isocaloric, and isovolemic. Rats receiving subcutaneous injection of saline rather than tumor cells received high Arg + BCAA TPN as pair-fed controls. The flooding dose method of 14C-leucine was used for the analysis of protein synthesis. With the feeding of high Arg + BCAA TPN, the tumor-bearing rats revealed a smaller increase of tumor volume and lower tumor fractional rates of growth (Kg) and synthesis (Ks) as well as protein synthesis (PS), compared with the high BCAA TPN and regular TPN in tumor-bearing rats. There were no significant differences of Ks and PS in liver and muscle between TPN groups, whereas tumor-bearing rats infused with high Arg + BCAA TPN displayed higher levels of whole-body Ks and PS than other TPN groups in tumor-bearing rats and pair-fed nontumorous rats. Except for liver RNA content which showed a lower level in tumor-bearing rats with high Arg + BCAA TPN, no other differences of DNA and RNA contents were found in tumor, liver, and muscle of the different TPN groups. The current results indicate that individual amino acids can influence tumor growth and protein metabolism, and that arginine, in combination with BCAA, may reduce tumor growth through a reduction in protein synthesis.
Amino Acids, Branched-Chain↗
Association between Branched-Chain amino acids and Epilepsy: A Mendelian randomized study.
BACKGROUND: Branched-chain amino acids (BCAAs) have been affected epilepsy, yet conclusions remain inconclusive, lacking causal evidence regarding whether BCAAs affect epilepsy. Systematic exploration of the causal relationship between BCAAs and epilepsy could hand out new ideas for the treatment of epilepsy. METHODS: Utilizing bidirectional Mendelian randomization (MR) study, we investigated the causal relationship between BCAA levels and epilepsy. BCAA levels from genome-wide association studies (GWAS), including total BCAAs, leucine levels, isoleucine levels, and valine levels, were employed. Causal relationships were explored applying the method of inverse variance-weighted (IVW) and MR-Egger, followed by sensitivity analyses of the results to evaluate heterogeneity and pleiotropy. RESULTS: Through strict genetic variant selection, we find some related SNPs, total BCAA levels (9), leucine levels (11), isoleucine levels (7), and valine levels (6) as instrumental variables for our MR analysis. Following IVW and sensitivity analysis, total BCAAs levels (OR = 1.14, 95 % CI = 1.019 ∼ 1.285, P = 0.022) and leucine levels (OR = 1.15, 95 % CI = 1.018 ∼ 1.304, P = 0.025) had significant correlation with epilepsy. CONCLUSIONS: There exists a causal relationship between the levels of total BCAAs and leucine with epilepsy, offering the new ideas into epilepsy potential mechanisms, holding significant implications for its prevention and treatment.
Humans↗
Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.
BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.
Amino Acids, Branched-Chain↗
Branched-chain amino acids increase the seizure threshold to picrotoxin in rats.
During infusion of branched-chain amino acids (BCAAs) in humans, changes in ventilatory drive, appetite, and sleep have been reported. The mechanism by which BCAAs exert their effects on CNS remains unclear. Picrotoxin is a proconvulsant drug, acting as an antagonist on the GABA-benzodiazepine receptor complex. Twenty rats were randomized to receive either an IP injection with 4% BCAAs (300 mg/kg; 8 ml/kg) (n = 10) or placebo (saline 8 ml/kg) (n = 10). The mean latency time from injection to onset of seizures was recorded as an indication of the seizure threshold. Latency time was significantly longer for BCAAs than for placebo, 11.2 (+/- 1.9) vs. 8.3 (+/- 1.8) min. Thus, a BCAA injection increased the seizure threshold to picrotoxin (p < 0.03). This suggests that BCAA infusion may exert effects on the GABA-benzodiazepine receptor complex.
Amino Acids, Branched-Chain↗
Protein-sparing effect of intravenously administered branched chain amino acids in adult rats.
Branched chain amino acids (BCAA) serve as intermediate energy substrates for peripheral tissues. Experiments were conducted to evaluate protein-sparing properties of BCAA at different doses without dextrose. Forty healthy male adult Wistar rats, weighing 437 +/- 34 gm, were randomly assigned to one of five groups. Four groups of eight rats were cannulated at the jugular vein and infused with 3% amino acid solutions containing 13, 23, 50 or 100% BCAA; an additional eight fasted rats served as controls. Results show that weight loss was not significantly different between groups, but was lower than in the fasted rats. Nitrogen balance (NB) was least negative in the 23% BCAA group, followed by 13, 50 and 100% BCAA. Protein-sparing index (PSI), defined as that portion of the infused nitrogen that is used for sparing body proteins, agreed with the calculated fat/protein ratios. Higher PSI and fat/protein ratios resulted from solutions containing balanced amino acid patterns (13 and 23%). No obvious imbalances in plasma amino acid patterns were observed. It is concluded that more protein conservation can be achieved with amino acid solutions containing a balanced amino acid pattern and that the effect of additional BCAA on protein conservation is limited in adult rats.
Amino Acids↗
OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.
Acute myeloid leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDXs) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting BCAAs further reduced chemoresistant AML cells, but relapse still occurred. Among the persisting cells, we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate- and iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA. We found that OGFOD1 upregulates protein synthesis in AML, driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML while sparing normal hematopoiesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation. Targeting OGFOD1 may offer a distinctive, translation-modifying means of reducing the chemopersisting cells that drive relapse.
Leukemia, Myeloid, Acute↗
Changes in the exercise-induced hormone response to branched chain amino acid administration.
It was the aim of the present experiment to detect possible effects of branched-chain amino acids (BCAA) on the endocrine response to 1 h of continuous running. Blood samples were collected from 14 long-distance runners (age 24-42 years) in two different trials performed at 1-week intervals. In both trials (E and P) blood samples were collected at the following times: 9 a.m. (basal values sample), 10.30 a.m. (sample 90), 11.30 a.m. (sample 150), 12.30 p.m. (sample 210); the athletes performed 1 h of running at a constant predetermined speed between samples 90 and 150. Following the basal sample a mixture containing BCAA (E trial), or not containing BCAA (P trial) was ingested. In both trials no hormone basal concentrations, except insulin, were changed before exercise. In P trial, following exercise (sample 150), human growth hormone (HGH), prolactin (PRL), adrenocorticotropic hormone (ACTH) and cortisol (C) increased, while testosterone (T) decreased. In sample 210, after 1 h of rest, while ACTH, PRL and HGH had recovered to basal concentrations, C remained elevated and T displayed a further decrease. In the E trial a similar pattern of change was observed in sample 150 for HGH, PRL, ACTH and C; in sample 210 HGH and PRL displayed significantly lower values than in the corresponding P trial samples. The T was not modified by the running exercise and increased during the recovery period. It is, therefore, suggested that BCAA administration before exercise affects the response of some anabolic hormones, mainly HGH and T.
Adrenocorticotropic Hormone↗
Blood amine acid levels in patients with insulin excess (functioning insulinoma) and insulin deficiency (diabetic ketosis).
Blood amino acid concentrations were determined in the postabsorptive state in nine patients with insulin excess (functioning insulinomas), nine juvenile-type diabetics with insulin deficiency (diabetic ketosis due to insulin withdrawal), six juvenile diabetics in moderate metabolic control, and five healthy control subjects. Blood branched-chain amino acid (BCAA) levels were elevated in diabetic ketosis and decreased in patients with insulinomas. Blood concentrations of BCAA were significantly correlated to blood glucose levels, and in diabetics they were also correlated to blood ketone bodies, serum free fatty acids, and glycerol levels. These data indicate an inverse relationship between circulating effective insulin levels and blood BCAA concentrations. It is suggested that blood levels of BCAA might represent an indicator of insulin-dependent alterations of protein metabolism.
Adenoma, Islet Cell↗
[Amino acid metabolism in surgical stress].
Amino acid metabolism under surgical stress, injury or infection was reviewed from the literature. The glucose-alanine cycle in coupling with branched chain amino acids (BCAA) metabolism plays a central role for gluconeogenesis, in such a catabolic state. Glutamine is as important as alanine for sparing glucose and furthermore for intestinal repair. Changes in plasma amino acid concentration and clearance following hepatectomy are described, and effects of BCAA solution are evaluated. It was suggested that BCAA improved the Fischer ratio by increasing, not only plasma BCAA level, but also AAA clearance.
Alanine↗
[Imbalance of amino acid metabolism in fulminant hepatitis and its management].
Fulminant hepatitis shows characteristic imbalance of amino acid levels; increased aromatic amino acid (AAA) and methionine. Elevated plasma AAA may cause hepatic encephalopathy and BCAA-enriched amino acids solution (BCAAs). Glucagon-Insulin (G-I) therapy and artificial liver support system have been proposed to correct the imbalance of amino acids. BCAAs and G-I therapy correct the aberrant amino acid patterns and artificial liver support system, including plasma pheresis, and charcoal haemoperfusion has also been used to reduce plasma amino acids levels. While imbalance of amino acids level in fulminant hepatitis is a result of acute necrosis of a large proportion of hepatocytes, careful and sufficient management of the disease is essential to normalize amino acid profiles.
Amino Acids, Branched-Chain↗
Splanchnic fluxes of amino acids after duodenal infusion of carbohydrate solutions containing free amino acids or oligopeptides in the non-anaesthetized pig.
Seven non-anaesthetized pigs (mean body-weight 64.6 kg) were used to study the intestinal absorption and hepatic metabolism of glucose and amino acids (AA) using carbohydrate solutions (maltose dextrin; 440 g/2 I), containing 110 g of either an enzymic milk-protein hydrolysate (PEP) with a large percentage of small peptides (about 50% with less than five AA residues) and very few free AA (8%) or a mixture of free AA (AAL) with an identical pattern, infused intraduodenally. Each pig was previously fitted under anaesthesia with electromagnetic flow probes around the portal vein and the hepatic artery, and with permanent catheters in the portal vein, carotid artery, one hepatic vein and the duodenum. Each solution was infused for 1 h after a fasting period (18 h) and each pig received both solutions at 8 d intervals. The observation period lasted 8 h. For most AA (his, lys, phe, thr, arg, tyr, pro) the absorption rate after infusion of PEP was significantly higher than after that of AAL during the 1st hour, but the differences quickly disappeared. After 8 h, the only differences concerned his and tyr (PEP > AAL) and met, glu and asp (AAL > PEP). There was a large uptake of blood AA by gut-wall cells, higher after AAL infusion than after PEP infusion, particularly for branched-chain AA (BCAA). The absorption of ammonia-nitrogen after both infusions was equivalent to two-thirds of urea-N passing from blood to intestinal tissues and lumen. Glucose absorbed within 8 h represented only 76% (PEP) or 69% (AAL) of the infused amounts. The cumulative hepatic total AA (TAA) uptake increased from 13 to 27% of the infused amounts between the 1st and the 8th hour after PEP infusion, and from 8 to 31% after AAL infusion. Most essential AA were largely taken up by the liver, with the exception of met (PEP) and thr and of BCAA, which were poorly retained for both solutions; there was a high uptake of ala and gly, and a release of asp, glu, and gln. Urea-N released by the liver within 8 h was equivalent to 23-25% absorbed amino-N and to around 1.5 times ammonia-N taken up by the liver within 8 h. Glucose was highly taken up by the liver during the first hours then released, the total uptake within 8 h representing about half the absorbed amount.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acids↗
Integrative metabolomic and proteomic analysis of diabetic kidney disease progression with younger-onset type 2 diabetes.
AIM: Younger-onset type 2 diabetes (YT2D) confers a disproportionately high risk of diabetic kidney disease (DKD), yet early biomarkers and underlying mechanisms remain poorly defined. We aimed to identify metabolites associated with DKD progression and integrate metabolomic and proteomic data to elucidate pathways involved in a multi-ethnic Asian cohort. MATERIALS AND METHODS: In this prospective study, 787 YT2D patients (diagnosed at ≤ age 40) were followed for a median of 5.7 years. DKD progression was defined as an annual decline in estimated glomerular filtration rate (eGFR) of ≥3 mL/min/1.73 m2 or ≥ 40% reduction in eGFR from baseline. Plasma metabolites were measured by nuclear magnetic resonance spectroscopy. Multivariable regression analysis was performed in a discovery (N = 550) and internal validation cohort (N = 237). Integrative metabolomic-proteomic analysis (N = 428) was performed using sparse partial least squares discriminant analysis (sPLS-DA). RESULTS: Ninety-eight metabolites were differentially expressed between DKD progressors and non-progressors, of which total branched-chain amino acids (BCAAs) (OR = 0.60, 95% CI 0.46-0.79), valine (OR = 0.62, 95% CI 0.48-0.81), and leucine (OR = 0.56, 95% CI 0.43-0.74) associated with DKD progression, independent of metabolic risk factors. Integrative analysis identified three components comprising 23 proteins and 30 metabolites, involved in the citrate cycle and apoptosis, which improved prediction of DKD progression beyond clinical risk factors (AUC 0.69-0.83). CONCLUSION: Lower plasma BCAA levels are independently associated with DKD progression in YT2D. Integrative multi-omics analysis highlights disruptions in metabolic and apoptotic pathways, providing insights into DKD pathophysiology and potential biomarkers for early risk stratification.
Humans↗
Effect of fasting, branched-chain amino acids, and glucocorticoids on histone H1 extractability from rat skeletal muscle.
The effect of 72 h fasting, nutritional therapy of fasted rats, and acute and chronic glucocorticoid treatment on the yield of histone H1 from rat hind limb muscles was determined. Fasting significantly enhanced the extractability of muscle H1. The effect of treating starved rats with glucose alone, or with glucose supplemented with branched-chain amino acids (BCAA), or with two commercial preparations of mixtures of essential and non-essential amino acids was evaluated. Treatment of starved rats with glucose alone significantly decreased H1 extractability from muscles, but isocaloric treatment with glucose supplemented with BCAA or two commercial preparations of amino acid mixtures was more effective. Glucocorticoid treatment for 5 days enhanced the yield of H1 from muscles less than starvation. The enhanced H1 extractability from muscles noted in starved rats is similar to that reported in rats with insulinopenic diabetes and may reflect changes in nuclear fragility.
Amino Acids, Branched-Chain↗
[Blood glucose, insulin, GH, and amino acids in rats receiving 3 levels of dietary proteins].
The effect of dietary protein content on the variations in plasma insulin, GH, glucose and both gluconeogenic and branched-chain amino acids (BCAA) levels, was studied in Wistar rats. For 21 days animals consumed ad libitum diets containing 4% (LP group) 10% (MP group) or 20% (HP group) protein. Body weight gain and plasma concentrations of the glucose, insulin and both the insulin/glucose (I/G) and insulin/GH (I/GH) ratios varied directly with the protein content of the diet. In contrast the relationships between dietary protein content and GH levels, were inverse. These results indicate that an increase of energy yielding nutrients availability and an decrease of tissue sensitivity to insulin was produced as the protein content of the diet was increased. The increase of plasma aspartate, serine, histidine and alanine levels on LP group suggest a low gluconeogenic process, and the higher rate of BCAA on HP group against to MP and LP groups can be related to a lower tissue uptake. Both effects can be mediated by the tissular sensitivity to insulin.
Amino Acids↗
The gut microbiota-obesity axis in the pathogenesis and prognosis of breast cancer.
BACKGROUND: Breast cancer (BC) remains a major global health concern, accounting for 11.7% of all cancer cases and ranking as the second leading cause of female cancer-related deaths worldwide. Increasing evidence highlights the interplay between gut microbiota (GM) dysbiosis and obesity-associated metabolic dysfunction in BC progression. This review aims to elucidate the role of GM in obese patients with BC. METHODS: A systematic literature search was conducted in PubMed and Web of Science databases for publications from July 2015 to January 2025. Search terms combined BC, GM, obesity, dysbiosis, immunity, and microbiome. Article selection prioritized studies investigating microbial alterations in BC patients, mechanistic links between obesity and cancer progression, and GM-targeted interventions. Both original studies and authoritative reviews were included, supplemented by manual reference screening. DISCUSSION: Obesity may trigger systemic inflammation, altered adipokine secretion, and disrupted steroid hormone metabolism via gut-derived β-glucuronidase activity, thereby exacerbating BC occurrence and recurrence. GM dysbiosis-driven metabolites such as branched-chain amino acids (BCAAs) and short-chain fatty acids (SCFAs) can activate oncogenic signaling pathways and immunosuppressive myeloid-derived suppressor cells (MDSCs), fostering tumor immune evasion. Conversely, dietary interventions, probiotics, and fecal microbiota transplantation (FMT) can alleviate dysbiosis, strengthen gut barriers, and restore anti-tumor immunity, improving chemotherapy response and reducing recurrence. However, challenges persist in deciphering BC subtype-related microbial signatures and optimizing microbiota-targeted therapies. CONCLUSION: Future longitudinal studies are needed to clarify causal relationships, validate microbial biomarkers, and translate preclinical findings into clinical applications. Addressing the gut-breast axis may offer transformative potential for precision oncology in obesity-driven BC.
Humans↗