Introduction
Dietary restriction (DR) has been shown to promote longevity and improve metabolic health across various organisms. While DR's benefits were initially attributed to reduced overall food intake, recent research suggests the ratio of dietary protein to carbohydrates plays a critical role. Branched-chain amino acids (BCAAs), essential amino acids constituting a significant portion of dietary protein, have emerged as key players in aging-related pathways and metabolic health. This article explores the potential role of BCAAs and their metabolites, branched-chain keto acids (BCKAs), in regulating human disease and age-associated metabolic pathways, focusing on metabolic tissues.
Branched-Chain Amino Acids (BCAAs) and Their Metabolism
BCAAs, comprised of leucine, isoleucine, and valine, are essential amino acids that must be obtained through diet. They are critical for muscle growth, reducing soreness and fatigue, preventing muscle wasting, and supporting liver health. These amino acids are absorbed in the intestines via Na+-dependent transporters and then transported across cell membranes of tissues via L-type Na+-dependent cotransporter LAT1 and its heterodimeric partner 4F2hc.
Metabolic Pathways of BCAAs
The first steps of BCAA degradation involve branched amino acid aminotransferase (BCAT) and branched-chain keto acid dehydrogenase (BCKDH). BCAT, existing as cytosolic BCAT1 and mitochondrial BCAT2, converts BCAAs into BCKAs and glutamate. BCAT1 is found in embryonic tissues, the brain, and the ovary, while BCAT2 is present in various tissues, including skeletal muscle and adipose tissue. Subsequently, BCKAs are converted into branched-chain acyl-CoA by the BCKDH complex, an α-keto acid dehydrogenase complex similar to pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes. This complex consists of E1 α-keto acid decarboxylase, E2 transacylase, and E3 dihydrolipoyl dehydrogenase subunits, utilizing cofactors like thiamine pyrophosphate, lipoate, FAD, and NAD+.
Branched-chain acyl-CoA is further degraded through parallel pathways. Isobutyryl CoA (from valine) is converted to propionyl CoA, entering the tricarboxylic acid (TCA) cycle via succinyl CoA. Isoleucine degradation yields acetyl-CoA and propionyl CoA, also feeding into the TCA cycle. Leucine catabolism produces isovaleryl CoA, which is converted to β-hydroxy-β-methylglutaryl CoA (HMG CoA) and eventually acetyl-CoA. These processes generate NADH and FAD(2H), suggesting BCAA catabolism can contribute to energy production via mitochondrial oxidative phosphorylation. BCAA catabolites can also be used for synthesizing fatty acids, cholesterol, ketone bodies, or glucose, depending on nutritional status and cellular needs.
Regulation of the BCAA Catabolic Pathway
The regulation of BCAA catabolism primarily occurs at the conversion of BCKA into branched-chain acyl-CoA by the BCKDH complex. This complex, located in the inner mitochondrial membrane, is allosterically inhibited by branched-chain acyl-CoA and NADH. The phosphorylation status of the complex also regulates its activity, with BCKDH kinase (BCKDK) phosphorylating serine 293 of BCKDHA (a component of the E1 subunit), inhibiting the complex. Conversely, protein phosphatase 2Cm (PP2Cm) removes the phosphate, activating the BCKDH complex.
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Chronic regulation involves transcriptional control of gene expression. Krȕppel-like factor 15 (KLF15) activates genes involved in BCAA catabolism in cardiac muscle, including BCAT2, BCKDHA, BCKDHB, DBT, and PP2Cm. Peroxisome proliferator-activated receptor (PPAR) γ, a transcription factor, regulates BCAA metabolism in adipose tissue, increasing the expression of genes like BCAT2, BCKDHA, BCKDHB, DBT, and DLD upon treatment with thiazolidinediones (TZDs).
Role of BCAA Catabolism in Cellular Physiology
Skeletal Muscle and Liver
Skeletal muscle exhibits the highest BCAT and BCKDH activity, making it a major site for BCAA catabolism. Exercise increases BCAA catabolism in skeletal muscle, providing energy via mitochondrial oxidative phosphorylation. Skeletal muscle catabolizes BCAAs and supplies intermediates like BCKA to other tissues. The liver, with low BCATs and high BCKDH expression, utilizes BCKAs from skeletal muscle for ATP production and lipid synthesis. BCKAs from leucine and isoleucine can generate glucose (gluconeogenesis) and ketone bodies based on metabolic needs.
Adipose Tissues
Adipose tissue plays a critical role in BCAA catabolism, as evidenced by increased plasma BCAA levels in BCATm knockout mice. Wild-type adipose tissue transplantation reduces plasma BCAA levels, indicating its importance in systemic BCAA homeostasis. Brown adipose tissue (BAT) utilizes BCAA to control adaptive thermogenesis in response to cold exposure, with SLC25A44 being essential for BCAA catabolism in BAT. BCAA catabolism in BAT is crucial for thermogenic capacity, BCAA homeostasis, and energy expenditure.
Brain
BCAAs readily cross the blood-brain barrier (BBB) via LAT1/4F2hc and other L-type carriers. In the brain, they participate in glutamate metabolism, protein synthesis, and energy generation. Approximately one-third of glutamate in the brain contains nitrogen from BCAAs, highlighting their importance in maintaining neuronal glutamate levels. BCAAs are also essential for generating gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter.
Systemic Control of BCAA Catabolism
Systemic BCAA catabolism occurs in various tissues, including skeletal muscle, BAT, kidney, liver, heart, and pancreas. Insulin or BCKDH activation increases BCAA catabolism in skeletal muscle in healthy rodents. However, in insulin-resistant states, BCAA catabolism is blocked in adipose tissue and the liver, shifting to cardiac and skeletal muscle, resulting in BCAA dysmetabolism.
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Diseases Associated with BCAA Catabolism
Maple Syrup Urine Disease (MSUD)
Maple syrup urine disease (MSUD) is an autosomal recessive genetic disorder caused by mutations in genes for the BCKDH complex, leading to elevated plasma levels of BCAA and BCKA.
Hyperammonemia and Liver Cirrhosis
In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, BCAA catabolism is activated, leading to decreased BCAA concentrations. BCAAs are recommended to improve mental functions, protein balance, and muscle performance in these conditions. However, clinical trials have not demonstrated significant benefits of BCAA-containing supplements.
In hyperammonemic conditions, enhanced glutamine availability and decreased BCAA levels facilitate the amination of branched-chain keto acids (BCKAs; α-ketoisocaproate, α-keto-β-methylvalerate, and α-ketoisovalerate) to the corresponding BCAAs, and that BCKA supplementation may offer advantages over BCAAs. Studies examining the effects of ketoanalogues of amino acids have provided proof that subjects with hyperammonemia can effectively synthesize BCAAs from BCKAs. Unfortunately, the benefits of BCKA administration have not been clearly confirmed. The shortcoming of most reports is the use of mixtures intended for patients with renal insufficiency, which might be detrimental for patients with liver injury. It is concluded that (i) BCKA administration may decrease ammonia production, attenuate cataplerosis, correct amino acid imbalance, and improve protein balance and (ii) studies specifically investigating the effects of BCKA, without the interference of other ketoanalogues, are needed to complete the information essential for decisions regarding their suitability in hyperammonemic conditions.
High levels of ammonia increase the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine), resulting in decreased BCAA levels in liver cirrhosis and UCDs. Due to their positive influence on protein balance and the detrimental role of decreased BCAA levels in the pathogenesis of hepatic encephalopathy, BCAAs have been recommended for patients with liver cirrhosis for almost 50 years. Unfortunately, the results of clinical trials do not strongly support the theory that BCAA-containing supplements have beneficial effects. Increased ammonia production and BCAA catabolism due to intensive exercise were the rationale for recommending BCAA-enriched supplements for athletes. Even in these cases, the benefits of BCAA-enriched supplements have not been as great as expected. It has been suggested that the positive effects of BCAA mixtures are blunted by their increased use in the BCAA aminotransferase reaction to form glutamate, as a pivotal step in ammonia detoxification to glutamine (GLN), in the muscles. Adverse consequences include the drain of α-ketoglutarate (α-KG) from the tricarboxylic acid (TCA) cycle (cataplerosis) and an increased influx of GLN to the visceral tissues, where it is catabolized into ammonia.
Branched-Chain Amino Acids (BCAAs) and BCAA Supplementation
BCAA supplements have been shown to build muscle, decrease muscle fatigue, and alleviate muscle soreness. In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) is activated and BCAA concentrations decrease. In these conditions, BCAAs are recommended to improve mental functions, protein balance, and muscle performance. However, clinical trials have not demonstrated significant benefits of BCAA-containing supplements.
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BCAAs are essential nutrients including leucine, isoleucine, and valine. They're found in meat, dairy, and legumes. BCAAs stimulate the building of protein in muscle and possibly reduce muscle breakdown. The "Branched-chain" refers to the chemical structure of these amino acids. Supplementing with BCAAs may decrease muscle soreness by reducing damage in exercised muscles.
BCAAs are used for reduced brain function in people with advanced liver disease and for a movement disorder often caused by antipsychotic drugs. They are also commonly used to improve athletic performance, prevent fatigue, reduce muscle breakdown, and other purposes, but there isn't enough reliable information to support these other uses.
Uses & Effectiveness
Taking BCAAs by mouth seems to improve liver function in people with poor brain function caused by liver disease. Taking BCAAs by mouth seems to reduce symptoms of this condition in adults and children taking antipsychotic drugs. Taking up to 50 grams of BCAAs by mouth twice daily for up to one year does not seem to improve outcomes in people with liver cancer who have had surgery. Taking BCAAs by mouth is not beneficial in people with ALS. In fact, it might make lung function worse and increase the chance of death in people with this condition.
Side Effects and Precautions
BCAAs are likely safe when used in doses of 12 grams daily for up to 2 years. It might cause some side effects, such as fatigue and loss of coordination. BCAAs should be used cautiously before or during activities that require motor coordination, such as driving. BCAAs might also cause stomach problems, including nausea, diarrhea, and bloating.
BCAAs are likely safe when taken in food amounts. They are possibly safe when taken by children in larger doses for up to 6 months. BCAA supplements have been linked with lung failure and higher death rates when used in patients with ALS. If you have ALS, do not use BCAA supplements until more is known. People with this condition can experience seizures and severe delays in mental and physical development when BCAAs are consumed. Don't use BCAAs if you have this condition. BCAA supplements might affect blood sugar levels. Watch for signs of low or high blood sugar and monitor your blood sugar carefully if you have diabetes and take BCAA supplements. BCAA supplements might affect blood sugar levels, and this might interfere with blood sugar control during and after surgery. Stop using BCAA supplements at least 2 weeks before a scheduled surgery.
Interactions
BCAA supplements can decrease how much levodopa is absorbed by the intestines or brain. By decreasing levodopa absorption, BCAAs can decrease the effects of levodopa. BCAA supplements might lower blood sugar levels. Taking BCAAs along with diabetes medications might cause blood sugar to drop too low. Monitor your blood sugar closely.
Dosing
BCAAs are important nutrients found in protein sources such as meat, dairy, and legumes. It's estimated that adults should consume about 68 mg/kg daily (leucine 34 mg/kg, isoleucine 15 mg/kg, valine 19 mg/kg). But other estimates suggest that adults might actually need 144 mg/kg daily. Recommended amounts for children depend on age. Speak with a healthcare provider to find out what dose might be best for a specific condition.
Branched-Chain Keto Acids (BCKAs)
The activity of BCAA aminotransferase, which enables the mutual conversion of BCAAs and BCKAs, is low in the liver and high in muscles. Therefore, most of the exogenous BCAAs (if they are not used for protein synthesis) are converted to the BCKAs in the muscles. The amino group of the BCAA is transferred to α-KG to form glutamate, which then acts as a source of an amino group to form alanine from pyruvate or as a substrate for ammonia detoxification to GLN. Since the activity of BCKA dehydrogenase, which catalyzes the second and irreversible step in the oxidation of BCAAs, is low in the skeletal muscles, most of the BCKAs are released together with GLN and alanine from the muscles into the blood
Due to the equilibrium nature of BCAA aminotransferase, the direction of the net flux of BCAA transamination is determined by the availability of the donors and acceptors of nitrogen. Hence, BCKA amination into BCAAs should be facilitated by a decreased BCAA and increased GLN availability, as occurs in liver cirrhosis, UCDs, and intensive exercise. A study that used isolated perfused livers demonstrated that the decreased delivery of GLN to hepatic tissue decreased the synthesis of BCAAs from BCKAs. A high efficiency of amination of BCKA in subjects with impaired liver function was demonstrated in rat models of severe liver injury and portal-systemic shunting by the increased utilization of labeled KIC for the synthesis of proteins (which indicates previous KIC conversion to leucine) in various organs, including the muscles. In the liver, however, KIC utilization for protein synthesis was unaffected or slightly reduced
Studies have shown that the exogenous load of BCKAs can shift the BCAA aminotransferase reaction towards BCAA production in several tissues, including the heart, brain, gut, kidneys, liver, and even the skeletal muscle. However, which tissue plays the main role in the amination of exogenous BCKAs is not clear. The route of BCKA administration might have significant influence. After oral consumption, enterocytes and the liver, in which GLN is catabolized and glutamate concentrations are nearly three times higher than in the muscles, might play a dominant role in the conversion of BCKAs to BCAAs. Abumrad et al. [45] found that 23% of KIC administered into the guts of postabsorptive dogs entered the bloodstream as leucine. The hepatic uptake of KIC was equivalent to 35% of the administered load, and of that, one-third was transaminated into leucine and two-thirds were converted into ketone bodies. Therefore, it may be supposed that most of the BCKAs, which were not converted into BCAAs in the gut and appeared in the portal blood, were oxidized in the liver due to its high BCKA dehydrogenase activity. Nevertheless, Khatra et al. [46] showed that, in patients with alcoholic cirrhosis, there was reduced activity of the hepatic BCKA dehydrogenase to 20% of normal, suggesting that this reduction may enhance the efficiency of oral BCKAs as substitutes for BCAAs. The parenteral administration of BCKAs should increase the role of tissues other than the liver and intestine in BCKA amination into BCAAs. The finding in favor of parenteral administration is the higher BCAA levels after BCKA infusion than after oral gavage, as observed by Okita et al. [47] in carbon tetrachloride-treated rats.
The replacement of BCAAs with BCKAs should decrease ammonia production due to a decreased nitrogen load and by the diversion of glutamate from the glutamate dehydrogenase reaction, in which ammonia is liberated, to synthesize BCAAs from BCKAs
The formation of α-KG from glutamate during the amination of BCKAs attenuates the drain of α-KG from the TCA cycle (cataplerosis), activated by the detoxification of ammonia into GLN in the muscles. BCKAs, which are not aminated to a corresponding BCAA, are catabolized. The catabolism of KIC leads to acetyl-CoA and acetoacetate formation (KIC is ketogenic); KIV is catabolized into succinyl-CoA (KIV is glucogenic), and KMV, to acetyl-CoA and succinyl-CoA (KMV is both glycogenic and ketogenic). Therefore, intermediates of KIV and KMV catabolism can enter the TCA cycle and act as anaplerotic substances, but not KIC metabolites.
Subjects with liver cirrhosis usually have a decreased ratio between BCAA concentrations and aromatic amino acid (AAA; tyrosine, phenylalanine, and tryptophan) concentrations, which plays a role in the pathogenesis of hepatic encephalopathy. Unfortunately, since the capacity of the body for BCKA decarboxylation is higher than that for amination, a high portion of exogenous BCKAs are catabolized. Schauder et al. [48] postulated that if BCKA-containing supplements were given to increase low BCAA concentrations, the dose would need to be significantly higher than that for BCAA-containing supplements. Therefore, in most conditions, BCKAs should not be considered as substances for separate use but rather as substances that suitably replace a part of the BCAA.
Significant numbers of data demonstrate the nitrogen-sparing effects of BCKAs. The BCKAs improved protein balance in isolated rat muscles, parenterally fed rats, fasting obese men, and patients undergoing major abdominal surgery and with Duchenne muscular dystrophy [36,49,50,51,52]. The effects can be mediated by the BCAAs-particularly leucine, which stimulates protein synthesis through the PI3K/Akt/mTOR signaling pathway [50]-and by ketone bodies generated in the metabolism of KIC and KMV [53]. A role may also be played by β-hydroxy-β-methylbutyrate (HMB), which is synthesized from KIC in the liver, decreases the activity of the ubiquitin-proteasome proteolytic pathway, and exerts protein anabolic effects in the muscles [54].
Although there is a good theoretical basis for recommending BCKAs for the treatment of patients with liver disease, the number of reports is very small and most are dated to the last century (Table 1). Nevertheless, these studies have provided proof that subjects with liver disease can effectively synthesize amino acids from their ketoanalogues [9,47,55]. Some studies have reported beneficial effects on the signs of hepatic encephalopathy [9,55].