Effects of branched-chain amino acids on muscles under hyperammonemic conditions

Abstract

The aim was to determine the effects of enhanced availability of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) on ammonia detoxification to glutamine (GLN) and protein metabolism in two types of skeletal muscle under hyperammonemic conditions. Isolated soleus (SOL, slow-twitch) and extensor digitorum longus (EDL, fast-twitch) muscles from the left leg of white rats were incubated in a medium with 1 mM ammonia (NH3 group), BCAAs at four times the concentration of the controls (BCAA group) or high levels of both ammonia and BCAA (NH3 + BCAA group). The muscles from the right leg were incubated in basal medium and served as paired controls. L-[1-C]leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. We observed decreased protein synthesis and glutamate and α-ketoglutarate (α-KG) levels and increased leucine oxidation, GLN levels, and GLN release into medium in muscles in NH3 group. Increased leucine oxidation, release of branched-chain keto acids and GLN into incubation medium, and protein synthesis in EDL were observed in muscles in the BCAA group. The addition of BCAAs to medium eliminated the adverse effects of ammonia on protein synthesis and adjusted the decrease in α-KG found in the NH3 group. We conclude that (i) high levels of ammonia impair protein synthesis, activate BCAA catabolism, enhance GLN synthesis, and decrease glutamate and α-KG levels and (ii) increased BCAA availability enhances GLN release from muscles and attenuates the adverse effects of ammonia on protein synthesis and decrease in α-KG.

Muscle wasting and branched‐chain amino acid, alpha‐ketoglutarate, and ATP depletion in a rat model of liver cirrhosis

“…The alterations indicate enhanced synthesis of GLN from GLU and the shift of GLU metabolism from its use as a donor of nitrogen to pyruvate for synthesis of ALA to GLN synthesis. The BCAAs decrease due to their use as donors of nitrogen to α‐KG for synthesis of GLU, which is a direct substrate for ammonia detoxification to GLN …”

“…The BCAAs decrease due to their use as donors of nitrogen to α-KG for synthesis of GLU, which is a direct substrate for ammonia detoxification to GLN. 12,13 Unfortunately, the number of studies which refer to amino acid changes in the muscles due to cirrhosis is limited and most of the data are older. A marked decrease in the BCAA in muscles in patients with cirrhosis was reported by Iob et al 32 Plauth et al 33 reported decreased levels of VAL and ILE, and unaltered concentration of LEU, in quadriceps femoris muscle.…”

“…Undoubtedly, maldigestion and malabsorption of food, the inhibitory effect of ammonia on protein synthesis and compromised gut barrier function resulting in bacterial infections all play a role . Several studies have shown that ammonia increases catabolism of branched‐chain amino acids (BCAAs; valine, leucine and isoleucine) in muscles and decreases their level in the blood . It has been postulated that enhanced ammonia detoxification to glutamine (GLN) may increase the drain of α‐ketoglutarate (α‐KG) from the tricarboxylic acid (TCA) cycle (cataplerosis) resulting in mitochondrial dysfunction and decreased ATP production …”

Branched-Chain Amino Acids and Branched-Chain Keto Acids in Hyperammonemic States: Metabolism and as Supplements

“…Several studies have demonstrated that high levels of ammonia increase the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) [ 4 , 5 , 6 , 7 ], resulting in decreased BCAA levels in liver cirrhosis [ 8 , 9 , 10 , 11 ] and UCDs [ 12 , 13 ]. 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 [ 8 ].…”

The Effect of Beta-Alanine versus Alkaline Agent Supplementation Combined with Branched-Chain Amino Acids and Creatine Malate in Highly-Trained Sprinters and Endurance Athletes: A Randomized Double-Blind Crossover Study

“…BCAAs can significantly affect the stimulation of the mammalian target of the rapamycin (mTOR) kinase pathway and thus stimulate the synthesis of muscle proteins, as well as have anti-catabolic activity, related to inhibition of muscle protein proteolysis [1,2,3]. The above mechanisms may explain the observed effect of BCAA supply on the exercise-induced muscle damage, pain, fatigue or injury reduction, and the acceleration of fat-free mass or strength recovery [1,2,4,5].…”