Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 13;12(10):971.
doi: 10.3390/metabo12100971.

Muscle Amino Acid and Adenine Nucleotide Metabolism during Exercise and in Liver Cirrhosis: Speculations on How to Reduce the Harmful Effects of Ammonia

Milan Holeček  1
Affiliations
Review

Muscle Amino Acid and Adenine Nucleotide Metabolism during Exercise and in Liver Cirrhosis: Speculations on How to Reduce the Harmful Effects of Ammonia

Milan Holeček. Metabolites. .

Abstract

Studies from the last decades indicate that increased levels of ammonia contribute to muscle wasting in critically ill patients. The aim of the article is to examine the effects of two different causes of hyperammonemia-increased ATP degradation in muscles during strenuous exercise and impaired ammonia detoxification to urea due to liver cirrhosis. During exercise, glycolysis, citric acid cycle (CAC) activity, and ATP synthesis in muscles increase. In cirrhosis, due to insulin resistance and mitochondrial dysfunction, glycolysis, CAC activity, and ATP synthesis in muscles are impaired. Both during exercise and in liver cirrhosis, there is increased ammonia detoxification to glutamine (Glu + NH3 + ATP → Gln + ADP + Pi), increased drain of ketoglutarate (α-KG) from CAC for glutamate synthesis by α-KG-linked aminotransferases, glutamate, aspartate, and α-KG deficiency, increased oxidation of branched-chain amino acids (BCAA; valine, leucine, and isoleucine), and protein-energy wasting in muscles. It is concluded that ammonia can contribute to muscle wasting regardless of the cause of its increased levels and that similar strategies can be designed to increase muscle performance in athletes and reduce muscle loss in patients with hyperammonemia. The pros and cons of glutamate, α-KG, aspartate, BCAA, and branched-chain keto acid supplementation are discussed.

Keywords: branched-chain amino acids; glutamic acid; glutamine; hyperammonemia.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 4
Figure 4
Ammonia and amino acid metabolism in muscles during exercise. Ammonia synthesis increases due to the enhanced turnover of adenine nucleotides. The main pathway of ammonia detoxification in muscles is glutamine synthesis. Increased glycolysis and CAC activity are essential for an adequate supply of α-KG and subsequent glutamate and glutamine synthesis. ASCT1 (alanine, serine, cysteine, and threonine carrier 1); BCAA, branched-chain amino acids; BCA-CoA, branched-chain acyl-CoA; BCKA, branched-chain keto acids; CAC, citric acid cycle; FA, fatty acids; LAT1 (large neutral amino acid transporter 1); OA, oxaloacetate; X-ag (transporter for aspartate and glutamate).
Figure 1
Figure 1
Ammonia synthesis and detoxification to glutamine in muscles. 1, ATPase; 2, creatine kinase; 3, adenylate kinase (myokinase); 4, AMP deaminase; 5, glutamine synthetase; 6, BCAA aminotransferase; 7, BCKA dehydrogenase; 8, ALT; 9, AST; 10, adenylosuccinate synthetase; 11, adenylosuccinate lyase; 12, fumarase. BCAA, branched-chain amino acids; BCA-CoA, branched-chain acyl-CoA; CAC, citric acid cycle; Cr, creatine; CrP, creatine phosphate; IMP, inosine monophosphate; OA, oxaloacetate; Pi, inorganic phosphate.
Figure 2
Figure 2
Biochemical pathways and transporters involved in ammonia and amino acid metabolism in skeletal muscle in a physiological state at rest. 1, AMP deaminase; 2, glutamine synthetase; 3, BCAA aminotransferase; 4, BCKA dehydrogenase; 5, AST; 6, ALT; 7, pyruvate dehydrogenase; 8, pyruvate carboxylase. ASCT1 (alanine, serine, cysteine, and threonine carrier 1); BCAA, branched-chain amino acids; BCA-CoA, branched-chain acyl-CoA; BCKA, branched-chain keto acids; FA, fatty acids; LAT1, large neutral amino acid transporter 1; OA, oxaloacetate; X-ag, a transporter for aspartate and glutamate.
Figure 3
Figure 3
Compartmentation of ammonia and amino acid metabolism in muscles. 1, glutamine synthetase; 2, BCAA aminotransferase; 3, BCKA dehydrogenase; 4, ALT; 5, mitochondrial AST; 6, cytosolic AST; 7, malate dehydrogenase; 8, pyruvate dehydrogenase; 9, pyruvate carboxylase. AGC, aspartate-glutamate carrier; ASCT1 (alanine, serine, cysteine, and threonine carrier 1); BCAA, branched-chain amino acids; BCA-CoA, branched-chain acyl-CoA; BCKA, branched-chain keto acids; CAC, citric acid cycle; LAT1 (large neutral amino acid transporter 1); MKC, malate-ketoglutarate carrier; OA, oxaloacetate; PC, pyruvate carrier; PNC, purine nucleotide cycle; X-ag, a transporter for aspartate and glutamate.
Figure 5
Figure 5
Ammonia and amino acid metabolism in cirrhosis. Ammonia levels increase due to impaired urea synthesis in the liver, portal-systemic shunts, and increased glutamine catabolism in visceral organs.
Figure 6
Figure 6
Ammonia and amino acid metabolism in cirrhosis. Increased ammonia detoxification to glutamine in muscles results in BCAA deficiency, cataplerosis (drain of α-KG from CAC), and mitochondrial dysfunction. Due to the limited activation of glycolysis and mitochondrial dysfunction, the detoxification of ammonia is less efficient than during exercise. ASCT1 (alanine, serine, cysteine, and threonine carrier 1); BCAA, branched-chain amino acids; BCA-CoA, branched-chain acyl-CoA; BCKA, branched-chain keto acids; CAC, citric acid cycle; FA, fatty acids; LAT1 (large neutral amino acid transporter 1); OA, oxaloacetate; X-ag (transporter for aspartate and glutamate).
Figure 7
Figure 7
Supposed effects of BCKA supplementation on BCAA and ammonia synthesis. 1, BCAA aminotransferase; 2, glutamate dehydrogenase.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Walker V. Ammonia metabolism and hyperammonemic disorders. Adv. Clin. Chem. 2014;67:73–150. - PubMed
    1. Walker V. Severe hyperammonaemia in adults not explained by liver disease. Ann. Clin. Biochem. 2012;49:214–228. doi: 10.1258/acb.2011.011206. - DOI - PubMed
    1. Yao Z.P., Li Y., Liu Y., Wang H.L. Relationship between the incidence of non-hepatic hyperammonemia and the prognosis of patients in the intensive care unit. World J. Gastroenterol. 2020;26:7222–7231. doi: 10.3748/wjg.v26.i45.7222. - DOI - PMC - PubMed
    1. Balcerac A., Bihan K., Lebrun-Vignes B., Thabut D., Salem J.E., Weiss N. Drug-associated hyperammonaemia: A Bayesian analysis of the WHO Pharmacovigilance Database. Ann. Intensive Care. 2022;12:55. doi: 10.1186/s13613-022-01026-4. - DOI - PMC - PubMed
    1. McDaniel J., Davuluri G., Hill E.A., Moyer M., Runkana A., Prayson R., van Lunteren E., Dasarathy S. Hyperammonemia results in reduced muscle function independent of muscle mass. Am. J. Physiol. 2016;310:G163–G170. doi: 10.1152/ajpgi.00322.2015. - DOI - PMC - PubMed

Grants and funding