Hyperammonemia and proteostasis in cirrhosis

Dasarathy, Srinivasan; Hatzoglou, Maria

doi:10.1097/mco.0000000000000426

Cited by 77 publications

(71 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In skeletal muscle, impairment of mTORC1 signaling during hyperammonemia can occur as consequence of: (a) elevated levels of myostatin; (b) increased phosphorylation and activation of either the amino acid deficiency sensor general control non‐depressible 2 kinase (GCN2) or the eukaryotic initiation factor 2 alpha (eIF2α), an essential factor for protein synthesis; and (c) an impaired production of energy with excessive cataplerosis of α‐KG.…”

Section: Ammonia and Autophagymentioning

confidence: 99%

Ammonia and autophagy: An emerging relationship with implications for disorders with hyperammonemia

Soria

Brunetti‐Pierri

2019

J of Inher Metab Disea

View full text Add to dashboard Cite

Macro)autophagy/autophagy is a highly regulated lysosomal degradative process by which cells recycle their own nutrients, such as amino acids and other metabolites, to be reused in different biosynthetic pathways. Ammonia is a diffusible compound generated daily from catabolism of nitrogen-containing molecules and from gastrointestinal microbiome. Ammonia homeostasis is tightly controlled in humans and ammonia is efficiently converted by the healthy liver into non-toxic urea (through ureagenesis) and glutamine (through glutamine synthetase). Impaired ammonia detoxification leads to systemic hyperammonemia, a life-threatening condition resulting in detrimental effects on central nervous system. Here, we review current understanding on the role of ammonia in modulation of autophagy and the potential implications in the pathogenesis and treatment of disorders with hyperammonemia.

show abstract

Section: Ammonia and Autophagymentioning

confidence: 99%

Ammonia and autophagy: An emerging relationship with implications for disorders with hyperammonemia

Soria

Brunetti‐Pierri

2019

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

“…The effects and underlying mechanism of ammonia-induced fatigue remain controversial, especially with regard to peripheral effects. Recent studies in cirrhosis patients have revealed that hyperammonaemia impairs protein synthesis and induces mitochondrial dysfunction in skeletal muscle [11][12][13] . However, whether hyperammonaemia disturbs whole-body energy metabolism has not been examined.…”

Section: Discussionmentioning

confidence: 99%

“…For example, it has been reported that ammonia activates phosphofructokinase and inhibits the oxidation of pyruvate to acetyl coenzyme A, which hinders the supply of adenosine triphosphate to skeletal muscle 5 . In addition, studies in cirrhosis patients have revealed that hyperammonaemia impairs protein synthesis and increases autophagy 11,12 , induces mitochondrial dysfunction due to cataplerosis of α-ketoglutarate, and lowers adenosine triphosphate content in muscle cells, which may contribute to skeletal muscle fatigue 12,13 . Since plasma concentrations of ammonia during exercise often reach or exceed those found in liver disease patients 14,15 , these toxic effects may also be transiently induced during exercise, resulting in muscle fatigue.…”

mentioning

confidence: 99%

Involvement of ammonia metabolism in the improvement of endurance performance by tea catechins in mice

Chen

Minegishi

Hasumura

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Blood ammonia increases during exercise, and it has been suggested that this increase is both a central and peripheral fatigue factor. Although green tea catechins (Gtcs) are known to improve exercise endurance by enhancing lipid metabolism in skeletal muscle, little is known about the relationship between ammonia metabolism and the endurance-improving effect of GTCs. Here, we examined how ammonia affects endurance capacity and how GTCs affect ammonia metabolism in vivo in mice and how GTCs affect mouse skeletal muscle and liver in vitro. in mice, blood ammonia concentration was significantly negatively correlated with exercise endurance capacity, and hyperammonaemia was found to decrease whole-body fat expenditure and fatty acid oxidation-related gene expression in skeletal muscle. Repeated ingestion of Gtcs combined with regular exercise training improved endurance capacity and the expression of urea cycle-related genes in liver. In C2C12 myotubes, hyperammonaemia suppressed mitochondrial respiration; however, pre-incubation with Gtcs rescued this suppression. together, our results demonstrate that hyperammonaemia decreases both mitochondrial respiration in myotubes and whole-body aerobic metabolism. thus, Gtc-mediated increases in ammonia metabolism in liver and resistance to ammonia-induced suppression of mitochondrial respiration in skeletal muscle may underlie the endurance-improving effect of GTCs.Exercise-induced fatigue is an important concern in sports, exercise, and rehabilitation because it is unavoidable and its early onset can hinder people from accomplishing their goals. Exercise-induced fatigue is commonly assessed as endurance capacity, based on the assumption that time to exhaustion correlates with the force generating capacity of muscle, and it is attributed to multiple factors, including the accumulation of fatigue metabolites, depletion of muscle glycogen, decrease of muscle pH, increase of muscle temperature, and production of inflammatory cytokines 1,2 . The complexity of the mechanisms underlying the development of exercise-induced fatigue makes it difficult to find approaches to mitigate its effects.Ammonia is a ubiquitous waste product of the metabolism of nitrogenous compounds, including amino acids and proteins, and has long been considered both a central and peripheral factor in the onset of exercise-induced fatigue 3 . During exercise, ammonia is produced via deamination of adenosine monophosphate 4,5 and the breakdown of branched-chain amino acids in skeletal muscle 6,7 . The production of ammonia increases with increasing intensity and duration of exercise [8][9][10] . Although the ammonia fatigue theory is not new, there remains a lack of conclusive evidence proving the roles of ammonia in the onset and development of exercise-induced fatigue.Recent evidence from exercise and disease studies has provided new insights into the role of ammonia during exercise. For example, it has been reported that ammonia activates phosphofructokinase and inhibits the oxidation of pyruvate to acety...

show abstract

“…Further, in both clinical observation and mammalian models, there is a direct link between hyperammonemia and increased myostatin expression (Dasarathy, Dodig, Muc, Kalhan, & McCullough, 2004;Kumar et al, 2017;Qiu et al, 2013Qiu et al, , 2012Tsien et al, 2015). Myostatin, a well-known negative regulator of muscle synthesis, plays a pivotal role in degenerative decline in muscle; therefore, the myostatin regulatory pathway is an important target for developing therapies for sarcopenia associated with cirrhosis (Dasarathy, 2012;Dasarathy & Hatzoglou, 2018;Dasarathy et al, 2017;García et al, 2010;Han & Mitch, 2011).…”

Section: Ammonia Toxicitymentioning

confidence: 99%

Differential ammonia metabolism and toxicity between avian and mammalian species, and effect of ammonia on skeletal muscle: A comparative review

Stern

Mozdziak

2019

Animal Physiology Nutrition

View full text Add to dashboard Cite

Comparative aspects of ammonia toxicity, specific to liver and skeletal muscle and skeletal muscle metabolism between avian and mammalian species are discussed in the context of models for liver disease and subsequent skeletal muscle wasting. The purpose of this review is to present species differences in ammonia metabolism and to specifically highlight observed differences in skeletal muscle response to excess ammonia in avian species. Ammonia, which is produced during protein catabolism and is an essential component of nucleic acid and protein biosynthesis, is detoxified mainly in the liver. While the liver is consistent as the main organ responsible for ammonia detoxification, there are evolutionary differences in ammonia metabolism and nitrogen excretory products between avian and mammalian species. In patients with liver disease and all mammalian models, inadequate ammonia detoxification and successive increased circulating ammonia concentration, termed hyperammonemia, leads to severe skeletal muscle atrophy, increased apoptosis and reduced protein synthesis, altogether having deleterious effects on muscle size and strength. Previously, an avian embryonic model, designed to determine the effects of increased circulating ammonia on muscle development, revealed that ammonia elicits a positive myogenic response. Specifically, induced hyperammonemia in avian embryos resulted in a reduction in myostatin, a well‐known inhibitor of muscle growth, expression, whereas myostatin expression is significantly increased in mammalian models of hyperammonemia. These interesting findings imply that species differences in ammonia metabolism allow avians to utilize ammonia for growth. Understanding the intrinsic physiological mechanisms that allow for ammonia to be utilized for growth has potential to reveal novel approaches to muscle growth in avian species and will provide new targets for preventing muscle degeneration in mammalian species.

show abstract

Hyperammonemia and proteostasis in cirrhosis

Abstract: Signaling via myostatin and eIF2α phosphorylation causes decreases in protein synthesis and mTORC1 activity with a parallel mitochondrial dysfunction and increased autophagy contributing to proteostasis perturbations during skeletal muscle hyperammonemia of liver disease.

Cited by 77 publications

References 40 publications

Ammonia and autophagy: An emerging relationship with implications for disorders with hyperammonemia

Ammonia and autophagy: An emerging relationship with implications for disorders with hyperammonemia

Involvement of ammonia metabolism in the improvement of endurance performance by tea catechins in mice

Differential ammonia metabolism and toxicity between avian and mammalian species, and effect of ammonia on skeletal muscle: A comparative review

Contact Info

Product

Resources

About