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Hyperammonemia and proteostasis in cirrhosis.
Srinivasan Dasarathy1, Maria Hatzoglou2
1Departments of Gastroenterology, Hepatology and Pathobiology, Liver Metabolism Research, Center for Human Nutrition, Cleveland Clinic Lerner College of Medicine, Lerner Research Institute, Cleveland Clinic.
Current Opinion in Clinical Nutrition and Metabolic Care
|October 17, 2017
Summary
Skeletal muscle loss in cirrhosis is linked to impaired protein balance. Ammonia buildup disrupts muscle protein synthesis and increases autophagy, contributing to sarcopenia in liver disease.
Area of Science:
- Biochemistry
- Cell Biology
- Gastroenterology
Background:
- Sarcopenia, or skeletal muscle loss, is a common and detrimental complication of cirrhosis.
- Proteostasis, the maintenance of protein homeostasis, is crucial for preserving muscle mass.
- Disordered skeletal muscle proteostasis is a key factor in the pathophysiology of liver disease.
Purpose of the Study:
- To review the mechanisms of disordered skeletal muscle proteostasis in the context of liver disease.
- To elucidate the role of ammonia and its downstream signaling in muscle wasting.
- To identify potential therapeutic targets for restoring muscle mass in cirrhosis.
Main Methods:
- Review of existing literature on skeletal muscle proteostasis and liver disease.
- Analysis of cellular signaling pathways affected by hyperammonemia.
- Examination of molecular mechanisms regulating protein synthesis and degradation.
Main Results:
- Hyperammonemia in skeletal muscle impairs protein synthesis and enhances autophagy.
- Key signaling pathways involved include myostatin upregulation and eIF2α phosphorylation, both reducing mTORC1 activity.
- Ammonia also induces mitochondrial dysfunction and bioenergetic deficits via cataplerosis of α-ketoglutarate.
Conclusions:
- Myostatin and eIF2α signaling disrupt muscle protein synthesis and mTORC1 activity.
- Mitochondrial dysfunction and increased autophagy contribute to proteostasis imbalance in cirrhotic muscle.
- Therapeutic strategies may involve ammonia reduction, targeting hyperammonemic stress response pathways, and amino acid level regulation.