ArticleAmerican journal of physiology. Endocrinology and metabolism2012
Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis.
Article in American journal of physiology. Endocrinology and metabolism, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
110 citing papers in PubMed, 2 syntheses or guidelines pooled it, 210 citations in OpenAlex.
- The effects of sarcopenia on the prognosis of patients with acute-on-chronic liver failure: a systematic review and meta-analysis.Frontiers in nutrition · 2025Pooled it
- Association between sarcopenia and hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: a systematic review and meta-analysis.Abdominal radiology (New York) · 2024Pooled it
- Trial
- Randomised clinical trial: effect of adding branched chain amino acids to exercise and standard-of-care on muscle mass in cirrhotic patients with sarcopenia.Hepatology international · 2022Trial
- Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis.Hepatology (Baltimore, Md.) · 2015Trial
- Revisiting gut microbiota-driven ammonia metabolism: from disease burden to physiological adaptation.Gut microbes · 2026Review
- Review
- Current management strategies for sarcopenia and frailty in cirrhosis: Missing link in transplant candidacy.World journal of hepatology · 2026Review
- Review
- Impact of myokines on chronic liver diseases: exploring the effects of metabolic dysfunction-associated steatotic liver disease (MASLD) on skeletal muscle. A narrative review.European journal of translational myology · 2025Article
- Voluntary Activity Wheel Running Improves Hyperammonaemia-Induced Skeletal Muscle Molecular and Metabolic Perturbations in Mice.Journal of cachexia, sarcopenia and muscle · 2025Article
- Chemotactic Zn micromotor for treatment of high blood ammonia-associated hepatic encephalopathy.Nature communications · 2025Article
- [Assessment and management of malnutrition in patients with cirrhosis combined with hepatic encephalopathy].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2025Review
- Attenuating hyperammonemia preserves protein synthesis and muscle mass via restoration of perturbed metabolic pathways in bile duct-ligated rats.Metabolic brain disease · 2025Article
- Hepatic encephalopathy treatment after transjugular intrahepatic portosystemic shunt: a new perspective on the gut microbiota.Frontiers in medicine · 2025Review
- Chronic polypharmacy, monotherapy, and deprescribing: Understanding complex effects on the hepatic proteome of aging mice.Aging cell · 2025Article
- Ultrasound-Defined Sarcopenia Independently Predicts Acute Decompensation in Advanced Chronic Liver Disease.Journal of cachexia, sarcopenia and muscle · 2024Article
- Frailty in liver transplantation: Exploring prescribing exercise as medicine to improve patient outcomes.Liver international : official journal of the International Association for the Study of the Liver · 2024Review
- Bibliometrics and knowledge mapping of the pathogenesis of hepatic encephalopathy in patients with liver cirrhosis.Heliyon · 2024Article
- Sirtuin 5 alleviates apoptosis and autophagy stimulated by ammonium chloride in bovine mammary epithelial cells.Experimental and therapeutic medicine · 2024Article
50 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
Abstract
Hyperammonemia and sarcopenia (loss of skeletal muscle) are consistent abnormalities in cirrhosis and portosystemic shunting. We have shown that muscle ubiquitin-proteasome components are not increased with hyperammonemia despite sarcopenia. This suggests that an alternative mechanism of proteolysis contributes to sarcopenia in cirrhosis. We hypothesized that autophagy could be this alternative pathway since we observed increases in classic autophagy markers, increased LC3 lipidation, beclin-1 expression, and p62 degradation in immunoblots of skeletal muscle protein in cirrhotic patients. We observed similar changes in these autophagy markers in the portacaval anastamosis (PCA) rat model. To determine the mechanistic relationship between hyperammonemia and autophagy, we exposed murine C(2)C(12) myotubes to ammonium acetate. Significant increases in LC3 lipidation, beclin-1 expression, and p62 degradation occurred by 1 h, whereas autophagy gene expression (LC3, Atg5, Atg7, beclin-1) increased at 24 h. C(2)C(12) cells stably expressing GFP-LC3 or GFP-mCherry-LC3 constructs showed increased formation of mature autophagosomes supported by electron microscopic studies. Hyperammonemia also increased autophagic flux in mice, as quantified by an in vivo autophagometer. Because hyperammonemia induces nitration of proteins in astrocytes, we quantified global muscle protein nitration in cirrhotic patients, in the PCA rat, and in C(2)C(12) cells treated with ammonium acetate. Increased protein nitration was observed in all of these systems. Furthermore, colocalization of nitrated proteins with GFP-LC3-positive puncta in hyperammonemic C(2)C(12) cells suggested that autophagy is involved in degradation of nitrated proteins. These observations show that increased skeletal muscle autophagy in cirrhosis is mediated by hyperammonemia and may contribute to sarcopenia of cirrhosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.