title: Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB-mediated mechanism.
abstract: Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea. We observed elevated levels of ammonia in both plasma samples and skeletal muscle biopsies from cirrhotic patients compared with healthy controls. Furthermore, skeletal muscle from cirrhotics had increased expression of myostatin, a known inhibitor of skeletal muscle accretion and growth. In vivo studies in mice showed that hyperammonemia reduced muscle mass and strength and increased myostatin expression in wild-type compared with postdevelopmental myostatin knockout mice. We postulated that hyperammonemia is an underlying link between hepatic dysfunction in cirrhosis and skeletal muscle loss. Therefore, murine C2C12 myotubes were treated with ammonium acetate resulting in intracellular concentrations similar to those in cirrhotic muscle. In this system, we demonstrate that hyperammonemia stimulated myostatin expression in a NF-κB-dependent manner. This finding was also observed in primary murine muscle cell cultures. Hyperammonemia triggered activation of IκB kinase, NF-κB nuclear translocation, binding of the NF-κB p65 subunit to specific sites within the myostatin promoter, and stimulation of myostatin gene transcription. Pharmacologic inhibition or gene silencing of NF-κB abolished myostatin up-regulation under conditions of hyperammonemia. Our work provides unique insights into hyperammonemia-induced myostatin expression and suggests a mechanism by which sarcopenia develops in cirrhotic patients.
authors.affiliation: Departments of Pathobiology and Molecular Cardiology, Lerner Research Institute, Department of Gastroenterology, Digestive Disease Institute, and Departments of Hepatobiliary and Transplant Surgery and Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Jia
authors.initials: J
authors.lastname: Qiu
authors.forename: Samjhana
authors.initials: S
authors.lastname: Thapaliya
authors.forename: Ashok
authors.initials: A
authors.lastname: Runkana
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tsien
authors.forename: Maradumane L
authors.initials: ML
authors.lastname: Mohan
authors.forename: Arvind
authors.initials: A
authors.lastname: Narayanan
authors.forename: Bijan
authors.initials: B
authors.lastname: Eghtesad
authors.forename: Paul E
authors.initials: PE
authors.lastname: Mozdziak
authors.forename: Christine
authors.initials: C
authors.lastname: McDonald
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.forename: Stephen
authors.initials: S
authors.lastname: Welle
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Dasarathy
mesh_terms: D000085:Acetates; D000818:Animals; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D022124:Hyperammonemia / Q000209:etiology / Q000503:physiopathology*; D015151:Immunoblotting; D008103:Liver Cirrhosis / Q000150:complications*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000085:Acetates; D055435:Myostatin; D016328:NF-kappa B; C018824:ammonium acetate
keywords: portosystemic shunting; signaling