title: Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis.
abstract: Sarcopenia or skeletal muscle loss is a frequent, potentially reversible complication in cirrhosis that adversely affects clinical outcomes. Hyperammonemia is a consistent abnormality in cirrhosis that results in impaired skeletal muscle protein synthesis and breakdown (proteostasis). Despite the availability of effective ammonia-lowering therapies, whether lowering ammonia restores proteostasis and increases muscle mass is unknown. Myotube diameter, protein synthesis, and molecular responses in C2C12 murine myotubes to withdrawal of ammonium acetate following 24-hour exposure to 10 mM ammonium acetate were complemented by in vivo studies in the hyperammonemic portacaval anastomosis rat and sham-operated, pair-fed Sprague-Dawley rats treated with ammonia-lowering therapy by l-ornithine l-aspartate and rifaximin orally for 4 weeks. We observed reduced myotube diameter, impaired protein synthesis, and increased autophagy flux in response to hyperammonemia, which were partially reversed following 24-hour and 48-hour withdrawal of ammonium acetate. Consistently, 4 weeks of ammonia-lowering therapy resulted in significant lowering of blood and skeletal muscle ammonia, increase in lean body mass, improved grip strength, higher skeletal muscle mass and diameter, and an increase in type 2 fibers in treated compared to untreated portacaval anastomosis rats. The increased skeletal muscle myostatin expression, reduced mammalian target of rapamycin complex 1 function, and hyperammonemic stress response including autophagy markers normally found in portacaval anastomosis rats were reversed by treatment with ammonia-lowering therapy. Despite significant improvement, molecular and functional readouts were not completely reversed by ammonia-lowering measures.
  
  
  
  Ammonia-lowering therapy results in improvement in skeletal muscle phenotype and function and molecular perturbations of hyperammonemia; these preclinical studies complement previous studies on ammonia-induced skeletal muscle loss and lay the foundation for prolonged ammonia-lowering therapy to reverse sarcopenia of cirrhosis. (Hepatology 2017;65:2045-2058).
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
authors.forename: Avinash
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
authors.forename: Gangarao
authors.initials: G
authors.lastname: Davuluri
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
authors.forename: Rafaella Nascimento E
authors.initials: RNE
authors.lastname: Silva
authors.affiliation: Department of Kinesiology, University of Texas A&M, College Station, TX.
authors.forename: Marielle P K J
authors.initials: MPKJ
authors.lastname: Engelen
authors.affiliation: Department of Kinesiology, University of Texas A&M, College Station, TX.
authors.forename: Gabrie A M
authors.initials: GAM
authors.lastname: Ten Have
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, OH.
authors.forename: Richard
authors.initials: R
authors.lastname: Prayson
authors.affiliation: Department of Kinesiology, University of Texas A&M, College Station, TX.
authors.forename: Nicolaas E P
authors.initials: NEP
authors.lastname: Deutz
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, OH.|Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Dasarathy
mesh_terms: D000641:Ammonia / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004195:Disease Models, Animal; D006706:Homeostasis / Q000502:physiology; D022124:Hyperammonemia / Q000150:complications*; D007274:Injections, Intraperitoneal; D008103:Liver Cirrhosis / Q000150:complications* / Q000473:pathology; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012294:Rifamycins / Q000494:pharmacology*; D000078262:Rifaximin; D055948:Sarcopenia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
chemical_list: D009124:Muscle Proteins; D012294:Rifamycins; D000641:Ammonia; D000078262:Rifaximin