{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T07:46:53Z","timestamp":1792482413164,"version":"4.5.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T00:00:00Z","timestamp":1493337600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T00:00:00Z","timestamp":1493337600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>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\u2010lowering 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\u2010hour exposure to 10 mM ammonium acetate were complemented by<jats:italic toggle=\"yes\">in vivo<\/jats:italic>studies in the hyperammonemic portacaval anastomosis rat and sham\u2010operated, pair\u2010fed Sprague\u2010Dawley rats treated with ammonia\u2010lowering therapy by<jats:sc>l<\/jats:sc>\u2010ornithine<jats:sc>l<\/jats:sc>\u2010aspartate 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\u2010hour and 48\u2010hour withdrawal of ammonium acetate. Consistently, 4 weeks of ammonia\u2010lowering 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\u2010lowering therapy. Despite significant improvement, molecular and functional readouts were not completely reversed by ammonia\u2010lowering measures.<jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Ammonia\u2010lowering therapy results in improvement in skeletal muscle phenotype and function and molecular perturbations of hyperammonemia; these preclinical studies complement previous studies on ammonia\u2010induced skeletal muscle loss and lay the foundation for prolonged ammonia\u2010lowering therapy to reverse sarcopenia of cirrhosis. (H<jats:sc>epatology<\/jats:sc>2017;65:2045\u20102058).<\/jats:p>","DOI":"10.1002\/hep.29107","type":"journal-article","created":{"date-parts":[[2017,2,13]],"date-time":"2017-02-13T12:16:53Z","timestamp":1486988213000},"page":"2045-2058","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":222,"title":["Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis"],"prefix":"10.1097","volume":"65","author":[{"given":"Avinash","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Pathobiology,Cleveland Clinic,Cleveland,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangarao","family":"Davuluri","sequence":"additional","affiliation":[{"name":"Department of Pathobiology,Cleveland Clinic,Cleveland,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaella Nascimento e","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Pathobiology,Cleveland Clinic,Cleveland,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle P.K.J.","family":"Engelen","sequence":"additional","affiliation":[{"name":"Department of Kinesiology,University of Texas A&M,College Station,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrie A.M.","family":"Ten Have","sequence":"additional","affiliation":[{"name":"Department of Kinesiology,University of Texas A&M,College Station,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Prayson","sequence":"additional","affiliation":[{"name":"Department of Pathology,Cleveland Clinic,Cleveland,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolaas E.P.","family":"Deutz","sequence":"additional","affiliation":[{"name":"Department of Kinesiology,University of Texas A&M,College 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