Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis
| Autor: | Mariëlle P.K.J. Engelen, Gabrie A. M. Ten Have, Gangarao Davuluri, Richard A. Prayson, Srinivasan Dasarathy, Rafaella Nascimento e Silva, Nicolaas E. P. Deutz, Avinash Kumar |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Liver Cirrhosis Male medicine.medical_specialty Sarcopenia Muscle Proteins Myostatin Rifaximin Article Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Ammonia Internal medicine medicine Autophagy Animals Homeostasis Hyperammonemia Muscle Skeletal Analysis of Variance Hepatology biology Myogenesis business.industry Portacaval anastomosis Skeletal muscle Recovery of Function medicine.disease Rifamycins Rats Disease Models Animal 030104 developmental biology Proteostasis medicine.anatomical_structure Endocrinology biology.protein 030211 gastroenterology & hepatology business Injections Intraperitoneal |
| Zdroj: | Hepatology (Baltimore, Md.). 65(6) |
| ISSN: | 1527-3350 |
| Popis: | 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. Conclusion 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). |
| Databáze: | OpenAIRE |
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