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Ethanol sensitizes skeletal muscle to ammonia-induced molecular perturbations.
Kant, Sashi; Davuluri, Gangarao; Alchirazi, Khaled A; Welch, Nicole; Heit, Claire; Kumar, Avinash; Gangadhariah, Mahesha; Kim, Adam; McMullen, Megan R; Willard, Belinda; Luse, Donal S; Nagy, Laura E; Vasiliou, Vasilis; Marini, Anna Maria; Weiner, I David; Dasarathy, Srinivasan.
Afiliação
  • Kant S; From the Departments of Inflammation and Immunity.
  • Davuluri G; From the Departments of Inflammation and Immunity.
  • Alchirazi KA; From the Departments of Inflammation and Immunity.
  • Welch N; From the Departments of Inflammation and Immunity.
  • Heit C; the Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
  • Kumar A; From the Departments of Inflammation and Immunity.
  • Gangadhariah M; From the Departments of Inflammation and Immunity.
  • Kim A; From the Departments of Inflammation and Immunity.
  • McMullen MR; From the Departments of Inflammation and Immunity.
  • Willard B; Metabolomic and Proteomics Core, Cleveland Clinic, Cleveland, Ohio 44195.
  • Luse DS; Cardiovascular and Metabolic Sciences, and.
  • Nagy LE; From the Departments of Inflammation and Immunity.
  • Vasiliou V; the Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut 06510.
  • Marini AM; the Biology of Membrane Transport Laboratory, Department of Molecular Biology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles CP300, 6041 Gosselies, Belgium.
  • Weiner ID; the Division of Nephrology, Hypertension, and Renal Transplantation, Department of Medicine, School of Medicine, University of Florida, Gainesville, Florida 32610, and.
  • Dasarathy S; the Nephrology and Hypertension Section, North Florida/South Georgia Veterans Health System, Gainesville, Florida 32608.
J Biol Chem ; 294(18): 7231-7244, 2019 05 03.
Article em En | MEDLINE | ID: mdl-30872403
Ethanol causes dysregulated muscle protein homeostasis while simultaneously causing hepatocyte injury. Because hepatocytes are the primary site for physiological disposal of ammonia, a cytotoxic cellular metabolite generated during a number of metabolic processes, we determined whether hyperammonemia aggravates ethanol-induced muscle loss. Differentiated murine C2C12 myotubes, skeletal muscle from pair-fed or ethanol-treated mice, and human patients with alcoholic cirrhosis and healthy controls were used to quantify protein synthesis, mammalian target of rapamycin complex 1 (mTORC1) signaling, and autophagy markers. Alcohol-metabolizing enzyme expression and activity in mouse muscle and myotubes and ureagenesis in hepatocytes were quantified. Expression and regulation of the ammonia transporters, RhBG and RhCG, were quantified by real-time PCR, immunoblots, reporter assays, biotin-tagged promoter pulldown with proteomics, and loss-of-function studies. Alcohol and aldehyde dehydrogenases were expressed and active in myotubes. Ethanol exposure impaired hepatocyte ureagenesis, induced muscle RhBG expression, and elevated muscle ammonia concentrations. Simultaneous ethanol and ammonia treatment impaired protein synthesis and mTORC1 signaling and increased autophagy with a consequent decreased myotube diameter to a greater extent than either treatment alone. Ethanol treatment and withdrawal followed by ammonia exposure resulted in greater impairment in muscle signaling and protein synthesis than ammonia treatment in ethanol-naive myotubes. Of the three transcription factors that were bound to the RhBG promoter in response to ethanol and ammonia, DR1/NC2 indirectly regulated transcription of RhBG during ethanol and ammonia treatment. Direct effects of ethanol were synergistic with increased ammonia uptake in causing dysregulated skeletal muscle proteostasis and signaling perturbations with a more severe sarcopenic phenotype.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Músculo Esquelético / Etanol / Amônia Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Músculo Esquelético / Etanol / Amônia Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article