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Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis.
Tsien, Cynthia; Davuluri, Gangarao; Singh, Dharmvir; Allawy, Allawy; Ten Have, Gabriella A M; Thapaliya, Samjhana; Schulze, John M; Barnes, David; McCullough, Arthur J; Engelen, Marielle P K J; Deutz, Nicolaas E P; Dasarathy, Srinivasan.
Afiliação
  • Tsien C; Departments of Gastroenterology, Toronto General Hospital, Toronto, Canada.
  • Davuluri G; Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
  • Singh D; Departments of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH.
  • Allawy A; Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
  • Ten Have GA; Department of Kinesiology, Texas A&M University, College Station, TX.
  • Thapaliya S; Departments of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH.
  • Schulze JM; Molecular Structure Facility, University of California, Davis, CA.
  • Barnes D; Departments of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH.
  • McCullough AJ; Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
  • Engelen MP; Department of Kinesiology, Texas A&M University, College Station, TX.
  • Deutz NE; Department of Kinesiology, Texas A&M University, College Station, TX.
  • Dasarathy S; Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
Hepatology ; 61(6): 2018-29, 2015 Jun.
Article em En | MEDLINE | ID: mdl-25613922
ABSTRACT
UNLABELLED Skeletal muscle loss (sarcopenia) is a major clinical complication in alcoholic cirrhosis with no effective therapy. Skeletal muscle autophagic proteolysis and myostatin expression (inhibitor of protein synthesis) are increased in cirrhosis and believed to contribute to anabolic resistance. A prospective study was performed to determine the mechanisms of sarcopenia in alcoholic cirrhosis and potential reversal by leucine. In six well-compensated, stable, alcoholic patients with cirrhosis and eight controls, serial vastus lateralis muscle biopsies were obtained before and 7 hours after a single oral branched chain amino acid mixture enriched with leucine (BCAA/LEU). Primed-constant infusion of l-[ring-(2) H5 ]-phenylalanine was used to quantify whole-body protein breakdown and muscle protein fractional synthesis rate using liquid chromatography/mass spectrometry. Muscle expression of myostatin, mammalian target of rapamycin (mTOR) targets, autophagy markers, protein ubiquitination, and the intracellular amino acid deficiency sensor general control of nutrition 2 were quantified by immunoblots and the leucine exchanger (SLC7A5) and glutamine transporter (SLC38A2), by real-time polymerase chain reaction. Following oral administration, plasma BCAA concentrations showed a similar increase in patients with cirrhosis and controls. Skeletal muscle fractional synthesis rate was 9.63 ± 0.36%/hour in controls and 9.05 ± 0.68%/hour in patients with cirrhosis (P = 0.54). Elevated whole-body protein breakdown in patients with cirrhosis was reduced with BCAA/LEU (P = 0.01). Fasting skeletal muscle molecular markers showed increased myostatin expression, impaired mTOR signaling, and increased autophagy in patients with cirrhosis compared to controls (P < 0.01). The BCAA/LEU supplement did not alter myostatin expression, but mTOR signaling, autophagy measures, and general control of nutrition 2 activation were consistently reversed in cirrhotic muscle (P < 0.01). Expression of SLC7A5 was higher in the basal state in patients with cirrhosis than controls (P < 0.05) but increased with BCAA/LEU only in controls (P < 0.001).

CONCLUSIONS:

Impaired mTOR1 signaling and increased autophagy in skeletal muscle of patients with alcoholic cirrhosis is acutely reversed by BCAA/LEU.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Músculo Esquelético / Sarcopenia / Leucina / Cirrose Hepática Alcoólica Tipo de estudo: Etiology_studies / Observational_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Hepatology Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Músculo Esquelético / Sarcopenia / Leucina / Cirrose Hepática Alcoólica Tipo de estudo: Etiology_studies / Observational_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Hepatology Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Canadá