title: Acute acidosis attenuates leucine stimulated signal transduction and protein synthesis in rat skeletal muscle.
abstract: BACKGROUND
  Critical illnesses are often complicated by acute metabolic acidosis, which if persistent, adversely affects outcome. Among the harmful effects that it might cause are impaired utilization of nutrients, increased proteolysis and depressed protein synthesis, leading to muscle wasting. As the amino acid leucine stimulates protein synthesis by activating mTOR signaling, we explored whether in acidosis, impaired leucine-stimulated signaling might be a contributor to the depressed protein synthesis.
  
  
  METHODS
  Male pair-fed rats were gavaged with NH4Cl (acidosis) or NaCl (control) for 2 days and then gavaged once with leucine and sacrificed 45 min later. Extensor digitorum longus muscles were isolated, incubated with or without leucine and protein synthesis measured. The anterior tibial muscle signaling was analysed by Western immunobloting.
  
  
  RESULTS
  Despite pair-feeding, acidotic rats lost body and muscle weight vs. controls. Moreover, leucine-induced protein synthesis in isolated muscle from acidotic rats was impaired. In-vivo, 45 min after an oral leucine load, anterior tibial muscle mTOR and 4E-BP1 phosphorylation increased significantly and comparably in control and acidotic rats. In contrast, leucine-stimulated phosphorylation of S6K1, a regulator of translation initiation and protein synthesis, was attenuated to approximately 56% of the control value (p < 0.05).
  
  
  CONCLUSIONS
  This study reveals that an acute metabolic acidosis impairs leucine-stimulated protein synthesis and activation of signaling downstream of mTOR at the level of S6K1. We propose that this S6K1 abnormality may account in part, for the resistance to leucine-stimulated muscle protein synthesis, and may thereby contribute to the impaired nutrient utilization and ultimately the muscle wasting that develops in acidosis.
authors.affiliation: Research Service, Veterans Affairs Health Care Palo Alto, Palo Alto, Calif., USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Sood
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Kevin
authors.initials: K
authors.lastname: McIntire
authors.forename: Ralph
authors.initials: R
authors.lastname: Rabkin
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D007328:Insulin / Q000097:blood; D007930:Leucine / Q000097:blood*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D014176:Protein Biosynthesis; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007328:Insulin; C546845:mTOR protein, rat; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases; D007930:Leucine