title: Acute uremia suppresses leucine-induced signal transduction in skeletal muscle.
abstract: Adequate nutrient intake in acute uremia is a key part of patient management especially as food utilization is usually impaired. Leucine is important as it comprises about one-fifth of essential amino acid needs and, apart from serving as a substrate, it directly activates the mTOR signaling pathway stimulating protein synthesis and inhibiting autophagy. Here we tested whether leucine activation of the mTOR signaling pathway in muscle is severely disrupted in acute uremia. Several abnormalities were identified in bilateral ureteral ligated (model of acute uremia) compared to sham-operated pair-fed control rats. Levels of several signaling proteins increased significantly while leucine-induced phosphorylation of mTOR and downstream proteins, 4e-BP1 and S6K1, was completely suppressed. Levels of LC3B-II, a specific autophagosomal membrane-associated protein used as a marker of autophagy, increased threefold in uremia. Furthermore, while leucine suppressed LC3B-II levels in controls, it failed to do so in uremic rats. Muscle IL-6 mRNA levels increased, while IGF-1 mRNA levels decreased in uremia. These findings establish that, in acute uremia, severe resistance to leucine-induced activation of the mTOR anabolic signaling pathway develops. Thus, leucine resistance, together with the reduction in IGF-1 and increase in IL-6 expression, may explain why the anabolic effect of nutritional therapy is diminished in acute uremic patients.
authors.affiliation: 1] Research Service, Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, California, USA [2] Renal Division, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: McIntire
authors.affiliation: 1] Research Service, Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, California, USA [2] Renal Division, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1] Research Service, Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, California, USA [2] Renal Division, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Sood
authors.affiliation: 1] Research Service, Veterans Affairs Palo Alto Health Care System (VAPAHCS), Palo Alto, California, USA [2] Renal Division, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Rabkin
mesh_terms: D000208:Acute Disease; D058186:Acute Kidney Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000378:metabolism*; D008026:Ligation; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009752:Nutritional Status; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014511:Uremia / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D014513:Ureter / Q000601:surgery
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; C546845:mTOR protein, rat; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases; D007930:Leucine