HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 296/1/E105    most recent 90752.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Adegoke, O. A. J. Articles by Marliss, E. B. Search for Related Content PubMed PubMed Citation Articles by Adegoke, O. A. J. Articles by Marliss, E. B.

Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men

¹School of Kinesiology and Health Science, York University, Toronto, Ontario; and ²McGill Nutrition and Food Science Centre, McGill University and ³Division of Endocrinology and Metabolism, Department of Medicine, McGill University Health Centre/Royal Victoria Hospital, Montreal, Quebec, Canada; ⁴Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and ⁵Polypeptide Hormone Laboratory, McGill University, Montreal, Quebec, Canada

Submitted 5 September 2008 ; accepted in final form 24 October 2008

Since maximum anabolism occurs postprandially, we developed a simulated fed state with clamped hyperinsulinemia, physiological hyperglycemia, and hyperaminoacidemia (Hyper-3) and explored muscle cellular mechanisms. Whole body [1-¹³C]leucine and [3-³H]glucose kinetics in healthy men were compared between hyperinsulinemic, euglycemic, isoaminoacidemic (Hyper-1, n = 10) and Hyper-3 (n = 9) clamps. In Hyper-3 vs. Hyper-1, nonoxidative leucine R_d [rate of disappearance (synthesis)] was stimulated more (45 ± 4 vs. 24 ± 4 µmol/min, P < 0.01) and endogenous R_a [rate of appearance (breakdown)] was inhibited similarly; hence net balance increased more (86 ± 6 vs. 49 ± 2 µmol/min, P < 0.001). Glucose R_d was similar; thus Hyper-3 metabolic clearance rate (331 ± 23 vs. 557 ± 41 ml/min, P < 0.0005) and R_d/insulin (M, 0.65 ± 0.10 vs. 1.25 ± 0.10 mg·min^–1·pmol^–1·l, P < 0.001) were less, despite higher insulin (798 ± 74 vs. 450 ± 24 pmol/l, P < 0.005). In vastus lateralis muscle biopsies, phosphorylation of Akt (P = 0.025), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70^S6K1; P = 0.008), S6 (P = 0.049), and 4E-binding protein 1 (4E-BP1; P = 0.001) increased. With decreased eukaryotic initiation factor-4E (eIF4E)·4E-BP1 complex (P = 0.01), these are consistent with increased mTOR complex 1 (mTORC1) signaling and translation initiation of protein synthesis. Although mRNA expression of ubiquitin, MAFbx 1, and MuRF-1 was unchanged, total ubiquitinated proteins decreased 20% (P < 0.01), consistent with proteolysis suppression. The Hyper-3 clamp increases whole body protein synthesis, net anabolism, and muscle protein translation initiation pathways and decreases protein ubiquitination. The main contribution of hyperaminoacidemia is stimulation of synthesis rather than inhibition of proteolysis, and it attenuates the expected increment of glucose disposal.

translation initiation; ubiquitin pathway; leucine kinetics; glucose turnover; insulin resistance