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Molecular and Cellular Biology, January 2008, p. 61-70, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01405-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Muscle-Specific Deletion of Rictor Impairs Insulin-Stimulated Glucose Transport and Enhances Basal Glycogen Synthase Activity

Anil Kumar,^1* Thurl E. Harris,¹ Susanna R. Keller,² Kin M. Choi,^1, Mark A. Magnuson,³ and John C. Lawrence Jr.^1,

Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia 22908,¹ Internal Medicine, Division of Endocrinology, University of Virginia Health System, Charlottesville, Virginia 22908,² Center for Stem Cell Biology and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232³

Received 5 August 2007/ Returned for modification 31 August 2007/ Accepted 16 October 2007

Rictor is an essential component of mTOR (mammalian target of rapamycin) complex 2 (mTORC2), a kinase complex that phosphorylates Akt at Ser473 upon activation of phosphatidylinositol 3-kinase (PI-3 kinase). Since little is known about the role of either rictor or mTORC2 in PI-3 kinase-mediated physiological processes in adult animals, we generated muscle-specific rictor knockout mice. Muscle from male rictor knockout mice exhibited decreased insulin-stimulated glucose uptake, and the mice showed glucose intolerance. In muscle lacking rictor, the phosphorylation of Akt at Ser473 was reduced dramatically in response to insulin. Furthermore, insulin-stimulated phosphorylation of the Akt substrate AS160 at Thr642 was reduced in rictor knockout muscle, indicating a defect in insulin signaling to stimulate glucose transport. However, the phosphorylation of Akt at Thr308 was normal and sufficient to mediate the phosphorylation of glycogen synthase kinase 3 (GSK-3). Basal glycogen synthase activity in muscle lacking rictor was increased to that of insulin-stimulated controls. Consistent with this, we observed a decrease in basal levels of phosphorylated glycogen synthase at a GSK-3/protein phosphatase 1 (PP1)-regulated site in rictor knockout muscle. This change in glycogen synthase phosphorylation was associated with an increase in the catalytic activity of glycogen-associated PP1 but not increased GSK-3 inactivation. Thus, rictor in muscle tissue contributes to glucose homeostasis by positively regulating insulin-stimulated glucose uptake and negatively regulating basal glycogen synthase activity.

Published ahead of print on 29 October 2007.

Present address: Primanova Biosciences, Inc., 3235 Route 112, Medford, NY 11763.

Died on 19 December 2006.

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