Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity

A Kumar, TE Harris, SR Keller, KM Choi… - … and cellular biology, 2008 - Taylor & Francis
A Kumar, TE Harris, SR Keller, KM Choi, MA Magnuson, JC Lawrence Jr
Molecular and cellular biology, 2008Taylor & Francis
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 …
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.
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