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J. Biol. Chem., Vol. 280, Issue 10, 9509-9518, March 11, 2005

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Constitutive Activation of GSK3 Down-regulates Glycogen Synthase Abundance and Glycogen Deposition in Rat Skeletal Muscle Cells^*

Katrina MacAulay, Anne S. Blair, Eric Hajduch, Tatsuo Terashima**, Otto Baba**, Calum Sutherland¶, and Harinder S. Hundal||

From the Division of Molecular Physiology, Medical Sciences Institute/Wellcome Trust Building Complex, Faculty of Life Sciences, University of Dundee, DD1 5EH, the ^¶Department of Pharmacology and Neurosciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom and ^**Biostructural Science, Tokyo Medical and Dental University, 1-5-45 Yoshima, Bunkyo-ku, Tokyo 113-8549, Japan

The effects of inhibition or constitutive activation of glycogen synthase kinase-3 (GSK3) on glycogen synthase (GS) activity, abundance, and glycogen deposition in L6 rat skeletal muscle cells were investigated. GS protein expression increased 5-fold during differentiation of L6 cells (comparing cells at the end of day 5 with those at the beginning of day 3). However, exposure of undifferentiated myoblasts (day 3) to 50 µM SB-415286, a GSK3 inhibitor, led to a significant elevation in GS protein that was not accompanied by changes in the abundance of GLUT4, another late differentiation marker. In contrast, stable expression of a constitutively active form of GSK3 (GSK3^S9A) led to a significant reduction (80%) in GS protein that was antagonized by SB-415286. Inhibition of GSK3 or expression of the constitutively active GSK3^S9A did not result in any detectable changes in GS mRNA abundance. However, the increase in GS protein in undifferentiated myoblasts or that seen following incubation of cells expressing GSK3^S9A with GSK3 inhibitors was blocked by cycloheximide suggesting that GSK3 influences GS abundance possibly via control of mRNA translation. Consistent with the reduction in GS protein, cells expressing GSK3^S9A were severely glycogen depleted as judged using a specific glycogen-staining antibody. Inhibiting GSK3 in wild-type or GSK3^S9A-expressing cells using SB-415286 resulted in an attendant activation of GS, but not that of glucose transport. However, GS activation alone was insufficient for stimulating glycogen deposition. Only when muscle cells were incubated simultaneously with insulin and SB-415286 or with lithium (which stimulates GS and glucose transport) was an increase in glycogen accretion observed. Our findings suggest that GSK3 activity is an important determinant of GS protein expression and that while glycogen deposition in muscle cells is inherently dependent upon the activity/expression of GS, glucose transport is a key rate-determining step in this process.

Received for publication, October 13, 2004 , and in revised form, December 17, 2004.

^* This work was supported by the Biotechnology and Biological Sciences Research Council, Medical Research Council, and Diabetes UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Unité INSERM 671, Institut Biomédical des Cordeliers, 15 rue de l'ecole de Médecine, 75006 Paris, France.

^|| To whom correspondence should be addressed: Division of Molecular Physiology, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee, UK. Tel.: 44-1382-344969; Fax: 44-1382-345507; E-mail: h.s.hundal{at}dundee.ac.uk.

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