Effect of glycogen synthase overexpression on insulin-stimulated muscle glucose uptake and storage

1 Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, Texas 78712; and 2 Department of Pharmacology and Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908 Submitted 19 March 2003 ; accepted in final form 17 October 2003 Insulin-stimulated muscle glucose uptake is inversely associated with the muscle glycogen concentration. To investigate whether this association is a cause and effect relationship, we compared insulin-stimulated muscle glucose uptake in noncontracted and postcontracted muscle of GSL3-transgenic and wild-type mice. GSL3-transgenic mice overexpress a constitutively active form of glycogen synthase, which results in an abundant storage of muscle glycogen. Muscle contraction was elicited by in situ electrical stimulation of the sciatic nerve. Right gastrocnemii from GSL3-transgenic and wild-type mice were subjected to 30 min of electrical stimulation followed by hindlimb perfusion of both hindlimbs. Thirty minutes of contraction significantly reduced muscle glycogen concentration in wild-type (49%) and transgenic (27%) mice, although transgenic mice retained 168.8 ± 20.5 µmol/g glycogen compared with 17.7 ± 2.6 µmol/g glycogen for wild-type mice. Muscle of transgenic and wild-type mice demonstrated similar pre- (3.6 ± 0.3 and 3.9 ± 0.6 µmol·g -1 ·h -1 for transgenic and wild-type, respectively) and postcontraction (7.9 ± 0.4 and 7.0 ± 0.4 µmol·g -1 ·h -1 for transgenic and wild-type, respectively) insulin-stimulated glucose uptakes. However, the [ 14 C]glucose incorporated into glycogen was greater in noncontracted (151%) and postcontracted (157%) transgenic muscle vs. muscle of corresponding wild-type mice. These results indicate that glycogen synthase activity is not rate limiting for insulin-stimulated glucose uptake in skeletal muscle and that the inverse relationship between muscle glycogen and insulin-stimulated glucose uptake is an association, not a cause and effect relationship. glucose transporter-4; glycogen synthesis; insulin; muscle contraction; protein kinase B/Akt Address for reprint requests and other correspondence: J. L. Ivy, Exercise Physiology and Metabolism Laboratory, Dept. of Kinesiology and Health Education, Bellmont Hall 222, The Univ. of Texas at Austin, Austin, Texas 78712-0360 (E-mail: johnivy{at}mail.utexas.edu ).