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Proc Natl Acad Sci U S A. Oct 1, 1996; 93(20): 10707–10711.
PMCID: PMC38219

Increased glycogen accumulation in transgenic mice overexpressing glycogen synthase in skeletal muscle.

Abstract

To investigate the role of glycogen synthase in controlling glycogen accumulation, we generated three lines of transgenic mice in which the enzyme was overexpressed in skeletal muscle by using promoter-enhancer elements derived from the mouse muscle creatine kinase gene. In all three lines, expression was highest in muscles composed primarily of fast-twitch fibers, such as the gastrocnemius and anterior tibialis. In these muscles, glycogen synthase activity was increased by as much as 10-fold, with concomitant increases (up to 5-fold) in the glycogen content. The uridine diphosphoglucose concentrations were markedly decreased, consistent with the increase in glycogen synthase activity. Levels of glycogen phosphorylase in these muscles increased (up to 3-fold), whereas the amount of the insulin-sensitive glucose transporter 4 either remained unchanged or decreased. The observation that increasing glycogen synthase enhances glycogen accumulation supports the conclusion that the activation of glycogen synthase, as well as glucose transport, contributes to the accumulation of glycogen in response to insulin in skeletal muscle.

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  • Baron AD, Brechtel G, Wallace P, Edelman SV. Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am J Physiol. 1988 Dec;255(6 Pt 1):E769–E774. [PubMed]
  • Daniel PM, Love ER, Pratt OE. Insulin-stimulated entry of glucose into muscle in vivo as a major factor in the regulation of blood glucose. J Physiol. 1975 May;247(2):273–288. [PMC free article] [PubMed]
  • DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000–1007. [PubMed]
  • Kraegen EW, James DE, Jenkins AB, Chisholm DJ. Dose-response curves for in vivo insulin sensitivity in individual tissues in rats. Am J Physiol. 1985 Mar;248(3 Pt 1):E353–E362. [PubMed]
  • BROWN DH, PARK CR, DAUGHADAY WH, CORNBLATH M. The influence of preliminary soaking on glucose utilization by diaphragm. J Biol Chem. 1952 May;197(1):167–174. [PubMed]
  • Jue T, Rothman DL, Tavitian BA, Shulman RG. Natural-abundance 13C NMR study of glycogen repletion in human liver and muscle. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1439–1442. [PMC free article] [PubMed]
  • Shulman RG, Bloch G, Rothman DL. In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8535–8542. [PMC free article] [PubMed]
  • Ren JM, Marshall BA, Gulve EA, Gao J, Johnson DW, Holloszy JO, Mueckler M. Evidence from transgenic mice that glucose transport is rate-limiting for glycogen deposition and glycolysis in skeletal muscle. J Biol Chem. 1993 Aug 5;268(22):16113–16115. [PubMed]
  • Roach PJ. Control of glycogen synthase by hierarchal protein phosphorylation. FASEB J. 1990 Sep;4(12):2961–2968. [PubMed]
  • Skurat AV, Roach PJ. Phosphorylation of sites 3a and 3b (Ser640 and Ser644) in the control of rabbit muscle glycogen synthase. J Biol Chem. 1995 May 26;270(21):12491–12497. [PubMed]
  • Skurat AV, Wang Y, Roach PJ. Rabbit skeletal muscle glycogen synthase expressed in COS cells. Identification of regulatory phosphorylation sites. J Biol Chem. 1994 Oct 14;269(41):25534–25542. [PubMed]
  • Skurat AV, Peng HL, Chang HY, Cannon JF, Roach PJ. Rate-determining steps in the biosynthesis of glycogen in COS cells. Arch Biochem Biophys. 1996 Apr 15;328(2):283–288. [PubMed]
  • Lawrence JC., Jr Signal transduction and protein phosphorylation in the regulation of cellular metabolism by insulin. Annu Rev Physiol. 1992;54:177–193. [PubMed]
  • Rodnick KJ, Piper RC, Slot JW, James DE. Interaction of insulin and exercise on glucose transport in muscle. Diabetes Care. 1992 Nov;15(11):1679–1689. [PubMed]
  • Klip A, Marette A. Acute and chronic signals controlling glucose transport in skeletal muscle. J Cell Biochem. 1992 Jan;48(1):51–60. [PubMed]
  • Mueckler M. Facilitative glucose transporters. Eur J Biochem. 1994 Feb 1;219(3):713–725. [PubMed]
  • Robinson R, Robinson LJ, James DE, Lawrence JC., Jr Glucose transport in L6 myoblasts overexpressing GLUT1 and GLUT4. J Biol Chem. 1993 Oct 15;268(29):22119–22126. [PubMed]
  • Mueckler M, Holman G. Homeostasis without a GLUT. Nature. 1995 Sep 14;377(6545):100–101. [PubMed]
  • DANFORTH WH. GLYCOGEN SYNTHETASE ACTIVITY IN SKELETAL MUSCLE. INTERCONVERSION OF TWO FORMS AND CONTROL OF GLYCOGEN SYNTHESIS. J Biol Chem. 1965 Feb;240:588–593. [PubMed]
  • Jaynes JB, Johnson JE, Buskin JN, Gartside CL, Hauschka SD. The muscle creatine kinase gene is regulated by multiple upstream elements, including a muscle-specific enhancer. Mol Cell Biol. 1988 Jan;8(1):62–70. [PMC free article] [PubMed]
  • Johnson JE, Wold BJ, Hauschka SD. Muscle creatine kinase sequence elements regulating skeletal and cardiac muscle expression in transgenic mice. Mol Cell Biol. 1989 Aug;9(8):3393–3399. [PMC free article] [PubMed]
  • Shield MA, Haugen HS, Clegg CH, Hauschka SD. E-box sites and a proximal regulatory region of the muscle creatine kinase gene differentially regulate expression in diverse skeletal muscles and cardiac muscle of transgenic mice. Mol Cell Biol. 1996 Sep;16(9):5058–5068. [PMC free article] [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Thomas JA, Schlender KK, Larner J. A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem. 1968 Oct 24;25(1):486–499. [PubMed]
  • Gilboe DP, Larson KL, Nuttall FQ. Radioactive method for the assay of glycogen phosphorylases. Anal Biochem. 1972 May;47(1):20–27. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Azpiazu I, Saltiel AR, DePaoli-Roach AA, Lawrence JC. Regulation of both glycogen synthase and PHAS-I by insulin in rat skeletal muscle involves mitogen-activated protein kinase-independent and rapamycin-sensitive pathways. J Biol Chem. 1996 Mar 1;271(9):5033–5039. [PubMed]
  • DePaoli-Roach AA, Ahmad Z, Camici M, Lawrence JC, Jr, Roach PJ. Multiple phosphorylation of rabbit skeletal muscle glycogen synthase. Evidence for interactions among phosphorylation sites and the resolution of electrophoretically distinct forms of the subunit. J Biol Chem. 1983 Sep 10;258(17):10702–10709. [PubMed]
  • Wang Y, Roach PJ. Inactivation of rabbit muscle glycogen synthase by glycogen synthase kinase-3. Dominant role of the phosphorylation of Ser-640 (site-3a). J Biol Chem. 1993 Nov 15;268(32):23876–23880. [PubMed]
  • Donoviel DB, Shield MA, Buskin JN, Haugen HS, Clegg CH, Hauschka SD. Analysis of muscle creatine kinase gene regulatory elements in skeletal and cardiac muscles of transgenic mice. Mol Cell Biol. 1996 Apr;16(4):1649–1658. [PMC free article] [PubMed]
  • Ariano MA, Armstrong RB, Edgerton VR. Hindlimb muscle fiber populations of five mammals. J Histochem Cytochem. 1973 Jan;21(1):51–55. [PubMed]
  • Hintz CS, Lowry CV, Kaiser KK, McKee D, Lowry OH. Enzyme levels in individual rat muscle fibers. Am J Physiol. 1980 Sep;239(3):C58–C65. [PubMed]
  • Yamashita K, Yoshioka T. Profiles of creatine kinase isoenzyme compositions in single muscle fibres of different types. J Muscle Res Cell Motil. 1991 Feb;12(1):37–44. [PubMed]
  • Rossetti L, Hu M. Skeletal muscle glycogenolysis is more sensitive to insulin than is glucose transport/phosphorylation. Relation to the insulin-mediated inhibition of hepatic glucose production. J Clin Invest. 1993 Dec;92(6):2963–2974. [PMC free article] [PubMed]
  • NORMAN D, MENOZZI P, REID D, LESTER G, HECHTER O. Action of insulin on sugar permeability in rat diaphragm muscle. J Gen Physiol. 1959 Jul 20;42(6):1277–1299. [PMC free article] [PubMed]
  • Baqué S, Guinovart JJ, Gómez-Foix AM. Overexpression of muscle glycogen phosphorylase in cultured human muscle fibers causes increased glucose consumption and nonoxidative disposal. J Biol Chem. 1996 Feb 2;271(5):2594–2598. [PubMed]
  • Brozinick JT, Jr, Yaspelkis BB, 3rd, Wilson CM, Grant KE, Gibbs EM, Cushman SW, Ivy JL. Glucose transport and GLUT4 protein distribution in skeletal muscle of GLUT4 transgenic mice. Biochem J. 1996 Jan 1;313(Pt 1):133–140. [PMC free article] [PubMed]
  • Hansen PA, Gulve EA, Marshall BA, Gao J, Pessin JE, Holloszy JO, Mueckler M. Skeletal muscle glucose transport and metabolism are enhanced in transgenic mice overexpressing the Glut4 glucose transporter. J Biol Chem. 1995 Jan 27;270(4):1679–1684. [PubMed]
  • Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ. Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature. 1995 Sep 14;377(6545):151–155. [PubMed]

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