Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization

Clara Prats, Jorn W. Helge, Pernille Nordby, Klaus Qvortrup, Thorkil Ploug, Flemming Dela, Jorgen F. P. Wojtaszewski

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Glycogen synthase (GS) is considered the rate-limiting enzyme in glycogenesis but still today there is a lack of understanding on its regulation. We have previously shown phosphorylation-dependent GS intracellular redistribution at the start of glycogen re-synthesis in rabbit skeletal muscle (Prats, C., Cadefau, J. A., Cusso, R., Qvortrup, K., Nielsen, J. N., Wojtaszewki, J. F., Wojtaszewki, J. F., Hardie, D. G., Stewart, G., Hansen, B. F., and Ploug, T. (2005) J. Biol. Chem. 280, 23165-23172). In the present study we investigate the regulation of human muscle GS activity by glycogen, exercise, and insulin. Using immunocytochemistry we investigate the existence and relevance of GS intracellular compartmentalization during exercise and during glycogen re-synthesis. The results show that GS intrinsic activity is strongly dependent on glycogen levels and that such regulation involves associated dephosphorylation at sites 2 + 2a, 3a, and 3a + 3b. Furthermore, we report the existence of several glycogen metabolism regulatory mechanisms based on GS intracellular compartmentalization. After exhausting exercise, epinephrine-induced protein kinase A activation leads to GS site 1b phosphorylation targeting the enzyme to intramyofibrillar glycogen particles, which are preferentially used during muscle contraction. On the other hand, when phosphorylated at sites 2 + 2a, GS is preferentially associated with subsarcolemmal and intermyofibrillar glycogen particles. Finally, we verify the existence in human vastus lateralis muscle of the previously reported mechanism of glycogen metabolism regulation in rabbit tibialis anterior muscle. After overnight low muscle glycogen level and/or in response to exhausting exercise-induced glycogenolysis, GS is associated with spherical structures at the I-band of sarcomeres.
Original languageEnglish
JournalJournal of Biological Chemistry
Issue number23
Pages (from-to)15692-15700
Publication statusPublished - 2009
Externally publishedYes


  • exercise
  • glycogenolysis
  • muscle contraction
  • Lagomorpha Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Lagomorphs, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Vertebrates) - Leporidae [86040] rabbit common
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common adult male
  • epinephrine 51-43-4
  • glycogen 9005-79-2 metabolism regulation, intramyofibrillar particles, re-synthesis, regulatory mechanism, dephosphorylation
  • glycogen synthase 37338-93-5 EC activation, phosphorylation-dependent intracellular compartmentalization, glycogenesis, intrinsic activity
  • insulin 9004-10-8
  • protein kinase A 142008-29-5 EC activation
  • 10060, Biochemistry studies - General
  • 10064, Biochemistry studies - Proteins, peptides and amino acids
  • 10068, Biochemistry studies - Carbohydrates
  • 10802, Enzymes - General and comparative studies: coenzymes
  • 17504, Muscle - Physiology and biochemistry
  • Movement and Support
  • intermyofibril
  • muscle muscular system
  • sarcomeres muscular system
  • skeletal muscle muscular system
  • subsarcolemma
  • vastus lateralis muscle muscular system
  • immunocytochemistry laboratory techniques, immunologic techniques
  • Biochemistry and Molecular Biophysics
  • Muscular System


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