Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase pp1g/rgl

Y. Suzuki, C. Lanner, J. H. Kim, P. Giuseppe Vilardo, H. Zhang, J. Yang, L. D. Cooper, M. Steele, A. Kennedy, C. B. Bock, A. Scrimgeour, Jr Lawrence J.C., Anna De Paoli-Roach

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Abstract

The regulatory-targeting subunit (RGL, also called GM) of the muscle-specific glycogen-associated protein phosphatase PP1G targets the enzyme to glycogen where it modulates the activity of glycogen-metabolizing enzymes. PP1G/RGL has been postulated to play a central role in epinephrine and insulin control of glycogen metabolism via phosphorylation of RGL. To investigate the function of the phosphatase, RGL knockout mice were generated. Animals lacking RGL show no obvious defects. The RGL protein is absent from the skeletal and cardiac muscle of null mutants and present at ∼50% of the wild-type level in heterozygotes. Both the level and activity of C1 protein are also decreased by ∼50% in the RGL-deficient mice. In skeletal muscle, the glycogen synthase (GS) activity ratio in the absence and presence of glucose-6-phosphate is reduced from 0.3 in the wild type to 0.1 in the null mutant RGL mice, whereas the phosphorylase activity ratio in the absence and presence of AMP is increased from 0.4 to 0.7. Glycogen accumulation is decreased by ∼90%. Despite impaired glycogen accumulation in muscle, the animals remain normoglycemic. Glucose tolerance and insulin responsiveness are identical in wild-type and knockout mice, as are basal and insulin-stimulated glucose uptakes in skeletal muscle. Most importantly, insulin activated GS in both wild-type and RGL null mutant mice and stimulated a GS-specific protein phosphatase in both groups. These results demonstrate that RGL is genetically linked to glycogen metabolism, since its loss decreases PPI and basal GS activities and glycogen accumulation. However, PP1G/RGL is not required for insulin activation of GS in skeletal muscle, and rather another GS-specific phosphatase appears to be involved.

Original languageEnglish
Pages (from-to)2683-2694
Number of pages12
JournalMolecular and Cellular Biology
Volume21
Issue number8
DOIs
StatePublished - 2001

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Muscle Proteins
Phosphoprotein Phosphatases
Glycogen
Knockout Mice
Glycogen Synthase
Insulin
Skeletal Muscle
Phosphoric Monoester Hydrolases
Glucose
Muscles
Phosphorylases
Glucose-6-Phosphate
Enzymes
Adenosine Monophosphate
Heterozygote
Epinephrine
Myocardium
Proteins
Phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase pp1g/rgl. / Suzuki, Y.; Lanner, C.; Kim, J. H.; Giuseppe Vilardo, P.; Zhang, H.; Yang, J.; Cooper, L. D.; Steele, M.; Kennedy, A.; Bock, C. B.; Scrimgeour, A.; Lawrence J.C., Jr; De Paoli-Roach, Anna.

In: Molecular and Cellular Biology, Vol. 21, No. 8, 2001, p. 2683-2694.

Research output: Contribution to journalArticle

Suzuki, Y, Lanner, C, Kim, JH, Giuseppe Vilardo, P, Zhang, H, Yang, J, Cooper, LD, Steele, M, Kennedy, A, Bock, CB, Scrimgeour, A, Lawrence J.C., J & De Paoli-Roach, A 2001, 'Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase pp1g/rgl', Molecular and Cellular Biology, vol. 21, no. 8, pp. 2683-2694. https://doi.org/10.1128/MCB.21.8.2683-2694.2001
Suzuki, Y. ; Lanner, C. ; Kim, J. H. ; Giuseppe Vilardo, P. ; Zhang, H. ; Yang, J. ; Cooper, L. D. ; Steele, M. ; Kennedy, A. ; Bock, C. B. ; Scrimgeour, A. ; Lawrence J.C., Jr ; De Paoli-Roach, Anna. / Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase pp1g/rgl. In: Molecular and Cellular Biology. 2001 ; Vol. 21, No. 8. pp. 2683-2694.
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abstract = "The regulatory-targeting subunit (RGL, also called GM) of the muscle-specific glycogen-associated protein phosphatase PP1G targets the enzyme to glycogen where it modulates the activity of glycogen-metabolizing enzymes. PP1G/RGL has been postulated to play a central role in epinephrine and insulin control of glycogen metabolism via phosphorylation of RGL. To investigate the function of the phosphatase, RGL knockout mice were generated. Animals lacking RGL show no obvious defects. The RGL protein is absent from the skeletal and cardiac muscle of null mutants and present at ∼50{\%} of the wild-type level in heterozygotes. Both the level and activity of C1 protein are also decreased by ∼50{\%} in the RGL-deficient mice. In skeletal muscle, the glycogen synthase (GS) activity ratio in the absence and presence of glucose-6-phosphate is reduced from 0.3 in the wild type to 0.1 in the null mutant RGL mice, whereas the phosphorylase activity ratio in the absence and presence of AMP is increased from 0.4 to 0.7. Glycogen accumulation is decreased by ∼90{\%}. Despite impaired glycogen accumulation in muscle, the animals remain normoglycemic. Glucose tolerance and insulin responsiveness are identical in wild-type and knockout mice, as are basal and insulin-stimulated glucose uptakes in skeletal muscle. Most importantly, insulin activated GS in both wild-type and RGL null mutant mice and stimulated a GS-specific protein phosphatase in both groups. These results demonstrate that RGL is genetically linked to glycogen metabolism, since its loss decreases PPI and basal GS activities and glycogen accumulation. However, PP1G/RGL is not required for insulin activation of GS in skeletal muscle, and rather another GS-specific phosphatase appears to be involved.",
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AU - Lanner, C.

AU - Kim, J. H.

AU - Giuseppe Vilardo, P.

AU - Zhang, H.

AU - Yang, J.

AU - Cooper, L. D.

AU - Steele, M.

AU - Kennedy, A.

AU - Bock, C. B.

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AU - Lawrence J.C., Jr

AU - De Paoli-Roach, Anna

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