Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/RGL

doi:10.1128/MCB.21.8.2683-2694.2001

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Molecular and Cellular Biology, April 2001, p. 2683-2694, Vol. 21, No. 8
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2683-2694.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Insulin Control of Glycogen Metabolism in Knockout Mice Lacking the Muscle-Specific Protein Phosphatase PP1G/R_GL

Yoichi Suzuki,¹^, Carita Lanner,¹ Jong-Hwa Kim,¹ Pier Giuseppe Vilardo,¹ Hong Zhang,¹ Jie Yang,¹ Lori D. Cooper,¹ Marcella Steele,¹ Andrew Kennedy,¹ Cheryl B. Bock,² Angus Scrimgeour,³ John C. Lawrence Jr.,³ and Anna A. DePaoli-Roach¹^,^*

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202¹; Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710²; and Department of Pharmacology, University of Virginia, School of Medicine, Charlottesville, Virginia 22908³

Received 13 October 2000/Returned for modification 27 November 2000/Accepted 17 January 2001

The regulatory-targeting subunit (R_GL, also called G_M) of the muscle-specific glycogen-associated protein phosphatase PP1Gtargets the enzyme to glycogen where it modulates the activityof glycogen-metabolizing enzymes. PP1G/R_GL has been postulatedto play a central role in epinephrine and insulin control of glycogenmetabolism via phosphorylation of R_GL. To investigate the functionof the phosphatase, R_GL knockout mice were generated. Animalslacking R_GL show no obvious defects. The R_GL protein is absentfrom the skeletal and cardiac muscle of null mutants and presentat ~50% of the wild-type level in heterozygotes. Both the leveland activity of C1 protein are also decreased by ~50% in the R_GL-deficientmice. In skeletal muscle, the glycogen synthase (GS) activityratio in the absence and presence of glucose-6-phosphate is reducedfrom 0.3 in the wild type to 0.1 in the null mutant R_GL mice,whereas the phosphorylase activity ratio in the absence and presenceof AMP is increased from 0.4 to 0.7. Glycogen accumulation isdecreased by ~90%. Despite impaired glycogen accumulation in muscle,the animals remain normoglycemic. Glucose tolerance and insulinresponsiveness are identical in wild-type and knockout mice, asare basal and insulin-stimulated glucose uptakes in skeletal muscle.Most importantly, insulin activated GS in both wild-type and R_GLnull mutant mice and stimulated a GS-specific protein phosphatasein both groups. These results demonstrate that R_GL is geneticallylinked to glycogen metabolism, since its loss decreases PP1 andbasal GS activities and glycogen accumulation. However, PP1G/R_GLis not required for insulin activation of GS in skeletal muscle,and rather another GS-specific phosphatase appears to beinvolved.

^* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine,635 Barnhill Dr., Indianapolis, IN 46202-5122. Phone: (317) 274-1585.Fax: (317) 274-4686. E-mail: adepaoli{at}iupui.edu.

Present address: Department of Medical Genetics, Tohoku University School of Medicine, Sendai 980-77,Japan.

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