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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/RGL

Yoichi Suzuki,1,dagger 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 (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 PP1 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.

* 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.

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

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.


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