Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase PP1G/R-GL

The regulatory-targeting subunit (R-GL, also called G(M)) of the muscle-spe cific glycogen-associated protein phosphatase PP1G targets the enzyme to gl ycogen where it modulates the activity of glycogen-metabolizing enzymes. PP 1G/R-GL has been postulated to play a central role in epinephrine and insul in control of glycogen metabolism via phosphorylation of R-GL. To investiga te the function of the phosphatase, R-GL knockout mice were generated. Anim als lacking R-GL show no obvious defects. The R-GL protein is absent from t he skeletal and cardiac muscle of null mutants and present at similar to 50 % of the wild-type level in heterozygotes. Both the level and activity of C 1 protein are also decreased by similar to 50% in the R-GL-deficient mice. In skeletal muscle, the glycogen synthase (GS) activity ratio in the absenc e and presence of glucose-6-phosphate is reduced from 0.3 in the wild type to 0.1 in the null mutant R-GL mice, whereas the phosphorylase activity rat io in the absence and presence of AMP is increased from 0.4 to 0.7. Glycoge n accumulation is decreased by similar to 90%. Despite impaired glycogen ac cumulation in muscle, the animals remain normoglycemic, Glucose tolerance a nd insulin responsiveness are identical in wild-type and knockout mice, as are basal and insulin-stimulated glucose uptakes in skeletal muscle. Most i mportantly, insulin activated GS in both wild-type and R-GL null mutant mic e and stimulated a GS-specific protein phosphatase in both groups. These re sults demonstrate that R,, is genetically linked to glycogen metabolism, si nce its loss decreases PPI and basal GS activities and glycogen accumulatio n. However, PP1G/R-GL is not required for insulin activation of CS in skele tal muscle, and rather another GS-specific phosphatase appears to be involv ed.