Angus Scrimgeour

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

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, RGLknockout 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 RGLnull 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.

Zinc Intervention Strategies: Costs and Health Benefits

Zinc is required for such processes as growth, immunity and reproduction. Even in developed countries, many people have a marginal intake of zinc and several common dietary constituents can impair its absorption. Attention to the zinc nutrition of at-risk groups such as the malnourished, children, pregnant women, the elderly and immuno-compromised individuals is therefore required. New information about zinc and cancer risk has emerged. Zinc deficiency has been shown to upregulate expression of the tumor suppressor protein, p53; and impairs the DNA binding abilities of p53, NFκB, and AP-1 transcription factors. These studies suggest that a decrease in cellular zinc alone results in a loss of DNA integrity, increasing the potential for cancer risk. Conversely, zinc supplementation decreases oxidative stress and improves immune function, which may be a mechanism for its cancer preventive activity. Successful programs to increase global zinc intakes through a combination of supplementation, dietary diversification, fortification, biofortification, zinc-fertilizers, phytate reduction and/or utilizing enzymes like phytase are necessary. Industry should help to define feasible, affordable fortification strategies, identify appropriate food vehicles and fortificants, develop quality assurance systems, and implement educational campaigns to reach target populations. Fortification of staple foods, such as bread or breakfast cereals, offers a means of increasing zinc intake among the majority of the population that consume these foods and can help to ensure dietary adequacy. Biofortification is an alternate strategy for improving zinc content in staple crops, provided that there is adequate genetic biodiversity/natural variation in concentrations of relevant micronutrients. Crops with enhanced micronutrient content are most relevant to developing countries, where micronutrient deficiencies are widespread. Scientific community members need to determine the country-specific prevalence of zinc deficiency, the sensory acceptability and efficacy of the chosen zinc compound and food products, develop and implement educational campaigns to reach target populations, and verify the overall effectiveness of zinc-supplementation program(s).