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Regulation and Function of the Muscle Glycogen-Targeting Subunit of Protein Phosphatase 1 (G_M) in Human Muscle Cells Depends on the COOH-Terminal Region and Glycogen Content

¹ Department de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain
² Sarah Stedman Center for Nutritional Studies, and Departments of Pharmacology and Cancer Biology, Biochemistry, and Medicine, Duke University Medical Center, Durham, North Carolina
³ Department of Medicine, Section on Endocrinology, University of Chicago, Chicago, Illinois

G_M, the muscle-specific glycogen-targeting subunit of protein phosphatase 1 (PP1) targeted to the sarcoplasmic reticulum, was proposed to regulate recovery of glycogen in exercised muscle, whereas mutation truncation of its COOH-terminal domain is known to be associated with type 2 diabetes. Here, we demonstrate differential effects of G_M overexpression in human muscle cells according to glycogen concentration. Adenovirus-mediated delivery of G_M slightly activated glycogen synthase (GS) and inactivated glycogen phosphorylase (GP) in glycogen-replete cells, causing an overaccumulation of glycogen and impairment of glycogenolysis after glucose deprivation. Differently, in glycogen-depleted cells, G_M strongly increased GS activation with no further enhancement of early glycogen resynthesis and without affecting GP. Effects of G_M on GS and GP were abrogated by treatment with dibutyryl cyclic AMP. Expression of a COOH-terminal deleted-mutant (G_MC), lacking the membrane binding sequence to sarcoplasmic reticulum, failed to activate GS in glycogen-depleted cells, while behaving similar to native G_M in glycogen-replete cells. This is explained by loss of stability of the G_MC protein following glycogen-depletion. In summary, G_M promotes glycogen storage and inversely regulates GS and GP activities, while, specifically, synthase phosphatase activity of G_M-PP1 is inhibited by glycogen. The conditional loss of function of the COOH-terminal deleted G_M construct may help to explain the reported association of truncation mutation of G_M with insulin resistance in human subjects.

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