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

  1. Carlos Lerín1,
  2. Eulàlia Montell1,
  3. Teresa Nolasco1,
  4. Cathy Clark2,
  5. Matthew J. Brady3,
  6. Christopher B. Newgard2 and
  7. Anna M. Gómez-Foix1
  1. 1Department de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain
  2. 2Sarah Stedman Center for Nutritional Studies, and Departments of Pharmacology and Cancer Biology, Biochemistry, and Medicine, Duke University Medical Center, Durham, North Carolina
  3. 3Department of Medicine, Section on Endocrinology, University of Chicago, Chicago, Illinois
  1. Address correspondence and reprint requests to Anna M. Gómez-Foix, Departament de Bioquímica i Biologia Molecular, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1, E-08028, Barcelona, Spain. E-mail: agomez{at}bq.ub.es

Abstract

GM, 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 GM overexpression in human muscle cells according to glycogen concentration. Adenovirus-mediated delivery of GM 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, GM strongly increased GS activation with no further enhancement of early glycogen resynthesis and without affecting GP. Effects of GM on GS and GP were abrogated by treatment with dibutyryl cyclic AMP. Expression of a COOH-terminal deleted-mutant (GMΔC), lacking the membrane binding sequence to sarcoplasmic reticulum, failed to activate GS in glycogen-depleted cells, while behaving similar to native GM in glycogen-replete cells. This is explained by loss of stability of the GMΔC protein following glycogen-depletion. In summary, GM promotes glycogen storage and inversely regulates GS and GP activities, while, specifically, synthase phosphatase activity of GM-PP1 is inhibited by glycogen. The conditional loss of function of the COOH-terminal deleted GM construct may help to explain the reported association of truncation mutation of GM with insulin resistance in human subjects.

Footnotes

    • Accepted June 10, 2003.
    • Received March 5, 2003.
| Table of Contents