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From the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Drs. Raben, Lu, Lee, and Plotz), National Institutes of Health, Bethesda, MD; Department of Neurology and Pathology (Dr. Danon), New York University School of Medicine, New York; Department of Neurology (Dr. Shliselfield), New York University School of Medicine, New York; Department of Biochemistry (Drs. Skurat and Roach), Indiana University School of Medicine, Indianapolis; Department of Pharmacology (Dr. Lawrence), University of Virginia, Charlottesville; Department of Neurology (Drs. Musumeci, Shanske, and DiMauro), Columbia University College of Physicians and Surgeons, New York.
Address correspondence and reprint requests to Dr. Nina Raben, National Institutes of Health, NIAMS, Building10/9N244, 9000 Rockville Pike, Bethesda, MD, 20892; e-mail: rabenn{at}arb.niams.nih.gov
BACKGROUND: The authors previously reported the generation of a knockout mouse model of Pompe disease caused by the inherited deficiency of lysosomal acid alpha-glucosidase (GAA). The disorder in the knockout mice (GAA-/-) resembles the human disease closely, except that the clinical symptoms develop late relative to the lifespan of the animals. In an attempt to accelerate the course of the disease in the knockouts, the authors increased the level of cytoplasmic glycogen by overexpressing glycogen synthase (GSase) or GlutI glucose transporter.
METHODS: GAA-/- mice were crossed to transgenic mice overexpressing GSase or GlutI in skeletal muscle.
RESULTS: Both transgenics on a GAA knockout background (GS/GAA-/- and GlutI/GAA-/-) developed a severe muscle wasting disorder with an early age at onset. This finding, however, is not the major focus of the study. Unexpectedly, the mice bearing the GSase transgene, but not those bearing the GlutI transgene, accumulated structurally abnormal polysaccharide (polyglucosan) similar to that observed in patients with Lafora disease, glycogenosis type IV, and glycogenosis type VII. Ultrastructurally, the periodic acid-Schiff (PAS)-positive polysaccharide inclusions were composed of short, amorphous, irregular branching filaments indistinguishable from classic polyglucosan bodies. The authors show here that increased level of GSase in the presence of normal glycogen branching enzyme (GBE) activity leads to polyglucosan accumulation. The authors have further shown that inactivation of lysosomal acid alpha-glucosidase in the knockout mice does not contribute to the process of polyglucosan formation.
CONCLUSIONS: An imbalance between GSase and GBE activities is proposed as the mechanism involved in the production of polyglucosan bodies. The authors may have inadvertently created a "muscle polyglucosan disease" by simulating the mechanism for polyglucosan formation.
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