Journal Article

Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease

Gaelle Douillard-Guilloux, Nina Raben, Shoichi Takikita, Arnaud Ferry, Alban Vignaud, Isabelle Guillet-Deniau, Maryline Favier, Beth L. Thurberg, Peter J. Roach, Catherine Caillaud and Emmanuel Richard

in Human Molecular Genetics

Volume 19, issue 4, pages 684-696
Published in print February 2010 | ISSN: 0964-6906
Published online December 2009 | e-ISSN: 1460-2083 | DOI:
Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease

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Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease.

Journal Article.  7345 words.  Illustrated.

Subjects: Genetics and Genomics

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