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.