Objectives: 

Pompe disease (PD) is a rare autosomal recessive disorder caused by the deficiency of the lysosomal enzyme acid alpha glucosidase and results in the accumulation of glycogen in multiple tissues, although the major clinical manifestations are seen in cardiac and skeletal muscle. Enzyme replacement therapy is at present the only approved treatment for PD but shows limited efficacy in some patients and does not completely correct the disease phenotype. We have used a mouse model of PD in order to focus on a better understanding of the cellular pathophysiological mechanisms of the disease. We have performed the phenotypic characterization of this murine model and studied the effect of glycogen accumulation on the energy status of skeletal muscle cells.

Materials: 

A Gaa knockout (KO) mouse colony has been established in our laboratory. Glycogen accumulation was monitored by periodic acid-Schiff (PAS) staining. Open field activity test was used to measure locomotor activity. The content of adenosine-5'-triphosphate (ATP) was quantified by using luciferin-luciferase reaction method (ATP Determination Kit). Isolated fibers from gastrocnemius were used to perform immunofluorescence staining of lysosomes.

Results: 

Gaa KO mice showed an abnormal accumulation of glycogen in skeletal muscle, which was increased with age, as well as an altered distribution of the lysosomes in the core of fibers. Using the open field test we found that motor ability of Gaa KO animals was significantly decreased compared to that of wild-type. We also found differences in the content of ATP in fibers isolated from Gaa KO and from wild-type mice.

Conclusions: 

Overall, our Gaa KO colony recapitulates critical phenotypic features of PD, and is a good experimental model to study the mechanisms of the disease. The different energy status of muscle with glycogen accumulation may help to explain the progressive skeletal muscle weakness of Pompe patients.