Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease

TLDR

Glycogen storage disease type II (Pompe disease) is a lysosomal disorder caused by acid α‑glucosidase deficiency that affects heart and skeletal muscle. The model aims to elucidate GSDII pathogenesis and to test therapeutic interventions. The model was created by knocking out the Gaa gene in embryonic stem cells. Gaa‑/‑ mice lack acid α‑glucosidase, accumulate glycogen in liver, heart, and muscle from birth, develop large deposits by 13 weeks, show lysosomal pathology, remain fertile, and exhibit cardiac enlargement and ECG abnormalities without overt symptoms.

Abstract

Glycogen storage disease type II (GSDII; Pompe disease), caused by inherited deficiency of acid α-glucosidase, is a lysosomal disorder affecting heart and skeletal muscles. A mouse model of this disease was obtained by targeted disruption of the murine acid α-glucosidase gene (Gaa) in embryonic stem cells. Homozygous knockout mice (Gaa -/-) lack Gaa mRNA and have a virtually complete acid α-glucosidase deficiency. Glycogen-containing lysosomes are detected soon after birth in liver, heart and skeletal muscle cells. By 13 weeks of age, large focal deposits of glycogen have formed. Vacuolar spaces stain positive for acid phosphatase as a sign of lysosomal pathology. Both male and female knockout mice are fertile and can be intercrossed to produce progeny. The first born knockout mice are at present 9 months old. Overt clinical symptoms are still absent, but the heart is typically enlarged and the electrocardiogram is abnormal. The mouse model will help greatly to understand the pathogenic mechanism of GSDII and is a valuable instrument to explore the efficacy of different therapeutic interventions.