The glycogen storage disease type II (GSD II) is a rare, multisystemic disease with variable rates of disease progression that is also called Pompe disease. It is caused by alterations in the acid α-glucosidase (GAA) gene, resulting in reduced levels of this enzyme that in turn leads to a reduced degradation and thus accumulation of glycogen mostly in different muscle tissues. Most common symptoms include cardiac dysfunction, muscle weakness, hypotonia, respiratory problems and a strongly reduced life expectancy. To model this lysosomal storage disease, we analyzed the 6neo mouse line that has a Gaa knockout resulting in reduced GAA enzyme levels and thus a progressive accumulation of glycogen in different muscle tissues. Our preliminary analyses of muscle and motor deficits show reduced muscle strength in the wire hanging test of 6neo mice at 24 weeks of age compared to wild type littermates (A). In the grip strength test significant differences of 6neo mice can already be observed at the age of 8 weeks that progressively worsen with age (B). Evaluation of motor deficits using the beam walk test revealed that 6neo mice slip more often compared to wild type littermates at the age of 24 weeks (C+D). Our results suggest that 6neo mice closely mimic the muscle phenotype observed in Pompe disease patients, making this mouse a useful tool to evaluate new compounds against this devastating disease.
Figure: Muscle and motor deficits in the 6neo mouse model of Pompe disease. 6neo mice at the age of 8 and 24 weeks were tested for hanging time in the wire hanging test (A), for mean grip strength in the grip strength test (B) and for number of slips (C) and slips per speed (D) in the beam walk test (C+D). WT: n = 24; 6neo: n = 48; mean + SEM; two-way ANOVA followed by Bonferroni’s multiple comparison post hoc test; **/##p<0.01, ***/###p<0.001; *significance between genotypes; #significance between age groups.
Further analyses of 6neo mouse pathological features like enzyme and substrate levels as well as survival rate are currently in progress.