Differential muscular glycogen clearance after enzyme replacement therapy in a mouse model of Pompe disease

Abstract Glycogen storage disease in the α-glucosidase knockout 6neo(−)/6neo(−) (GAA KO) mouse, a model of Pompe disease, results in the pathologic accumulation of glycogen primarily within skeletal myocytes and cardiomyocytes. Intravenous administration of recombinant human α-glucosidase (rhGAA, Myozyme ® , aglucosidase alfa) can result in significant glycogen clearance from both cardiomyocytes and skeletal myocytes, however, the degree of clearance varies from one skeletal muscle type to another. We sought to determine what role muscle fiber type predominance played in this variability. To examine this question in the GAA KO mouse model we delivered intravenous doses of 100 mg/kg rhGAA on Day 1, and Day 14, and harvested a variety of fast and slow twitch muscles on Day 28. We measured glycogen clearance, muscle fiber type content and capillary density by light microscopy with computer morphometry. Recombinant human-GAA administration resulted in differential clearance of glycogen in the various muscles examined. Slow twitch-predominant muscles cleared glycogen significantly more efficiently than fast twitch-predominant muscles. There was a strong correlation between capillary density and glycogen clearance ( r  = 0.55), suggesting that at the high doses used in this study the differential glycogen clearance observed between muscles is largely due to differential bioavailability of rhGAA regulated by blood flow.