Raben N, Danon M, Gilbert A L, Dwivedi S, Collins B, Thurberg B L, Mattaliano R J, Nagaraju K, Plotz P H
Arthritis and Rheumatism Branch, National Institutes of Health, US HHS NIH NIAMS, 9000 Rockville Pike, Bld 10/9N244, Bethesda, MD 20892, USA.
Mol Genet Metab. 2003 Sep-Oct;80(1-2):159-69. doi: 10.1016/j.ymgme.2003.08.022.
Deficiency of acid alpha-glucosidase (GAA) results in widespread cellular deposition of lysosomal glycogen manifesting as myopathy and cardiomyopathy. When GAA-/- mice were treated with rhGAA (20 mg/kg/week for up to 5 months), skeletal muscle cells took up little enzyme compared to liver and heart. Glycogen reduction was less than 50%, and some fibers showed little or no glycogen clearance. A dose of 100 mg/kg/week resulted in approximately 75% glycogen clearance in skeletal muscle. The enzyme reduced cardiac glycogen to undetectable levels at either dose. Skeletal muscle fibers with residual glycogen showed immunoreactivity for LAMP-1/LAMP-2, indicating that undigested glycogen remained in proliferating lysosomes. Glycogen clearance was more pronounced in type 1 fibers, and histochemical analysis suggested an increased mannose-6-phosphate receptor immunoreactivity in these fibers. Differential transport of enzyme into lysosomes may explain the strikingly uneven pattern of glycogen removal. Autophagic vacuoles, a feature of both the mouse model and the human disease, persisted despite glycogen clearance. In some groups a modest glycogen reduction was accompanied by improved muscle strength. These studies suggest that enzyme replacement therapy, although at much higher doses than in other lysosomal diseases, has the potential to reverse cardiac pathology and to reduce the glycogen level in skeletal muscle.
酸性α-葡萄糖苷酶（GAA）缺乏会导致溶酶体糖原在细胞内广泛沉积，表现为肌病和心肌病。当用重组人酸性α-葡萄糖苷酶（rhGAA，20mg/kg/周，持续5个月）治疗GAA基因敲除小鼠时，与肝脏和心脏相比，骨骼肌细胞摄取的酶很少。糖原减少不到50%，一些肌纤维几乎没有或没有糖原清除。剂量为100mg/kg/周时，骨骼肌中的糖原清除率约为75%。两种剂量下，该酶均可将心脏糖原降低至检测不到的水平。残留糖原的骨骼肌纤维对溶酶体相关膜蛋白1/2（LAMP-1/LAMP-2）呈免疫反应性，表明未消化的糖原保留在增殖的溶酶体中。1型纤维中的糖原清除更为明显，组织化学分析表明这些纤维中的甘露糖-6-磷酸受体免疫反应性增加。酶向溶酶体的差异转运可能解释了糖原清除模式明显不均一的现象。尽管糖原已被清除，但自噬泡（小鼠模型和人类疾病的共同特征）仍然存在。在一些组中，适度的糖原减少伴随着肌肉力量的改善。这些研究表明，酶替代疗法虽然剂量比其他溶酶体疾病高得多，但有可能逆转心脏病变并降低骨骼肌中的糖原水平。
