Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Hum Mol Genet. 2010 Feb 15;19(4):684-96. doi: 10.1093/hmg/ddp535. Epub 2009 Dec 3.
Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to lysosomal glycogen accumulation. Affected individuals store glycogen mainly in cardiac and skeletal muscle tissues resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe infantile form. Enzyme replacement therapy has already proved some efficacy, but results remain variable especially in skeletal muscle. Substrate reduction therapy was successfully used to improve the phenotype in several lysosomal storage disorders. We have recently demonstrated that shRNA-mediated reduction of glycogen synthesis led to a significant reduction of glycogen accumulation in skeletal muscle of GSDII mice. In this paper, we analyzed the effect of a complete genetic elimination of glycogen synthesis in the same GSDII model. GAA and glycogen synthase 1 (GYS1) KO mice were inter-crossed to generate a new double-KO model. GAA/GYS1-KO mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in double-KO mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in GAA/GYS1-KO mice, resulting in improved exercise capacity. These data demonstrate that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in GSDII mice and offers a new perspective for the treatment of Pompe disease.
糖原贮积病 II 型（GSDII）或庞贝病是一种常染色体隐性遗传病，由酸性α-葡萄糖苷酶（GAA）缺乏引起，导致溶酶体糖原积累。受影响的个体主要在心脏和骨骼肌组织中储存糖原，导致最严重的婴儿型肥厚型心肌病和呼吸衰竭。酶替代疗法已经证明了一些疗效，但结果仍然存在差异，特别是在骨骼肌中。底物减少疗法已成功用于改善几种溶酶体贮积症的表型。我们最近证明，通过 shRNA 介导的糖原合成减少可导致 GSDII 小鼠骨骼肌中糖原积累显著减少。在本文中，我们分析了在相同的 GSDII 模型中完全消除糖原合成的效果。GAA 和糖原合酶 1（GYS1）KO 小鼠进行杂交以产生新的双 KO 模型。GAA/GYS1-KO 小鼠的心脏和骨骼肌中的糖原含量明显减少，溶酶体肿胀和自噬增加明显减少，心脏肥大完全纠正。此外，在 GSDII 模型中观察到的葡萄糖代谢和胰岛素耐量异常在双 KO 小鼠中得到纠正。在 11 个月大的 GSDII 小鼠中观察到的肌肉萎缩在 GAA/GYS1-KO 小鼠中不那么明显，从而提高了运动能力。这些数据表明，长期消除肌肉糖原合成可显著改善 GSDII 小鼠的结构、代谢和功能缺陷，并为庞贝病的治疗提供了新的视角。
