Autophagy in skeletal muscle: implications for Pompe disease.
Autophagy in skeletal muscle: implications for Pompe disease.
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DOI：
10.5414/cpp47042
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发表时间：
2009
影响因子：
0.8
通讯作者：
Raben N
中科院分区：
文献类型：
--
作者：
Shea L;Raben N
庞贝病是由遗传性酸性α-葡萄糖苷酶(GaA)缺乏引起的，GaA是一种溶酶体酶，催化糖原分解为葡萄糖。在没有GAA的情况下，虽然主要的临床表现是心肌和骨骼肌，但肿大的、充满糖原的溶酶体在多个组织中积聚。多年来，人们认为充满糖原的溶酶体破裂是庞贝病患者肌肉深度损伤的主要原因。在这里，我们提出的证据表明，在Pompe病患者和GAA基因敲除小鼠中，肌肉组织中的生产性自噬失败是导致疾病病理的重要原因。在GAA基因敲除的小鼠模型中，自噬小泡的逐渐积累仅限于富含II型的肌肉纤维。自噬小体的这种积聚不仅扰乱了肌肉纤维中的收缩装置，而且还干扰了酶替代疗法，因为它充当了重组酶的接收器，阻止了它有效地运送到溶酶体。我们的数据表明，有必要重新检查庞贝病的可能病理机制，并表明庞贝病患者的成功治疗将需要考虑这种疾病中发生的自噬的戏剧性失败。
Pompe disease is caused by an inherited deficiency of acid α-glucosidase (GAA), a lysosomal enzyme that catalyzes the breakdown of glycogen to glucose. In the absence of GAA, enlarged, glycogen-laden lysosomes accumulate in multiple tissues, although the major clinical manifestations are seen in cardiac and skeletal muscle. For many years, it was believed that the rupture of glycogen-filled lysosomes was the major cause of the profound muscle damage observed in patients with Pompe disease. Here, we present evidence that a failure of productive autophagy in muscle tissue contributes strongly to disease pathology in both patients with Pompe disease and GAA-knockout mice. In the GAA-knockout mouse model, progressive accumulation of autophagic vesicles is restricted to Type II-rich muscle fibers. Not only does this build-up of autophagosomes disrupt the contractile apparatus in the muscle fibers, it also interferes with enzyme replacement therapy by acting as a sink for the recombinant enzyme and preventing its efficient delivery to the lysosomes. Our data indicate that a re-examination of the presumed pathological mechanism in Pompe disease is necessary, and suggest that successful treatment of patients with Pompe disease will require consideration of the dramatic failure of autophagy that occurs in this disease.