Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA.
Mol Genet Metab. 2010 Dec;101(4):324-31. doi: 10.1016/j.ymgme.2010.08.001. Epub 2010 Aug 7.
Pompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase, the enzyme that degrades glycogen in the lysosomes. The disease manifests as a fatal cardiomyopathy and skeletal muscle myopathy in infants; in milder late-onset forms skeletal muscle is the major tissue affected. We have previously demonstrated that autophagic inclusions in muscle are prominent in adult patients and the mouse model. In this study we have evaluated the contribution of the autophagic pathology in infants before and 6 months after enzyme replacement therapy. Single muscle fibers, isolated from muscle biopsies, were stained for autophagosomal and lysosomal markers and analyzed by confocal microscopy. In addition, unstained bundles of fixed muscles were analyzed by second harmonic imaging. Unexpectedly, the autophagic component which is so prominent in juvenile and adult patients was negligible in infants; instead, the overwhelming characteristic was the presence of hugely expanded lysosomes. After 6 months on therapy, however, the autophagic buildup becomes visible as if unmasked by the clearance of glycogen. In most fibers, the two pathologies did not seem to coexist. These data point to the possibility of differences in the pathogenesis of Pompe disease in infants and adults.
庞贝病是一种溶酶体贮积症，由酸性α-葡萄糖苷酶缺乏引起，该酶在溶酶体中降解糖原。这种疾病在婴儿中表现为致命性的心肌病和骨骼肌肌病；在较温和的晚发性形式中，骨骼肌是主要受影响的组织。我们之前已经证明，在成年患者和小鼠模型中，肌肉中的自噬包含物很明显。在这项研究中，我们评估了酶替代治疗前和治疗后 6 个月婴儿的自噬病理变化。从肌肉活检中分离出的单个肌纤维，用自噬体和溶酶体标记物染色，并通过共聚焦显微镜进行分析。此外，还通过二次谐波成像分析了未经染色的固定肌肉束。出乎意料的是，在青少年和成年患者中如此明显的自噬成分在婴儿中微不足道；相反，压倒性的特征是存在巨大扩张的溶酶体。然而，经过 6 个月的治疗后，自噬堆积变得可见，就好像糖原的清除使它暴露出来。在大多数纤维中，这两种病理似乎不会共存。这些数据表明婴儿和成人中庞贝病的发病机制可能存在差异。
