Glycogen accumulation in smooth muscle of a Pompe disease mouse model.
Glycogen accumulation in smooth muscle of a Pompe disease mouse model.
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DOI：
10.1540/jsmr.57.8
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
ElMallah MK
中科院分区：
文献类型：
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作者：
McCall AL;Dhindsa JS;Bailey AM;Pucci LA;Strickland LM;ElMallah MK
庞贝病是一种由 GAA 基因突变引起的溶酶体贮积病，该基因编码酸性 α-葡萄糖苷酶 (GAA)——一种溶酶体糖原降解所必需的酶。 GAA 的缺乏会导致心肌、骨骼肌以及运动神经元中糖原的积累。 FDA 批准的唯一一种庞贝病治疗方法——酶替代疗法 (ERT)——可以提高患者的生存率，但也暴露了庞贝病以前未被识别的临床表现。这些临床体征和症状包括气管支气管软化、血管动脉瘤和胃肠道不适。总之，这些以前未被认识的病理表明，除了骨骼肌和心肌外，GAA 缺乏还会影响平滑肌。因此，我们试图表征 Gaa−/− 小鼠模型中气道、血管、胃肠道和泌尿生殖系统的平滑肌病理学特征。与野生型小鼠相比，Gaa−/− 小鼠的主动脉、气管、食道、胃和膀胱的平滑肌细胞中糖原水平升高。此外，溶酶体膜蛋白（LAMP1）和自噬体膜蛋白（LC3）丰度增加，表明多个组织中存在液泡积累。综上所述，我们发现 GAA 缺乏会导致平滑肌细胞随后出现病理变化，如果治疗不当，可能会导致危及生命的并发症。
Pompe disease is a lysosomal storage disease caused by mutations within the GAA gene, which encodes acid α-glucosidase (GAA)—an enzyme necessary for lysosomal glycogen degradation. A lack of GAA results in an accumulation of glycogen in cardiac and skeletal muscle, as well as in motor neurons. The only FDA approved treatment for Pompe disease—an enzyme replacement therapy (ERT)—increases survival of patients, but has unmasked previously unrecognized clinical manifestations of Pompe disease. These clinical signs and symptoms include tracheo-bronchomalacia, vascular aneurysms, and gastro-intestinal discomfort. Together, these previously unrecognized pathologies indicate that GAA-deficiency impacts smooth muscle in addition to skeletal and cardiac muscle. Thus, we sought to characterize smooth muscle pathology in the airway, vascular, gastrointestinal, and genitourinary in the Gaa−/− mouse model. Increased levels of glycogen were present in smooth muscle cells of the aorta, trachea, esophagus, stomach, and bladder of Gaa−/− mice, compared to wild type mice. In addition, there was an increased abundance of both lysosome membrane protein (LAMP1) and autophagosome membrane protein (LC3) indicating vacuolar accumulation in several tissues. Taken together, we show that GAA deficiency results in subsequent pathology in smooth muscle cells, which may lead to life-threatening complications if not properly treated.