Raben Nina, Baum Rebecca, Schreiner Cynthia, Takikita Shoichi, Mizushima Noboru, Ralston Evelyn, Plotz Paul
Arthritis and Rheumatism Branch, NIAMS, NIH, Bethesda, MD 20892-1820, USA.
Autophagy. 2009 Jan;5(1):111-3. doi: 10.4161/auto.5.1.7293. Epub 2009 Jan 30.
The role of autophagy, a catabolic lysosome-dependent pathway, has recently been recognized in a variety of disorders, including Pompe disease, which results from a deficiency of the glycogen-degrading lysosomal hydrolase acid-alpha glucosidase (GAA). Skeletal and cardiac muscle are most severely affected by the progressive expansion of glycogen-filled lysosomes. In both humans and an animal model of the disease (GAA KO), skeletal muscle pathology also involves massive accumulation of autophagic vesicles and autophagic buildup in the core of myofibers, suggesting an induction of autophagy. Only when we suppressed autophagy in the skeletal muscle of the GAA KO mice did we realize that the excess of autophagy manifests as a functional deficiency. This failure of productive autophagy is responsible for the accumulation of potentially toxic aggregate-prone ubiquitinated proteins, which likely cause profound muscle damage in Pompe mice. Also, by generating muscle-specific autophagy-deficient wild-type mice, we were able to analyze the role of autophagy in healthy skeletal muscle.
自噬是一种分解代谢的、依赖溶酶体的途径，其作用最近在包括庞贝病在内的多种疾病中得到了认可。庞贝病是由糖原降解溶酶体水解酶酸性α-葡萄糖苷酶（GAA）缺乏引起的。骨骼肌和心肌受充满糖原的溶酶体逐渐扩张的影响最为严重。在人类和该疾病的动物模型（GAA基因敲除小鼠）中，骨骼肌病理还涉及自噬小泡的大量积累和肌纤维核心中的自噬堆积，提示自噬被诱导。只有当我们抑制GAA基因敲除小鼠骨骼肌中的自噬时，才意识到自噬过度表现为功能缺陷。这种自噬无效导致了易聚集的潜在毒性泛素化蛋白的积累，这可能是导致庞贝病小鼠严重肌肉损伤的原因。此外，通过构建肌肉特异性自噬缺陷的野生型小鼠，我们能够分析自噬在健康骨骼肌中的作用。
