Role of autophagy in glycogen breakdown and its relevance to chloroquine myopathy.
Role of autophagy in glycogen breakdown and its relevance to chloroquine myopathy.
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DOI：
10.1371/journal.pbio.1001708
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发表时间：
2013-11
期刊：
影响因子：
9.8
通讯作者：
Perrimon N
中科院分区：
文献类型：
--
作者：
Zirin J;Nieuwenhuis J;Perrimon N
一种新的氯喹肌病果蝇模型系统揭示了糖原是如何针对溶酶体的，以及这一过程对肌肉细胞的意义。一些肌病与糖原的自噬和溶酶体降解缺陷有关，但仍不清楚糖原是如何靶向溶酶体的，以及这一过程对肌肉细胞有什么意义。我们已经建立了一个果蝇黑腹果蝇模型来研究骨骼肌糖原自噬，使用氯喹(CQ)来模拟完全依赖核心自噬基因的空泡性肌病。我们证明，自噬是应对饥饿时糖原最有效的降解所必需的。此外，我们发现CQ诱导的肌病可以通过减少自噬或糖原合成来改善，后者可能是由于糖原合成酶通过与Atg8的相互作用而直接调节自噬。溶酶体是细胞器，作为细胞的处置系统。众所周知，溶酶体可以降解糖原，这一功能的缺陷会在动物体内引发含有糖原的囊泡积聚，从而导致空泡性肌病--这种疾病会导致肌肉无力。然而，目前尚不清楚糖原是如何和为什么通过这个系统降解的，以及它对此类疾病的病理有什么意义。在这里，我们通过建立一个果蝇模型系统来研究骨骼肌糖原自噬来解决这些问题。通过给果蝇喂食氯喹(CQ)，我们诱导了一种与大量充满糖原的小泡积累相关的空泡性肌病，并分析了自噬和糖原代谢酶在这一过程中的作用。我们证明了CQ诱导的糖原自噬完全依赖于核心保守的自噬基因，并且这种自噬是由营养剥夺以Tor依赖的方式触发的。有趣的是，虽然糖原自噬和酶促糖原分解可以相互补偿，但同时抑制这两个系统会阻止糖原分解。最后，我们证明CQ诱导的肌病可以通过减少自噬或糖原合成来改善，后者可能是由于糖原合成酶-参与将葡萄糖转化为糖原的主要酶-通过与自噬小体的相互作用而调节自噬的直接作用。
A novel Drosophila model system of chloroquine myopathy reveals how glycogen is targeted to the lysosome and what the significance of this process is for muscle cells. Several myopathies are associated with defects in autophagic and lysosomal degradation of glycogen, but it remains unclear how glycogen is targeted to the lysosome and what significance this process has for muscle cells. We have established a Drosophila melanogaster model to study glycogen autophagy in skeletal muscles, using chloroquine (CQ) to simulate a vacuolar myopathy that is completely dependent on the core autophagy genes. We show that autophagy is required for the most efficient degradation of glycogen in response to starvation. Furthermore, we show that CQ-induced myopathy can be improved by reduction of either autophagy or glycogen synthesis, the latter possibly due to a direct role of Glycogen Synthase in regulating autophagy through its interaction with Atg8. Lysosomes are organelles that work as a disposal system for the cell. It is known that lysosomes can degrade glycogen and that defects in this function trigger the accumulation of vesicles containing glycogen in animals that lead to vacuolar myopathies—diseases that result in muscle weakness. However, it remains unclear how and why glycogen is degraded through this system, and what significance it has for the pathology of such diseases. Here, we addressed these questions by establishing a fruitfly model system to study glycogen autophagy in skeletal muscles. By feeding the flies chloroquine (CQ), we induce a vacuolar myopathy associated with massive accumulation of glycogen-filled vesicles, and assay the role of autophagy and glycogen metabolic enzymes in this process. We show that CQ-induced glycogen autophagy is completely dependent on the core conserved autophagy genes and that this autophagy is triggered by nutrient deprivation in a Tor-dependent manner. Interestingly, while glycogen autophagy and enzymatic glycogen breakdown can compensate for each other, concurrent inhibition of both systems blocks glycogen breakdown. Finally, we show that CQ-induced myopathy can be improved by reduction of either autophagy or glycogen synthesis, the latter possibly due to a direct role of glycogen synthase—the main enzyme involved in converting glucose to glycogen—in regulating autophagy through its interaction with the autophagosome.
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影响因子：
3.5
作者：
Aguado C;Sarkar S;Korolchuk VI;Criado O;Vernia S;Boya P;Sanz P;de Córdoba SR;Knecht E;Rubinsztein DC
通讯作者：
Rubinsztein DC
影响因子：
11
作者：
EADIE, MJ;FERRIER, TM
通讯作者：
FERRIER, TM
影响因子：
4.1
作者：
HERS, HG
通讯作者：
HERS, HG
影响因子：
27.4
作者：
Casado, E;Gratacós, J;Larrosa, M
通讯作者：
Larrosa, M
影响因子：
3.5
作者：
Juhász, G;Csikós, G;Sass, M
通讯作者：
Sass, M