Maduramicin inactivation of Akt impairs autophagic flux leading to accumulated autophagosomes-dependent apoptosis in skeletal myoblast cells.
Maduramicin inactivation of Akt impairs autophagic flux leading to accumulated autophagosomes-dependent apoptosis in skeletal myoblast cells.
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马杜霉素使 Akt 失活会损害自噬流，导致骨骼肌成肌细胞中积累的自噬体依赖性细胞凋亡
DOI：
10.1016/j.biocel.2019.105573
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发表时间：
2019-09
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影响因子：
--
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马杜霉素（Maduramicin，Mad）是一种聚醚类离子载体抗生素，广泛用于家禽球虫病的防治，如果使用不当，可引起动物和人类骨骼肌变性、心力衰竭甚至死亡。在这里，我们发现，疯诱导凋亡的剂量依赖性，这是与骨骼肌成肌细胞（C2 C12和L 6）细胞的自噬流量受损。这得到了Mad治疗导致细胞中自噬体增加以及伴随的LC 3-II和p62升高的发现的支持。此外，Mad增加了细胞中mCherry和GFP串联标记的LC 3斑点的共定位，表明自噬通量的阻断。此外，加入氯喹（CQ）加强了基础和疯狂增强LC 3-II和p62水平，自噬体形成和细胞凋亡，而雷帕霉素预处理减轻了暴露于疯狂的细胞的影响。此外，我们注意到Mad处理使Akt失活呈剂量依赖性。Akt与抑制剂X的抑制增强了Mad-induced磷酸化Akt的减少，LC 3-II和p62水平的增加，自噬体形成和细胞凋亡，而异位表达的组成性活性Akt呈现对这些事件的抗性。总的来说，这些结果表明，Akt的Mad失活损害自噬通量，导致骨骼肌成肌细胞中累积的自噬体依赖性凋亡。我们的研究结果表明，操纵Akt活性，以提高自噬流量是一个很有前途的战略，对疯狂诱导的肌毒性。
It has been clinically documented that maduramicin (Mad), a polyether ionophore antibiotic widely used in the control of coccidiosis in poultry worldwide, can elicit skeletal muscle degeneration, heart failure, and even death in animals and humans, if improperly used. Here, we show that Mad induced apoptosis dose-dependently, which was associated with impaired autophagic flux in skeletal myoblast (C2C12 and L6) cells. This is supported by the findings that Mad treatment resulted in increase of autophagosomes with a concomitant elevation of LC3-II and p62 in the cells. Also, Mad increased co-localization of mCherry and GFP tandem-tagged LC3 puncta in the cells, suggesting a blockage of autophagic flux. Furthermore, addition of chloroquine (CQ) strengthened the basic and Mad-enhanced LC3-II and p62 levels, autophagosome formation and cell apoptosis, whereas pretreatment with rapamycin alleviated the effects in the cells exposed to Mad. Moreover, we noticed that Mad treatment inactivated Akt dose-dependently. Inhibition of Akt with inhibitor X potentiated Mad-induced decrease in phosphorylated Akt, and increases in LC3-II and p62 levels, autophagosome formation and cell apoptosis, whereas ectopic expression of constitutively active Akt rendered resistance to these events. Collectively, these results indicate that Mad inactivation of Akt impairs autophagic flux leading to accumulated autophagosomes-dependent apoptosis in skeletal myoblast cells. Our findings suggest that manipulation of Akt activity to improve autophagic flux is a promising strategy against Mad-induced myotoxicity.
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影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
影响因子：
6.1
作者：
BROWN, MA;RAJAN, S
通讯作者：
RAJAN, S
影响因子：
4.8
作者：
Bruntz, Ronald C.;Taylor, Harry E.;Brown, H. Alex
通讯作者：
Brown, H. Alex
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1038/nri3532
发表时间：
2013-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Deretic V;Saitoh T;Akira S
通讯作者：
Akira S