Rescue of myogenic defects in Rb-deficient cells by inhibition of autophagy or by hypoxia-induced glycolytic shift.
Rescue of myogenic defects in Rb-deficient cells by inhibition of autophagy or by hypoxia-induced glycolytic shift.
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DOI：
10.1083/jcb.201005067
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发表时间：
2010-10-18
期刊：
影响因子：
--
通讯作者：
Zacksenhaus E
中科院分区：
文献类型：
--
作者：
Ciavarra G;Zacksenhaus E
PRb可抑制成肌细胞的凋亡和肌管的自噬，但不能激活成肌细胞的分化程序。视网膜母细胞瘤肿瘤抑制因子(PRB)被认为通过抑制细胞增殖和凋亡以及刺激谱系特异性转录因子来协调终末分化。在这项研究中，我们表明在没有pRB的情况下，分化的原代成肌细胞融合形成短的肌管，这些肌管永远不会抽动和通过非凋亡机制退化。缩短的肌管表现出线粒体网络受损、线粒体核周聚集、自噬降解和三磷酸腺苷产量减少。Bcl2和自噬抑制剂可以恢复线粒体的功能，挽救肌肉的退化，导致长的、颤动的肌管的形成，这些肌管表达正常水平的肌肉特异性蛋白，并稳定地退出细胞周期。低氧诱导的糖酵解开关也以低氧诱导因子-1(HIF-1)依赖的方式挽救Rb慢性或急性失活后的肌源性缺陷。这些结果表明，pRb可以抑制成肌细胞的凋亡和肌管的自噬，但不需要激活分化程序，同时也揭示了pRb与细胞代谢之间的新联系。
pRb is required to inhibit apoptosis in myoblasts and autophagy in myotubes but not for activation of the myogenic differentiation program. The retinoblastoma tumor suppressor (pRb) is thought to orchestrate terminal differentiation by inhibiting cell proliferation and apoptosis and stimulating lineage-specific transcription factors. In this study, we show that in the absence of pRb, differentiating primary myoblasts fuse to form short myotubes that never twitch and degenerate via a nonapoptotic mechanism. The shortened myotubes exhibit an impaired mitochondrial network, mitochondrial perinuclear aggregation, autophagic degradation, and reduced adenosine triphosphate production. Bcl-2 and autophagy inhibitors restore mitochondrial function and rescue muscle degeneration, leading to formation of long, twitching myotubes that express normal levels of muscle-specific proteins and stably exit the cell cycle. A hypoxia-induced glycolytic switch also rescues the myogenic defect after either chronic or acute inactivation of Rb in a hypoxia-inducible factor-1 (HIF-1)–dependent manner. These results demonstrate that pRb is required to inhibit apoptosis in myoblasts and autophagy in myotubes but not to activate the differentiation program, and they also reveal a novel link between pRb and cell metabolism.
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