Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
J Cell Biol. 2010 Oct 18;191(2):291-301. doi: 10.1083/jcb.201005067. Epub 2010 Oct 11.
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.
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并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搐，并通过非凋亡机制退化。缩短的肌管表现出受损的线粒体网络、线粒体核周聚集、自噬降解和减少的三磷酸腺苷产生。Bcl-2 和自噬抑制剂恢复线粒体功能并挽救肌肉退化，导致形成长的、抽搐的肌管，表达正常水平的肌肉特异性蛋白并稳定退出细胞周期。缺氧诱导的糖酵解开关也以缺氧诱导因子-1（HIF-1）依赖性方式挽救 Rb 慢性或急性失活后的成肌缺陷。这些结果表明，pRb 需要抑制成肌细胞中的细胞凋亡和肌管中的自噬，但不需要激活分化程序，并且它们还揭示了 pRb 与细胞代谢之间的新联系。
