Rescue of myogenic defects in Rb-deficient cells by inhibition of autophagy or by hypoxia-induced glycolytic shift

被引:34
作者
Ciavarra, Giovanni [1 ]
Zacksenhaus, Eldad [1 ,2 ]
机构
[1] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON M5S 1A1, Canada
[2] Univ Hlth Network, Toronto Gen Res Inst, Div Cell & Mol Biol, Toronto, ON M5G 2M1, Canada
关键词
RETINOBLASTOMA GENE; MUSCLE-CELLS; TRANSCRIPTION FACTOR; CHIMERIC MICE; DIFFERENTIATION; PROTEIN; PRB; DEGRADATION; ACTIVATION; APOPTOSIS;
D O I
10.1083/jcb.201005067
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 pRb 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.
引用
收藏
页码:291 / 301
页数:11
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