Hypoxia inhibits myogenic differentiation through accelerated MyoD degradation
Hypoxia inhibits myogenic differentiation through accelerated MyoD degradation
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DOI：
10.1074/jbc.m313931200
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发表时间：
2004-04-16
影响因子：
4.8
通讯作者：
Germani, A
中科院分区：
文献类型：
--
作者：
Di Carlo, A;De Mori, R;Germani, A
细胞在低氧条件下经历各种生物反应，包括新陈代谢状态和生长速度的变化。在这里，我们研究了低氧对培养的肌源性细胞分化能力的影响。成肌细胞暴露于低氧强烈抑制多核肌管的形成和分化标志物的表达。我们发现缺氧可逆地抑制MyoD、Myf5和Mygenin的表达。骨骼肌分化的一个关键步骤是上调细胞周期依赖的激酶抑制因子p21和p27以及视网膜母细胞瘤基因(Prb)的产物。在低氧条件下分化培养的成肌细胞不能上调p21和pRb，尽管细胞周期被G(1)期阻断，p27积聚和pRb低磷酸化是证明的。低氧依赖的分化抑制与泛素-蛋白酶体途径的MyoD降解有关。C2C12成肌细胞中MyoD的过表达盖过了低氧条件下诱导的分化障碍。因此，通过诱导MyoD降解的低氧阻止了早期成肌分化标记物的积累，如肌肉生成素、p21和pRb，阻止了永久细胞周期退出和终末分化。我们的研究揭示了低氧对肌源性细胞产生的一种新的抗分化作用，并发现MyoD的降解是低氧的相关靶点。
Cells undergo a variety of biological responses when placed in hypoxic conditions, including alterations in metabolic state and growth rate. Here we investigated the effect of hypoxia on the ability of myogenic cells to differentiate in culture. Exposure of myoblasts to hypoxia strongly inhibited multinucleated myotube formation and the expression of differentiation markers. We showed that hypoxia reversibly inhibited MyoD, Myf5, and myogenin expression. One key step in skeletal muscle differentiation involves the up-regulation of the cell cycle-dependent kinase inhibitors p21 and p27 as well as the product of the retinoblastoma gene (pRb). Myoblasts cultured under hypoxic conditions in differentiation medium failed to up-regulate both p21 and pRb despite the G(1) cell cycle arrest, as evidenced by p27 accumulation and pRb hypophosphorylation. Hypoxia-dependent inhibition of differentiation was associated with MyoD degradation by the ubiquitin-proteasome pathway. MyoD overexpression in C2C12 myoblasts overrode the differentiation block imposed by hypoxic conditions. Thus, hypoxia by inducing MyoD degradation blocked accumulation of early myogenic differentiation markers such as myogenin and p21 and pRb, preventing both permanent cell cycle withdraw and terminal differentiation. Our study revealed a novel anti-differentiation effect exerted by hypoxia in myogenic cells and identified MyoD degradation as a relevant target of hypoxia.