Estrogen-related receptor α regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway
Estrogen-related receptor α regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway
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DOI：
10.1152/ajpcell.00033.2011
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发表时间：
2011-09-01
影响因子：
5.5
通讯作者：
Huss, Janice M.
中科院分区：
文献类型：
--
作者：
Murray, Jennifer;Huss, Janice M.
穆雷·J，胡斯·J·M。雌激素相关受体α通过调节ERK信号转导通路调节骨骼肌细胞分化。Am J Physiol Cell Physiol 301：C630-C645,2011。首次发表于2011年5月11日；doi：10.1152/ajpcell.00033.2011。-肌细胞分化涉及信号转导途径和转录因子之间的复杂相互作用。雌激素相关受体(ERRs)调节能量底物的摄取、线粒体的呼吸和生物发生，并可能针对横纹肌的结构基因程序。然而，ERRα在调节心肌细胞分化中的作用尚不清楚。ERRα和PGC-1α在肌肉发生早期与代谢和骨骼肌特异性基因协同上调。我们分析了ERRα过度表达和功能丧失在肌源性模型中的作用。在C2C12心肌细胞中，ERRα过表达促进了分化，而XCT790处理则延缓了肌细胞的发生，并导致肌管线粒体减少，肌节排列紊乱。ERRα/-原代心肌细胞表现出延迟的肌发生，导致结构不成熟的肌管，肌节组装和线粒体功能减少。然而，在ERRα/-细胞中，肌节和代谢基因的表达不受影响或上调。相反，ERRα/-肌细胞在肌发生早期表现出异常的ERK激活，这与肌管形成的延迟一致。XCT790处理也增加了C2C12中ERK的磷酸化，而ERRα过表达则降低了早期ERK的激活，这与这些处理对分化的相反作用是一致的。在ERRα/肌细胞和XCT790处理的C2C12中，MKP-1的瞬时诱导丢失，MKP-1在肌肉发生开始时介导ERK去磷酸化。Errα-PGC-1α复合体激活编码MKP-1的DUSP1基因，并在C2C12细胞的早期分化过程中占据近5‘调控区。最后，用MEK抑制剂治疗ERRα/-肌细胞可以挽救正常的ERK信号转导和肌肉发生。总之，这些数据表明，ERRα是正常骨骼肌细胞分化所必需的，通过调节MAP激酶信号。
Murray J, Huss JM. Estrogen-related receptor alpha regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway. Am J Physiol Cell Physiol 301: C630-C645, 2011. First published May 11, 2011; doi: 10.1152/ajpcell.00033.2011.-Myocyte differentiation involves complex interactions between signal transduction pathways and transcription factors. The estrogen-related receptors (ERRs) regulate energy substrate uptake, mitochondrial respiration, and biogenesis and may target structural gene programs in striated muscle. However, ERR alpha's role in regulating myocyte differentiation is not known. ERR alpha and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) are coordinately upregulated with metabolic and skeletal muscle-specific genes early in myogenesis. We analyzed effects of ERR alpha overexpression and loss of function in myogenic models. In C2C12 myocytes ERR alpha overexpression accelerated differentiation, whereas XCT790 treatment delayed myogenesis and resulted in myotubes with fewer mitochondria and disorganized sarcomeres. ERR alpha-/- primary myocytes showed delayed myogenesis, resulting in structurally immature myotubes with reduced sarcomeric assembly and mitochondrial function. However, sarcomeric and metabolic gene expression was unaffected or upregulated in ERR alpha-/- cells. Instead, ERR alpha-/- myocytes exhibited aberrant ERK activation early in myogenesis, consistent with delayed myotube formation. XCT790 treatment also increased ERK phosphorylation in C2C12, whereas ERR alpha overexpression decreased early ERK activation, consistent with the opposing effects of these treatments on differentiation. The transient induction of MAP kinase phosphatase-1 (MKP-1), which mediates ERK dephosphorylation at the onset of myogenesis, was lost in ERR alpha-/- myocytes and in XCT790-treated C2C12. The ERR alpha-PGC-1 alpha complex activates the Dusp1 gene, which encodes MKP-1, and ERR alpha occupies the proximal 5' regulatory region during early differentiation in C2C12 myocytes. Finally, treatment of ERR alpha-/- myocytes with MEK inhibitors rescued normal ERK signaling and myogenesis. Collectively, these data demonstrate that ERR alpha is required for normal skeletal myocyte differentiation via modulation of MAP kinase signaling.