Matching of calcineurin activity to upstream effectors is critical for skeletal muscle fiber growth.
Matching of calcineurin activity to upstream effectors is critical for skeletal muscle fiber growth.
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DOI：
10.1083/jcb.151.3.663
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发表时间：
2000-10-30
期刊：
影响因子：
--
通讯作者：
Michel RN
中科院分区：
文献类型：
--
作者：
Dunn SE;Chin ER;Michel RN
钙调神经磷酸酶依赖性途径与骨骼肌对功能性超负荷（OV）的肥大反应有关（Dunn，S.E.，J.L. Burns和R.N.米歇尔1999. J.Biol.Chem.274：21908-21912）。在这里，我们表明，骨骼肌过表达的钙调神经磷酸酶（CnA*）的活化形式表现出的表型与野生型对应物在正常负重条件下，并响应OV与细胞大小和缓慢的纤维数类似的翻倍。尽管CnA* 肌肉显示出三倍高的钙调磷酸酶活性和增强的钙调磷酸酶靶点NFATc 1，MEF 2A和MEF 2D的去磷酸化，这些适应性还是发生了。此外，当钙调神经磷酸酶信号转导受到环孢菌素A的损害时，OV野生型小鼠的肌肉显示出较低分子量形式的CnA，最初在衰竭的心脏中检测到，而CnA* 肌肉则没有这种表现。我们还表明，OV诱导的生长和类型转换被阻止在过表达一种肽的转基因小鼠的肌纤维中，该肽抑制钙调蛋白向靶酶的信号传导。两者合计，这些研究结果提供的证据表明，钙调神经磷酸酶和其活性相关的上游信号元件是至关重要的肌肉适应OV，除非显着受损，这种酶的内源性水平可以适应上游钙依赖性信号事件的大波动。
Calcineurin-dependent pathways have been implicated in the hypertrophic response of skeletal muscle to functional overload (OV) (Dunn, S.E., J.L. Burns, and R.N. Michel. 1999. J. Biol. Chem. 274:21908–21912). Here we show that skeletal muscles overexpressing an activated form of calcineurin (CnA*) exhibit a phenotype indistinguishable from wild-type counterparts under normal weightbearing conditions and respond to OV with a similar doubling in cell size and slow fiber number. These adaptations occurred despite the fact that CnA* muscles displayed threefold higher calcineurin activity and enhanced dephosphorylation of the calcineurin targets NFATc1, MEF2A, and MEF2D. Moreover, when calcineurin signaling is compromised with cyclosporin A, muscles from OV wild-type mice display a lower molecular weight form of CnA, originally detected in failing hearts, whereas CnA* muscles are spared this manifestation. We also show that OV-induced growth and type transformations are prevented in muscle fibers of transgenic mice overexpressing a peptide that inhibits calmodulin from signaling to target enzymes. Taken together, these findings provide evidence that both calcineurin and its activity-linked upstream signaling elements are crucial for muscle adaptations to OV and that, unless significantly compromised, endogenous levels of this enzyme can accommodate large fluctuations in upstream calcium-dependent signaling events.
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影响因子：
11.4
作者：
Morin, S;Charron, F;Nemer, M
通讯作者：
Nemer, M
影响因子：
10.5
作者：
Chin, ER;Olson, EN;Williams, RS
通讯作者：
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DOI：
10.1152/ajpcell.1997.273.2.c371
发表时间：
1997-08-01
影响因子：
5.5
作者：
Dunn, SE;Michel, RN
通讯作者：
Michel, RN
影响因子：
0.7
作者：
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通讯作者：
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DOI：
10.1073/pnas.86.20.7780
发表时间：
1989-10-01
影响因子：
11.1
作者：
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通讯作者：
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