Genetic loss of calcineurin blocks mechanical overload-induced skeletal muscle fiber type switching but not hypertrophy
Genetic loss of calcineurin blocks mechanical overload-induced skeletal muscle fiber type switching but not hypertrophy
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DOI：
10.1074/jbc.m313800200
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发表时间：
2004-06-18
影响因子：
4.8
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
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作者：
Parsons, SA;Millay, DP;Molkentin, JD
丝氨酸/苏氨酸磷酸酶钙调神经磷酸酶是真核细胞内钙激活反应的重要调节因子。在高等真核生物中，钙/钙调蛋白介导的钙调磷酸酶活化促进活化T细胞的转录因子核因子（NFAT）的直接去磷酸化和核转位。最近，围绕钙调神经磷酸酶在介导骨骼肌细胞肥大中的作用存在争议。在这里，我们研究了钙调神经磷酸酶缺陷小鼠在机械过载（MOV）刺激或胰岛素样生长因子-1（IGF-1）刺激后骨骼肌肥大生长的能力。采用了两种不同的钙调磷酸酶缺乏模型：钙调磷酸酶Abeta基因靶向小鼠，其显示总钙调磷酸酶减少约50%，和钙调磷酸酶B1-LoxP靶向小鼠与肌球蛋白轻链1f cre敲入等位基因杂交，其显示仅在骨骼肌中总钙调磷酸酶损失大于80%。钙调神经磷酸酶Abeta-/-和钙调神经磷酸酶B1-LoxP（fl/fl）-MLC-cre小鼠在响应IGF-1处理或MOV刺激的肌肉生长中基本上没有显示出缺陷，尽管钙调神经磷酸酶Abeta-/-小鼠显示出足底总纤维数量的基础缺陷和生长的轻度继发性减少，这与肌发生中的发育缺陷一致。两组基因靶向小鼠在MOV或IGF-1刺激后均显示Akt活化的正常增加。然而，在钙调神经磷酸酶B1-LoxP（fl/fl）-MLC-cre小鼠中，过负荷介导的纤维类型转换显著受损。NFAT-荧光素酶报告基因转基因小鼠未能显示IGF-1或MOV诱导的肥大和钙调神经磷酸酶-NFAT-依赖性信号在体内之间的相关性。我们的结论是，钙调神经磷酸酶的表达是重要的，在肌形成和纤维类型转换，但不是肌肉生长在肥大刺激。
The serine/threonine phosphatase calcineurin is an important regulator of calcium-activated intracellular responses in eukaryotic cells. In higher eukaryotes, calcium/calmodulin-mediated activation of calcineurin facilitates direct dephosphorylation and nuclear translocation of the transcription factor nuclear factor of activated T-cells ( NFAT). Recently, controversy has surrounded the role of calcineurin in mediating skeletal muscle cell hypertrophy. Here we examined the ability of calcineurin-deficient mice to undergo skeletal muscle hypertrophic growth following mechanical overload (MOV) stimulation or insulin-like growth factor-1 (IGF-1) stimulation. Two distinct models of calcineurin deficiency were employed: calcineurin Abeta gene-targeted mice, which show a approximate to50% reduction in total calcineurin, and calcineurin B1-LoxP-targeted mice crossed with a myosin light chain 1f cre knock-in allele, which show a greater than 80% loss of total calcineurin only in skeletal muscle. Calcineurin Abeta-/- and calcineurin B1-LoxP(fl/fl)-MLC-cre mice show essentially no defects in muscle growth in response to IGF-1 treatment or MOV stimulation, although calcineurin Abeta-/- mice show a basal defect in total fiber number in the plantaris and a mild secondary reduction in growth, consistent with a developmental defect in myogenesis. Both groups of gene-targeted mice show normal increases in Akt activation following MOV or IGF-1 stimulation. However, overload-mediated fiber-type switching was dramatically impaired in calcineurin B1-LoxP(fl/fl)-MLC-cre mice. NFAT-luciferase reporter transgenic mice failed to show a correlation between IGF-1- or MOV-induced hypertrophy and calcineurin-NFAT-dependent signaling in vivo. We conclude that calcineurin expression is important during myogenesis and fiber-type switching, but not for muscle growth in response to hypertrophic stimuli.