Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle.
Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle.
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DOI：
10.1038/ncomms9526
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发表时间：
2015-10-08
影响因子：
16.6
通讯作者：
Ward CW
中科院分区：
文献类型：
--
作者：
Kerr JP;Robison P;Shi G;Bogush AI;Kempema AM;Hexum JK;Becerra N;Harki DA;Martin SS;Raiteri R;Prosser BL;Ward CW
在横纹肌中，X-ROS是微管网络传递的机械应力激发活性氧的机械传导途径。X-ROS调节健康肌肉中的Ca 2+信号传导，但在杜氏肌营养不良症（DMD）等疾病中，微管改变驱动X-ROS升高，破坏Ca 2+稳态并损害功能。在这里，我们表明，脱酪氨酸，α-微管蛋白的翻译后修饰，影响X-ROS信号，收缩速度和细胞骨架力学。在DMD的mdx小鼠模型中，体外脱酪氨酸的药理学减少消除了异常的X-ROS和Ca 2+信号传导，并且在体内它可以防止DMD的特征，包括工作负荷诱导的心律失常和骨骼肌收缩诱导的损伤。我们的结论是，脱酪氨酸微管增加横纹肌的细胞骨架刚度和机械转导，并针对这种翻译后修饰可能有广泛的治疗潜力，在肌营养不良症。 微管是肌肉细胞中机械能的转换器。在这里，作者表明，机械转导是由小鼠心脏和骨骼肌中微管的翻译后脱酪氨酸调节的，并且减少脱酪氨酸可以改善杜氏肌营养不良症模型的症状。
In striated muscle, X-ROS is the mechanotransduction pathway by which mechanical stress transduced by the microtubule network elicits reactive oxygen species. X-ROS tunes Ca2+ signalling in healthy muscle, but in diseases such as Duchenne muscular dystrophy (DMD), microtubule alterations drive elevated X-ROS, disrupting Ca2+ homeostasis and impairing function. Here we show that detyrosination, a post-translational modification of α-tubulin, influences X-ROS signalling, contraction speed and cytoskeletal mechanics. In the mdx mouse model of DMD, the pharmacological reduction of detyrosination in vitro ablates aberrant X-ROS and Ca2+ signalling, and in vivo it protects against hallmarks of DMD, including workload-induced arrhythmias and contraction-induced injury in skeletal muscle. We conclude that detyrosinated microtubules increase cytoskeletal stiffness and mechanotransduction in striated muscle and that targeting this post-translational modification may have broad therapeutic potential in muscular dystrophies. Microtubules are transducers of mechanical energy in muscle cells. Here, the authors show that mechanotransduction is regulated by post-translational detyrosination of microtubules in mouse heart and skeletal muscle, and that reducing detyrosination ameliorates symptoms in a model of Duchenne muscular dystrophy.