Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease
Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease
复制标题
DOI：
10.1172/jci61134
复制
发表时间：
2012-04-01
影响因子：
15.9
通讯作者：
Chen, Ju
中科院分区：
文献类型：
--
作者：
Sheikh, Farah;Ouyang, Kunfu;Chen, Ju
肌动蛋白-肌球蛋白相互作用提供了每一次心跳的驱动力。目前的观点是肌动蛋白结合的调节蛋白在钙依赖性心肌收缩的激活中起主导作用。相比之下，心肌中肌球蛋白调节蛋白（例如肌球蛋白轻链-2（MLC 2））调节的相关性和性质仍然知之甚少。通过整合基因靶向小鼠和计算模型，我们已经确定了心室Mlc 2（Mlc 2 v）磷酸化在调节心肌收缩中不可或缺的作用。心肌肌球蛋白循环动力学，直接控制肌动蛋白-肌球蛋白的相互作用，直接受到影响，但令人惊讶的是，Mlc 2 v磷酸化也反馈到合作影响钙依赖性激活的细丝。这些机制的缺失导致心肌收缩松弛和心室扭转速率的早期缺陷。引人注目的是，这些缺陷之前的左心室功能障碍的心脏病和衰竭的小鼠模型与非磷酸化Mlc 2 v。因此，在横纹肌收缩中，Mlc 2磷酸化在调节肌动蛋白-肌球蛋白相互作用中具有直接和早期的作用，并且Mlc 2的去磷酸化或这些机制的丧失在心力衰竭中起关键作用。
Actin-myosin interactions provide the driving force underlying each heartbeat. The current view is that actin-bound regulatory proteins play a dominant role in the activation of calcium-dependent cardiac muscle contraction. In contrast, the relevance and nature of regulation by myosin regulatory proteins (for example, myosin light chain-2 [MLC2]) in cardiac muscle remain poorly understood. By integrating gene-targeted mouse and computational models, we have identified an indispensable role for ventricular Mlc2 (Mlc2v) phosphorylation in regulating cardiac muscle contraction. Cardiac myosin cycling kinetics, which directly control actin-myosin interactions, were directly affected, but surprisingly, Mlc2v phosphorylation also fed back to cooperatively influence calcium-dependent activation of the thin filament. Loss of these mechanisms produced early defects in the rate of cardiac muscle twitch relaxation and ventricular torsion. Strikingly, these defects preceded the left ventricular dysfunction of heart disease and failure in a mouse model with nonphosphorylatable Mlc2v. Thus, there is a direct and early role for Mlc2 phosphorylation in regulating actin-myosin interactions in striated muscle contraction, and dephosphorylation of Mlc2 or loss of these mechanisms can play a critical role in heart failure.