Roles for Cardiac MyBP-C in Maintaining Myofilament Lattice Rigidity and Prolonging Myosin Cross-Bridge Lifetime
Roles for Cardiac MyBP-C in Maintaining Myofilament Lattice Rigidity and Prolonging Myosin Cross-Bridge Lifetime
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DOI：
10.1016/j.bpj.2011.08.047
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发表时间：
2011-10-05
影响因子：
3.4
通讯作者：
Maughan, David W.
中科院分区：
文献类型：
--
作者：
Palmer, Bradley M.;Sadayappan, Sakthivel;Maughan, David W.
我们研究了心肌肌球蛋白结合蛋白-C（cMyBP-C）及其组成性非磷酸化状态对以下小鼠模型化学皮肤心肌条中肌丝晶格径向和纵向刚度的影响：非转基因（NTG）、cMyBP-C有效无效（t/t）、野生型cMyBP-C表达为lit（WT（t/t））和组成性非磷酸化cMyBP-C（AllP-（t/t））。我们发现，cMyBP-C在t/t中的缺失和未磷酸化的cMyBP-C在AllP-（t/t）中导致在NTG和WT（t/t）中未观察到的由僵直诱导的可压缩的心肌肌丝网格。这些结果表明，cMyBP-C的N-末端的存在和磷酸化为肌丝晶格提供了结构支持和径向刚性。严格条件下肌丝纵向刚度的检查表明，与NTG对照组相比，LIT中的跨桥依赖性刚度显著降低，但与WT（t/t）对照组相比，AllP-（t/t）中的跨桥依赖性刚度没有显著降低。当肌球蛋白亚型被控制时，t/t中cMyBP-C的缺失和AllP-（t/t）中未磷酸化的cMyBP-C都导致肌球蛋白跨桥寿命较短。这些数据共同表明，cMyBP-C通过N-末端向肌丝晶格提供径向刚性，并且cMyBP-C的磷酸化的破坏足以消除N-末端的这种结构作用并缩短跨桥寿命。虽然cMyBP-C的存在也提供了纵向刚性，但与径向刚性相比，N-末端的磷酸化对于维持晶格的纵向刚性是不必要的。
We investigated the influence of cardiac myosin binding protein-C (cMyBP-C) and its constitutively unphosphorylated status on the radial and longitudinal stiffnesses of the myofilament lattice in chemically skinned myocardial strips of the following mouse models: nontransgenic (NTG), effective null for cMyBP-C (t/t), wild-type cMyBP-C expressed into lit (WT(t/t)), and constitutively unphosphorylated cMyBP-C (AllP-(t/t)). We found that the absence of cMyBP-C in the t/t and the unphosphorylated cMyBP-C in the AllP-(t/t) resulted in a compressible cardiac myofilament lattice induced by rigor not observed in the NTG and WT(t/t). These results suggest that the presence and phosphorylation of the N-terminus of cMyBP-C provides structural support and radial rigidity to the myofilament lattice. Examination of myofilament longitudinal stiffness under rigor conditions demonstrated a significant reduction in cross-bridge-dependent stiffness in the lit compared with NTG controls, but not in the AllP-(t/t) compared with WT(t/t) controls. The absence of cMyBP-C in the t/t and the unphosphorylated cMyBP-C in the AllP-(t/t) both resulted in a shorter myosin cross-bridge lifetime when myosin isoform was controlled. These data collectively suggest that cMyBP-C provides radial rigidity to the myofilament lattice through the N-terminus, and that disruption of the phosphorylation of cMyBP-C is sufficient to abolish this structural role of the N-terminus and shorten cross-bridge lifetime. Although the presence of cMyBP-C also provides longitudinal rigidity, phosphorylation of the N-terminus is not necessary to maintain longitudinal rigidity of the lattice, in contrast to radial rigidity.