Gaps in our understanding of muscle mechanics demonstrate that the current model is incomplete. Increasingly, it appears that a role for titin in active muscle contraction might help to fill these gaps. While such a role for titin is increasingly accepted, the underlying molecular mechanisms remain unclear. The goals of this paper are to review recent studies demonstrating Ca²⁺-dependent interactions between N2A titin and actin in vitro, to explore theoretical predictions of muscle behavior based on this interaction, and to review experimental data related to the predictions. In a recent study, we demonstrated that Ca²⁺ increases the association constant between N2A titin and F-actin; that Ca²⁺ increases rupture forces between N2A titin and F-actin; and that Ca²⁺ and N2A titin reduce sliding velocity of F-actin and reconstituted thin filaments in motility assays. Preliminary data support a role for Ig83, but other Ig domains in the N2A region may also be involved. Two mechanical consequences are inescapable if N2A titin binds to thin filaments in active muscle sarcomeres: (1) the length of titin’s freely extensible I-band should decrease upon muscle activation; and (2) binding between N2A titin and thin filaments should increase titin stiffness in active muscle. Experimental observations demonstrate that these properties characterize wild type muscles, but not muscles from mdm mice with a small deletion in N2A titin, including part of Ig83. Given the new in vitro evidence for Ca²⁺-dependent binding between N2A titin and actin, it is time for skepticism to give way to further investigation.

中文翻译：

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钙依赖性肌肉中的纤细丝相互作用：观察和理论。

我们对肌肉力学的理解上的空白表明，当前模型不完整。越来越多的肌醇在主动肌肉收缩中的作用似乎可以帮助填补这些空白。尽管人们日益接受替丁的这种作用，但其潜在的分子机制仍不清楚。本文的目的是回顾最近的研究，这些研究表明N2A titin与肌动蛋白在体外具有Ca ²⁺依赖性相互作用，以这种相互作用为基础探索肌肉行为的理论预测，并复习与该预测有关的实验数据。在最近的一项研究中，我们证明了Ca ^2+会增加N2A titin和F-actin之间的缔合常数。钙²⁺增加N2A titin和F-actin之间的断裂力; Ca ²⁺和N2A titin降低了F-肌动蛋白和重组细丝在运动性测定中的滑动速度。初步数据支持Ig83的作用，但也可能涉及N2A区域中的其他Ig域。如果N2A肌醇蛋白与活跃的肌肉肉瘤中的细丝结合，则不可避免地会产生两个机械后果：（1）肌激活后，肌醇蛋白可自由延伸的I带的长度应减少；（2）N2A titin和细丝之间的结合应增加活跃肌肉的titin硬度。实验观察表明，这些特性是野生型肌肉的特征，而不是mdm肌肉的特征N2A titin（包括Ig83的一部分）缺失很小的小鼠。鉴于新的体外证据表明N2A titin和肌动蛋白之间存在Ca ²⁺依赖性结合，现在是怀疑论者应进一步研究的时候了。