Granzier Henk, Wu Yiming, Siegfried Labeit, LeWinter Martin
Department of Veterinary and Comparative Anatomy, Washington State University, Pullman, WA 99164-6520, USA.
Heart Fail Rev. 2005 Sep;10(3):211-23. doi: 10.1007/s10741-005-5251-7.
Titin is a giant protein that constitutes the third myofilament of the sarcomere. Single titin molecules anchor in the Z-disk and extend all the way to the M-line region of the sarcomere. Successive titin molecules are arranged head-to-head and tail-to-tail, providing a continuous filament along the full length of the myofibril. The majority of titin's I-band region is extensible and functions as a molecular spring that when extended develops passive force. We will discuss mechanisms for adjusting titin-based force, including alternative splicing and posttranslational modifications. Multiple biological functions can be assigned to different regions of the titin molecule. In addition to titin's role in determining passive muscle stiffness, recent evidence suggests a role in protein metabolism, compartmentalization of metabolic enzymes, binding of chaperones, and positioning of the membrane systems of the T-tubules and sarcoplasmic reticulum. We will also discuss titin-based force adjustments that occur in various muscle diseases and several disease-causing titin mutations that have been discovered. We will focus on the role of titin in heart failure patients that was recently investigated in patients with end-stage heart failure due to non-ischemic dilated cardiomyopathy. In end-stage failing hearts, compliant titin isoforms comprise a greater percentage of titin and changes in titin isoform expression in heart failure patients with DCM significantly impact diastolic filling by lowering myocardial stiffness.
肌联蛋白是一种巨大的蛋白质，构成肌节的第三条肌丝。单个肌联蛋白分子锚定在Z盘，并一直延伸到肌节的M线区域。连续的肌联蛋白分子头对头、尾对尾排列，沿着肌原纤维的全长提供一条连续的细丝。肌联蛋白大部分的I带区域是可伸展的，起着分子弹簧的作用，伸展时会产生被动力。我们将讨论调节基于肌联蛋白的力的机制，包括可变剪接和翻译后修饰。肌联蛋白分子的不同区域可赋予多种生物学功能。除了肌联蛋白在决定被动肌肉僵硬度方面的作用外，最近的证据表明它在蛋白质代谢、代谢酶的区室化、伴侣蛋白的结合以及T小管和肌浆网的膜系统定位中也发挥作用。我们还将讨论各种肌肉疾病中发生的基于肌联蛋白的力的调节以及已发现的几种致病的肌联蛋白突变。我们将重点关注最近在因非缺血性扩张型心肌病导致的终末期心力衰竭患者中研究的肌联蛋白在心力衰竭患者中的作用。在终末期衰竭心脏中，柔顺的肌联蛋白异构体在肌联蛋白中所占比例更大，扩张型心肌病心力衰竭患者中肌联蛋白异构体表达的变化通过降低心肌僵硬度显著影响舒张期充盈。
