Department of Anatomy and Cell Biology, University of Iowa College of Medicine, 1-324 BSB, 51 Newton Rd, Iowa City, IA, 52242, USA.
Departmewnt of Physiology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
J Muscle Res Cell Motil. 2021 Jun;42(2):355-366. doi: 10.1007/s10974-020-09595-2. Epub 2021 Feb 11.
Vertebrate cardiac muscle generates progressively larger systolic force when the end diastolic chamber volume is increased, a property called the "Frank-Starling Law", or "length dependent activation (LDA)". In this mechanism a larger force develops when the sarcomere length (SL) increased, and the overlap between thick and thin filament decreases, indicating increased production of force per unit length of the overlap. To account for this phenomenon at the molecular level, we examined several hypotheses: as the muscle length is increased, (1) lattice spacing decreases, (2) Ca sensitivity increases, (3) titin mediated rearrangement of myosin heads to facilitate actomyosin interaction, (4) increased SL activates cross-bridges (CBs) in the super relaxed state, (5) increased series stiffness at longer SL promotes larger elementary force/CB to account for LDA, and (6) stretch activation (SA) observed in insect muscles and LDA in vertebrate muscles may have similar mechanisms. SA is also known as delayed tension or oscillatory work, and universally observed among insect flight muscles, as well as in vertebrate skeletal and cardiac muscles. The sarcomere stiffness observed in relaxed muscles may significantly contributes to the mechanisms of LDA. In vertebrate striated muscles, the sarcomere stiffness is mainly caused by titin, a single filamentary protein spanning from Z-line to M-line and tightly associated with the myosin thick filament. In insect flight muscles, kettin connects Z-line and the thick filament to stabilize the sarcomere structure. In vertebrate cardiac muscles, titin plays a similar role, and may account for LDA and may constitute a molecular mechanism of Frank-Starling response.
脊椎动物心肌在舒张末期室腔容积增加时会产生逐渐增大的收缩力，这种特性称为“弗兰克-斯塔林定律”或“长度依赖性激活（LDA）”。在这种机制中，当肌节长度（SL）增加，粗、细肌丝重叠减少时，会产生更大的力，表明单位重叠长度的力产生增加。为了在分子水平上解释这种现象，我们研究了几种假设：当肌肉长度增加时，（1）晶格间距减小，（2）Ca 敏感性增加，（3）titin 介导肌球蛋白头部的重排以促进肌球蛋白与肌动蛋白的相互作用，（4）增加的 SL 激活超松弛状态下的交联桥（CB），（5）增加的串联刚度在更长的 SL 上促进更大的基本力/CB 以解释 LDA，以及（6）在昆虫肌肉中观察到的伸展激活（SA）和脊椎动物肌肉中的 LDA 可能具有相似的机制。SA 也称为延迟张力或振荡功，普遍存在于昆虫飞行肌肉以及脊椎动物骨骼肌和心肌中。在放松的肌肉中观察到的肌节刚度可能对 LDA 的机制有重要贡献。在脊椎动物横纹肌中，肌节刚度主要由 titin 引起，titin 是一种从 Z 线到 M 线延伸的单丝状蛋白，与肌球蛋白粗丝紧密结合。在昆虫飞行肌肉中，kettin 将 Z 线和粗丝连接起来，以稳定肌节结构。在脊椎动物心肌中，titin 发挥类似的作用，可能解释 LDA 并构成弗兰克-斯塔林反应的分子机制。
