Molecular mechanisms for length adaptation in smooth muscle cells

平滑肌存在于胃、肠、膀胱、血管和呼吸道等中空器官中。肌肉的收缩允许器官执行诸如排尿、沿消化道移动内容物以及控制血压和呼吸道阻力等功能。由于大多数中空器官在履行其功能时会经历较大的体积变化，因此平滑肌需要在比骨骼肌大得多的工作长度范围内保持其收缩能力。在很长一段时间里，解释骨骼肌收缩的理论也被用来解释平滑肌肉的收缩，尽管它不能适应平滑肌的大工作长度范围。越来越多的人认识到，平滑肌的亚细胞结构，称为细胞骨架，比骨骼肌更具流动性；它能够在保持收缩能力的同时，彻底改变其形状。这被认为是由于一种被称为长度适应的转变过程，在这个过程中，细胞骨架发生了可塑性重组。人们还认为，这种转变允许收缩细丝，即肌球蛋白和肌动蛋白细丝，保持彼此接触并产生张力。这一过程是在肌肉长度发生较大变化时启动的，它涉及到一系列事件，即现有细胞骨架结构的初始拆解，然后重新组装结构以适应新的细胞长度。然而，这种适应过程背后的分子机制在很大程度上是未知的。这项研究计划的目标是解开长度适应的分子机制，这是一种独特的平滑肌行为，对细胞的正常功能至关重要。我们的实验室在这一领域的研究中处于领先地位(我们创造了“长度适应”这个术语，现在已经出现在生理学教科书中)。有证据表明，肌球蛋白和肌动蛋白细丝在长度适应过程中解聚和重新聚合。我们计划研究与肌球蛋白和肌动蛋白细丝聚合相关的时间和空间事件，以及它们如何通过接头(或连接器)蛋白连接形成不同形状的细胞骨架，以适应不同的细胞尺寸。从研究中获得的知识将填补我们在理解平滑肌和其他细胞类型的长度适应的分子机制方面的空白，这些细胞利用细胞骨架的变形以及肌球蛋白分子在细胞功能(如张力产生、运动和细胞分裂)中的招募和重新分布。

Smooth muscle is found in hollow organs such as the stomach, intestine, urinary bladder, blood vessels, and airways. Contraction of the muscle allows the organs to perform functions like urination, moving the contents along the digestive tract, and the control of blood pressure and airway resistance. Because most of the hollow organs undergo large changes in volume while performing their functions, smooth muscle is required to maintain its ability to contract over a working length-range much larger than that in skeletal muscle. For a long time the theory explaining skeletal muscle contraction was also used to explain smooth muscle contraction, despite the fact that it cannot accommodate the large working length-range of smooth muscle. Increasingly it has been recognized that the subcellular structure of smooth muscle, call the cytoskeleton, is much more “fluid” than that in skeletal muscle; it is able to drastically alter its shape while maintaining its ability to contract. This is believed to be due to a transformation process called length adaptation during which plastic restructuring of the cytoskeleton takes place. It is also believed that the transformation allows the contractile filaments, called myosin and actin filaments, to maintain contact with each other and generate tension. The process is initiated when a large change in the muscle length occurs, and it involves sequential events with initial disassembly of existing cytoskeletal structures followed by reassembly of the structure to fit the new cell length. However, the molecular mechanism underlying this adaptation process is largely unknown. The goal of this research program is to unravel the molecular mechanism of length adaptation, a unique smooth muscle behavior essential for proper function of the cell. Our laboratory is a leader in this area of research (we coined the term “length adaptation” which has now appeared in physiology textbooks). There is evidence suggesting that the myosin and actin filaments depolymerize and repolymerize during length adaptation. We plan to investigate the temporal and spatial events associated with polymerization of myosin and actin filaments and how they are linked by adaptor (or connector) proteins to form different shapes of cytoskeleton tailored to different cell dimensions. Knowledge gained from the research will fill a void in our understanding of the molecular mechanisms of length adaptation in smooth muscle and other cell types that utilize deformation of the cytoskeleton and recruitment and redistribution of myosin molecules in cell functions like tension generation, movement, and cell division.