Department of Molecular Physiology and Biophysics, University of Vermont Larner College of Medicine, Burlington, VT, USA.
Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Nat Rev Cardiol. 2022 Jun;19(6):364-378. doi: 10.1038/s41569-022-00692-y. Epub 2022 Apr 19.
The microtubule network of cardiac muscle cells has unique architectural and biophysical features to accommodate the demands of the working heart. Advances in live-cell imaging and in deciphering the 'tubulin code' have shone new light on this cytoskeletal network and its role in heart failure. Microtubule-based transport orchestrates the growth and maintenance of the contractile apparatus through spatiotemporal control of translation, while also organizing the specialized membrane systems required for excitation-contraction coupling. To withstand the high mechanical loads of the working heart, microtubules are post-translationally modified and physically reinforced. In response to stress to the myocardium, the microtubule network remodels, typically through densification, post-translational modification and stabilization. Under these conditions, physically reinforced microtubules resist the motion of the cardiomyocyte and increase myocardial stiffness. Accordingly, modified microtubules have emerged as a therapeutic target for reducing stiffness in heart failure. In this Review, we discuss the latest evidence on the contribution of microtubules to cardiac mechanics, the drivers of microtubule network remodelling in cardiac pathologies and the therapeutic potential of targeting cardiac microtubules in acquired heart diseases.
心肌细胞的微管网络具有独特的结构和生物物理特性，以适应工作心脏的需求。活细胞成像技术的进步和对“微管密码”的破译，为这个细胞骨架网络及其在心力衰竭中的作用带来了新的曙光。基于微管的运输通过时空控制翻译来协调收缩装置的生长和维持，同时组织兴奋-收缩偶联所需的专门膜系统。为了承受工作心脏的高机械负荷，微管经过翻译后修饰和物理强化。在心肌受到压力时，微管网络会发生重塑，通常通过密集化、翻译后修饰和稳定化。在这些条件下，物理强化的微管抵抗心肌细胞的运动并增加心肌硬度。因此，经过修饰的微管已成为心力衰竭中降低硬度的治疗靶点。在这篇综述中，我们讨论了微管对心脏力学的最新贡献、心脏病理学中微管网络重塑的驱动因素以及靶向获得性心脏病中心肌微管的治疗潜力。
