Randall Centre for Cell and Molecular Biophysics, King's College London, SE1 1UL London, UK; Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, E1 4NS London, UK.
Department of Mechanical Engineering, Columbia University, New York 10027, USA.
Dev Cell. 2018 Feb 5;44(3):326-336.e3. doi: 10.1016/j.devcel.2017.12.024. Epub 2018 Jan 26.
Mechanical properties are cues for many biological processes in health or disease. In the heart, changes to the extracellular matrix composition and cross-linking result in stiffening of the cellular microenvironment during development. Moreover, myocardial infarction and cardiomyopathies lead to fibrosis and a stiffer environment, affecting cardiomyocyte behavior. Here, we identify that single cardiomyocyte adhesions sense simultaneous (fast oscillating) cardiac and (slow) non-muscle myosin contractions. Together, these lead to oscillating tension on the mechanosensitive adaptor protein talin on substrates with a stiffness of healthy adult heart tissue, compared with no tension on embryonic heart stiffness and continuous stretching on fibrotic stiffness. Moreover, we show that activation of PKC leads to the induction of cardiomyocyte hypertrophy in a stiffness-dependent way, through activation of non-muscle myosin. Finally, PKC and non-muscle myosin are upregulated at the costameres in heart disease, indicating aberrant mechanosensing as a contributing factor to long-term remodeling and heart failure.
力学特性是健康或疾病中许多生物学过程的线索。在心脏中，细胞外基质组成和交联的变化导致在发育过程中细胞微环境的变硬。此外，心肌梗死和心肌病导致纤维化和更硬的环境，影响心肌细胞的行为。在这里，我们发现单个心肌细胞黏附体感知同时发生的（快速振荡的）心脏和（缓慢的）非肌球蛋白收缩。两者共同导致在机械敏感衔接蛋白塔连蛋白上产生振荡张力，其在底物上的硬度与健康成人心脏组织相当，而在胚胎心脏硬度上没有张力，在纤维化硬度上则是连续拉伸。此外，我们表明 PKC 的激活通过非肌球蛋白的激活以依赖于硬度的方式诱导心肌细胞肥大。最后，PKC 和非肌球蛋白在心肌病的肌节处上调，表明异常的机械感觉是导致长期重塑和心力衰竭的一个因素。
