Bogatan Simina, Cevik Duygu, Demidov Valentin, Vanderploeg Jessica, Panchbhaya Abdullah, Vitkin Alex, Jacobs J Roger
Department of Biology, McMaster University, Hamilton, ON, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
PLoS One. 2015 Jun 25;10(6):e0131238. doi: 10.1371/journal.pone.0131238. eCollection 2015.
Mechanotransduction of tension can govern the remodeling of cardiomyocytes during growth or cardiomyopathy. Tension is signaled through the integrin adhesion complexes found at muscle insertions and costameres but the relative importance of signalling during cardiomyocyte growth versus remodelling has not been assessed. Employing the Drosophila cardiomyocyte as a genetically amenable model, we depleted the levels of Talin, a central component of the integrin adhesion complex, at different stages of heart growth and remodeling. We demonstrate a continuous requirement for Talin during heart growth to maintain the one-to-one apposition of myofibril ends between cardiomyocytes. Retracted myofibrils cannot regenerate appositions to adjacent cells after restoration of normal Talin expression, and the resulting deficit reduces heart contraction and lifespan. Reduction of Talin during heart remodeling after hatching or during metamorphosis results in pervasive degeneration of cell contacts, myofibril length and number, for which restored Talin expression is insufficient for regeneration. Resultant dilated cardiomyopathy results in a fibrillating heart with poor rhythmicity. Cardiomyocytes have poor capacity to regenerate deficits in myofibril orientation and insertion, despite an ongoing capacity to remodel integrin based adhesions.
张力的机械转导可在生长或心肌病过程中调控心肌细胞的重塑。张力通过在肌肉附着点和肌小节处发现的整合素黏附复合体进行信号传导，但在心肌细胞生长与重塑过程中信号传导的相对重要性尚未得到评估。利用果蝇心肌细胞作为遗传上易于操作的模型，我们在心脏生长和重塑的不同阶段降低了整合素黏附复合体的核心成分踝蛋白的水平。我们证明，在心脏生长过程中持续需要踝蛋白来维持心肌细胞之间肌原纤维末端的一对一并列。在恢复正常的踝蛋白表达后，回缩的肌原纤维无法与相邻细胞重新形成并列，由此产生的缺陷会降低心脏收缩力和寿命。在孵化后或变态过程中心脏重塑期间降低踝蛋白水平会导致细胞接触、肌原纤维长度和数量普遍退化，恢复踝蛋白表达不足以使其再生。由此产生的扩张型心肌病会导致心脏颤动，节律性差。尽管心肌细胞仍有能力重塑基于整合素的黏附，但它们在再生肌原纤维方向和插入方面的缺陷的能力较差。
