Molecular basis of length-dependent activation in cardiac muscle

The efficiency of the heart as a pump depends on an auto-regulatory mechanism, called length-dependent activation (LDA), that potentiates the strength of contraction in response to an increase in ventricular filling. Despite decades of investigation, the molecular basis of LDA in cardiac muscle is still unclear. Here we propose to use X-ray diffraction at the upgraded beamline ID02 to investigate the structural changes in the myofilaments induced by stretch in relaxed and partially calcium-activated demembranated cardiac trabeculae in near-physiological conditions. Because the disruption of LDA is a common pathogenic mechanism underlying cardiac dysfunction, the results of this research will provide new targets and assays for the development of new pharmacological approaches to treat heart failure in cardiac diseases.

心脏作为泵的效能依赖于一种被称为长度依赖性激活（length-dependent activation, LDA）的自主调节机制，该机制可在心室充盈量增加时增强心肌收缩强度。尽管已有数十年的研究探索，心肌中LDA的分子机制仍未阐明。本研究拟借助升级后的ID02光束线开展X射线衍射实验，探究在近似生理条件下，松弛状态及部分钙激活的去膜心肌小梁受牵拉时肌丝发生的结构变化。由于LDA功能失调是引发心功能异常的常见致病机制，本研究结果将为开发治疗心脏疾病所致心力衰竭的新型药理学手段提供全新靶点与检测方法。