Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Int J Mol Sci. 2023 Aug 2;24(15):12349. doi: 10.3390/ijms241512349.
Cardiac muscle contraction is regulated via Ca exchange with the hetero-trimeric troponin complex located on the thin filament. Binding of Ca to cardiac troponin C, a Ca sensing subunit within the troponin complex, results in a series of conformational re-arrangements among the thin filament components, leading to an increase in the formation of actomyosin cross-bridges and muscle contraction. Ultimately, a decline in intracellular Ca leads to the dissociation of Ca from troponin C, inhibiting cross-bridge cycling and initiating muscle relaxation. Therefore, troponin C plays a crucial role in the regulation of cardiac muscle contraction and relaxation. Naturally occurring and engineered mutations in troponin C can lead to altered interactions among components of the thin filament and to aberrant Ca binding and exchange with the thin filament. Mutations in troponin C have been associated with various forms of cardiac disease, including hypertrophic, restrictive, dilated, and left ventricular noncompaction cardiomyopathies. Despite progress made to date, more information from human studies, biophysical characterizations, and animal models is required for a clearer understanding of disease drivers that lead to cardiomyopathies. The unique use of engineered cardiac troponin C with the L48Q mutation that had been thoroughly characterized and genetically introduced into mouse myocardium clearly demonstrates that Ca sensitization in and of itself should not necessarily be considered a disease driver. This opens the door for small molecule and protein engineering strategies to help boost impaired systolic function. On the other hand, the engineered troponin C mutants (I61Q and D73N), genetically introduced into mouse myocardium, demonstrate that Ca desensitization under basal conditions may be a driving factor for dilated cardiomyopathy. In addition to enhancing our knowledge of molecular mechanisms that trigger hypertrophy, dilation, morbidity, and mortality, these cardiomyopathy mouse models could be used to test novel treatment strategies for cardiovascular diseases. In this review, we will discuss (1) the various ways mutations in cardiac troponin C might lead to disease; (2) relevant data on mutations in cardiac troponin C linked to human disease, and (3) all currently existing mouse models containing cardiac troponin C mutations (disease-associated and engineered).
心肌收缩是通过与位于细肌丝上的异三聚体肌钙蛋白复合物进行 Ca 交换来调节的。Ca 与肌钙蛋白复合物中的 Ca 感应亚基肌钙蛋白 C 结合，导致细肌丝成分之间发生一系列构象重排，导致肌球蛋白横桥形成增加，肌肉收缩。最终，细胞内 Ca 的下降导致 Ca 与肌钙蛋白 C 分离，抑制横桥循环并启动肌肉松弛。因此，肌钙蛋白 C 在调节心肌收缩和松弛中起着至关重要的作用。肌钙蛋白 C 的天然和工程突变可导致细肌丝成分之间的相互作用改变，并导致 Ca 与细肌丝结合和交换异常。肌钙蛋白 C 的突变与各种形式的心脏病有关，包括肥厚型、限制型、扩张型和左心室非致密性心肌病。尽管迄今为止已经取得了进展，但需要更多来自人类研究、生物物理特性和动物模型的信息，以便更清楚地了解导致心肌病的疾病驱动因素。具有已充分表征并在小鼠心肌中基因引入的 L48Q 突变的工程化肌钙蛋白 C 的独特使用清楚地表明，Ca 敏化本身不一定应该被视为疾病驱动因素。这为小分子和蛋白质工程策略打开了大门，以帮助增强受损的收缩功能。另一方面，已在小鼠心肌中基因引入的工程化肌钙蛋白 C 突变体（I61Q 和 D73N）表明，在基础条件下 Ca 脱敏可能是扩张型心肌病的驱动因素。除了增强我们对触发肥大、扩张、发病和死亡的分子机制的了解外，这些心肌病小鼠模型还可用于测试心血管疾病的新治疗策略。在这篇综述中，我们将讨论（1）肌钙蛋白 C 突变可能导致疾病的各种方式；（2）与人类疾病相关的肌钙蛋白 C 突变的相关数据；以及（3）所有现有的含有肌钙蛋白 C 突变的小鼠模型（与疾病相关和工程化）。
