背景:最近的实验数据支持以下观点:膜上的信号活动取决于其几何参数,例如表面积和曲率。然而,一个数学,缺少将形状与受体信号联系起来的生物物理概念。由于收缩和松弛的循环,心肌细胞的膜不断重塑。根据心肌细胞收缩的恒定体积行为,长度的缩短由两个相邻Z盘之间的Z盘肌丝晶格扩张和膜的动态变形来补偿。两种形态变化都强烈依赖于收缩频率。这里,我们提出了一个假设,即心肌细胞的动态几何形状对其可塑性和信号传导可能很重要。这种影响可能取决于跳动的心脏的频率,并且可能代表一个新的概念来解释频率变化如何影响心脏信号传导。方法:这个假设几乎不可能用实验来回答,因为体外心肌细胞几乎是二维的,并且是扁平的,而不是真正的体内形状。因此,我们设计了一个COMSOL多物理场程序来对人心肌细胞的动态几何进行数学建模,并探索搏动频率是否可以调节膜信号转导。Src激酶是心脏机械传导的重要组成部分。我们首先提出了Src主要位于科斯塔姆。然后,通过对Src介导的PDGFR信号通路的数值模拟,对频率依赖性信号效应进行了数学研究.建立了反应-对流-扩散偏微分方程,以模拟1至4Hz频率范围内收缩肌节圆盘中的PDGFR路径。结果:当心肌细胞以更高的速率搏动时,模拟显示更高浓度的磷酸-Src。在4、2和1Hz拍频下计算的磷酸Src浓度,与0Hz相比,为21.5%,9.4%,高出4.7%,分别。结论:在这里,我们为生物学中的一个新概念提供了数学证据。细胞形状直接转化为信号,特别是对心肌的重要影响,细胞不断重塑细胞膜。表面体积比的局部概念被证明会导致膜介导的信号传导发生变化,并且可能有助于解释心肌对生物力学应力的显着可塑性。
Background: Recent experimental data support the view that signaling activity at the membrane depends on its geometric parameters such as surface area and curvature. However, a mathematical, biophysical concept linking shape to receptor signaling is missing. The membranes of cardiomyocytes are constantly reshaped due to cycles of contraction and relaxation. According to constant-volume behavior of cardiomyocyte contraction, the length shortening is compensated by Z-disc myofilament lattice expansion and dynamic deformation of membrane between two adjacent Z-discs. Both morphological changes are strongly dependent on the frequency of contraction. Here, we developed the hypothesis that dynamic geometry of cardiomyocytes could be important for their plasticity and signaling. This effect may depend on the frequency of the beating heart and may represent a novel concept to explain how changes in frequency affect cardiac signaling. Methods: This hypothesis is almost impossible to answer with experiments, as the in-vitro cardiomyocytes are almost two-dimensional and flattened rather than being in their real in-vivo shape. Therefore, we designed a COMSOL multiphysics program to mathematically model the dynamic geometry of a human cardiomyocyte and explore whether the beating frequency can modulate membrane signal transduction. Src kinase is an important component of cardiac mechanotransduction. We first presented that Src mainly localizes at costameres. Then, the frequency-dependent signaling effect was studied mathematically by numerical simulation of Src-mediated PDGFR signaling pathway. The reaction-convection-diffusion partial differential equation was formulated to simulate PDGFR pathway in a contracting sarcomeric disc for a range of frequencies from 1 to 4 Hz. Results: Simulations exhibits higher concentration of phospho-Src when a cardiomyocyte beats with higher rates. The calculated phospho-Src concentration at 4, 2, and 1 Hz beat rates, comparing to 0 Hz, was 21.5%, 9.4%, and 4.7% higher, respectively. Conclusion: Here we provide mathematical evidence for a novel concept in biology. Cell shape directly translates into signaling, an effect of importance particularly for the myocardium, where cells continuously reshape their membranes. The concept of locality of surface-to-volume ratios is demonstrated to lead to changes in membrane-mediated signaling and may help to explain the remarkable plasticity of the myocardium in response to biomechanical stress.