Computational modeling of amylin-induced calcium dysregulation in rat ventricular cardiomyocytes.

Hyperamylinemia is a condition that accompanies obesity and precedes type II diabetes, and it is characterized by above-normal blood levels of amylin, the pancreas-derived peptide. Human amylin oligomerizes easily and can deposit in the pancreas [1], brain [2], and heart [3], where they have been associated with calcium dysregulation. In the heart, accumulating evidence suggests that human amylin oligomers form moderately cation-selective [4,5] channels that embed in the cell sarcolemma (SL). The oligomers increase membrane conductance in a concentration-dependent manner [5], which is correlated with elevated cytosolic Ca. These findings motivate our core hypothesis that non-selective inward Ca conduction afforded by human amylin oligomers increase cytosolic and sarcoplasmic reticulum (SR) Ca load, which thereby magnifies intracellular Ca transients. Questions remain however regarding the mechanism of amylin-induced Ca dysregulation, including whether enhanced SL Ca influx is sufficient to elevate cytosolic Ca load [6], and if so, how might amplified Ca transients perturb Ca-dependent cardiac pathways. To investigate these questions, we modified a computational model of cardiomyocytes Ca signaling to reflect experimentally-measured changes in SL membrane permeation and decreased sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) function stemming from acute and transgenic human amylin peptide exposure. With this model, we confirmed the hypothesis that increasing SL permeation alone was sufficient to enhance Ca transient amplitudes. Our model indicated that amplified cytosolic transients are driven by increased Ca loading of the SR and that greater fractional release may contribute to the Ca-dependent activation of calmodulin, which could prime the activation of myocyte remodeling pathways. Importantly, elevated Ca in the SR and dyadic space collectively drive greater fractional SR Ca release for human amylin expressing rats (HIP) and acute amylin-exposed rats (+Amylin) mice, which contributes to the inotropic rise in cytosolic Ca transients. These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca dysregulation in pre-diabetes.