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 Ca²⁺. These findings motivate our core hypothesis that non-selective inward Ca²⁺ conduction afforded by human amylin oligomers increase cytosolic and sarcoplasmic reticulum (SR) Ca²⁺ load, which thereby magnifies intracellular Ca²⁺ transients. Questions remain however regarding the mechanism of amylin-induced Ca²⁺ dysregulation, including whether enhanced SL Ca²⁺ influx is sufficient to elevate cytosolic Ca²⁺ load [6], and if so, how might amplified Ca²⁺ transients perturb Ca²⁺-dependent cardiac pathways. To investigate these questions, we modified a computational model of cardiomyocytes Ca²⁺ 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 Ca²⁺ transient amplitudes. Our model indicated that amplified cytosolic transients are driven by increased Ca²⁺ loading of the SR and that greater fractional release may contribute to the Ca²⁺-dependent activation of calmodulin, which could prime the activation of myocyte remodeling pathways. Importantly, elevated Ca²⁺ in the SR and dyadic space collectively drive greater fractional SR Ca²⁺ release for human amylin expressing rats (HIP) and acute amylin-exposed rats (+Amylin) mice, which contributes to the inotropic rise in cytosolic Ca²⁺ transients. These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca²⁺ dysregulation in pre-diabetes.