Alladi Ramakrishnan Hall

Revealing the significance of calcium dynamics in normal cardiac functioning using mathematical models

Samrat Chatterjee

THSTI, Faridabad

The coupling of intracellular calcium (Ca 2+ ) dynamics with mitochondrial bioenergetics is crucial for the functioning of cardiomyocytes both in healthy and disease conditions. A pathophysiological signature of the cardiac
dysfunction (CD) is commonly related to decreased ATP production due to mitochondrial functional impairment and to an increased mitochondrial calcium content ([Ca 2+ ] m ). The present study aimed to understand this CD condition using mathematical model and proposed potential therapeutic target to prevent such condition. We build a four-dimensional model with calcium content of different cellular component and ATP. We observed that a strong coupling of the [Ca 2+ ] m oscillations with the ATP synthesis rate ensures robust
calcium cycling and avoids CD. We also suggested a cardioprotective role of the mitochondrial calcium uniporter (MCU) and predicted that a mitochondrial sodium calcium exchanger (mNCX) could be a potential therapeutic target to restore the normal functioning of the cardiomyocyte. Diabetes is another reason that might also lead to CD. Calcium dynamics in cardiomyocytes is governed by ATP which depends on insulin dependent glucose concentration, via the glucose transporter type 4 (GLUT4). It would therefore be interesting to see how calcium dynamics changes in a cardiomyocyte under diabetic conditions. We proposed and analyzed another
four-dimensional ordinary differential equation (ODE) model to capture the interdependency of calcium dynamics on glucose uptake and ATP generation. More specifically, we looked for the role of GLUT4, energy metabolism, L-type channels, RyR2 channels, SERCA2a pumps and leakage rate in the normal functioning of cardiomyocytes. We observed that any divergence in the GLUT4 activity (especially a decrease in the glucose uptake rate) might cause abnormal calcium oscillation, leading to CD. Our study finally hypothesizes that a regulated sarcoplasmic reticulum (SR) calcium flux could be a possible
therapeutic strategy to maintain normal calcium dynamics in diabetic heart and to prevent possible CD.