Loss of Dystrophin Alters Calcium-Handling Maturation in Response to Microenvironment in Hipsc-Cardiomyocytes from Duchenne Muscular Dystrophy Patients

Abstract

Heart failure (HF) is a complex disease characterized by abnormal contraction, metabolic imbalance, and increased propensity for arrhythmias. Dysregulation of intracellular Na þ handling is a major (yet understudied) aspect of HF-induced remodeling of cardiac myocytes. Elevated late Na þ current (I NaL ) in HF prolongs the action potential (AP), thereby facilitating the development of arrhythmogenic early afterdepolarizations. Increased Na þ loading limits the ability of the Na þ /Ca 2þ exchanger to remove Ca 2þ , which along with the reduced sarcoplasmic reticulum (SR) Ca 2þ uptake and increased diastolic SR Ca 2þ leak leads to Ca 2þ overload, thus contributing to diastolic dysfunction and triggered arrhythmias (i.e., via delayed afterdepolarizations). Increased Ca 2þ signals enhance the activity of the Ca 2þ /calmodulin-dependent protein kinase II (CaMKII), which is upregulated and chronically active in HF and directly promotes I NaL , diastolic Na þ influx and SR Ca 2þ leak. To investigate quantitatively this vicious cycle of positive feedback in HF, we updated our computational model of the failing rabbit ventricular myocyte. We modified the main repolarizing and depolarizing currents to reproduce the HF-induced changes measured during AP-clamp experiments performed with physiologic Ca 2þ handling 5 CaMKII inhibition. We validated the cellular model using data describing the frequency-dependence of AP and Ca 2þ transient properties assessed in normal condition and when various branches of the feedback loop are blocked. This updated model serves as a framework to investigate the role of the CaMKII-Na þ -Ca 2þ -CaMKII feedback in promoting Ca 2þ and AP instabilities. Analysis of the relative roles of the interacting components that form the feedback loop within the integrated AP-Ca 2þ cycling-signaling model will allow the identification of the key relationships in the signaling network that could be targeted therapeutically to limit arrhythmias in HF.