Quantitative tests reveal that microtubules tune the healthy heart but underlie arrhythmias in pathology.

Abstract

Microtubule (MT) mechanotransduction links diastolic stretch to generation of NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS), signals we term X-ROS. While stretch-elicited X-ROS primes intracellular calcium (Ca2+) channels for synchronized activation in the healthy heart, the dysregulated excess in this pathway underscores asynchronous Ca2+ release and arrhythmia. Here, we expanded our existing computational models of Ca2+ signalling in heart to include MT-dependent mechanotransduction through X-ROS. Informed by new focused experimental tests to properly constrain our model, we quantify the role of X-ROS on excitation-contraction coupling in healthy and pathological conditions. This approach allowed for a mechanistic investigation that revealed new insights into X-ROS signalling in disease including changes in MT network density and post-translational modifications (PTMs), elevated NOX2 expression, altered Ca2+ release dynamics (i.e. Ca2+ sparks and Ca2+ waves), how NOX2 is activated by and responds to stretch, and finally the degree to which normalizing X-ROS can prevent Ca2+-dependent arrhythmias.