Abstract

Normal cardiac function requires coordinated contraction of working myocytes, which is initiated by a specific communication between Ca²⁺ channels on the transverse (T)-tubule membrane and ryanodine receptors on the sarcoplasmic reticulum (SR) membrane. Junctophilin-2 (JP2) is a structural protein that induces docking of SR to T-tubules to form dyads and that indirectly stabilizes the T-tubule network in ventricular cardiomyocytes. JP2 is frequently down-regulated in heart failure, in parallel with a disruption of the T-tubule network and loss of normal excitation-contraction coupling. Here we show that overexpression of JP2 stabilizes the T-tubule network and attenuates heart failure after cardiac stress. These data suggest that future treatment of heart disease may include strategies to stabilize the architecture of T-tubules and cardiac dyads.