Calpain‐Dependent Cleavage of Junctophilin‐2 and T‐Tubule Remodeling in a Mouse Model of Reversible Heart Failure

BACKGROUND: A highly organized transverse tubule (T‐tubule) network is necessary for efficient Ca(2+)‐induced Ca(2+) release and synchronized contraction of ventricular myocytes. Increasing evidence suggests that T‐tubule remodeling due to junctophilin‐2 (JP‐2) downregulation plays a critical role in the progression of heart failure. However, the mechanisms underlying JP‐2 dysregulation remain incompletely understood. METHODS AND RESULTS: A mouse model of reversible heart failure that is driven by conditional activation of the heterotrimeric G protein Gα(q) in cardiac myocytes was used in this study. Mice with activated Gα(q) exhibited disruption of the T‐tubule network and defects in Ca(2+) handling that culminated in heart failure compared with wild‐type mice. Activation of Gα(q)/phospholipase Cβ signaling increased the activity of the Ca(2+)‐dependent protease calpain, leading to the proteolytic cleavage of JP‐2. A novel calpain cleavage fragment of JP‐2 is detected only in hearts with constitutive Gαq signaling to phospholipase Cβ. Termination of the Gα(q) signal was followed by normalization of the JP‐2 protein level, repair of the T‐tubule network, improvements in Ca(2+) handling, and reversal of heart failure. Treatment of mice with a calpain inhibitor prevented Gα(q)‐dependent JP‐2 cleavage, T‐tubule disruption, and the development of heart failure. CONCLUSIONS: Disruption of the T‐tubule network in heart failure is a reversible process. Gα(q)‐dependent activation of calpain and subsequent proteolysis of JP‐2 appear to be the molecular mechanism that leads to T‐tubule remodeling, Ca(2+) handling dysfunction, and progression to heart failure in this mouse model.