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 Ca²⁺-induced Ca²⁺ 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 Ca²⁺ handling that culminated in heart failure compared with wild-type mice. Activation of Gα_q/phospholipase Cb signaling increased the activity of the Ca²⁺-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 Gα_q 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 Ca²⁺ 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, Ca²⁺ handling dysfunction, and progression to heart failure in this mouse model.