In Mice, Blocking One Enzyme Restored Two Proteins Lost to an Inherited Arrhythmia

In mice carrying the CASQ2 R33Q mutation, an enzyme called calpain breaks down triadin, one of the proteins heart cells use to control their internal calcium. That loss comes first, before the cell loses a second calcium protein, calsequestrin 2. Researchers at the Centro Nacional de Investigaciones Cardiovasculares in Madrid reported the result on September 22, 2026, with colleagues at the University of Pavia and the Istituti Clinici Scientifici Maugeri in Pavia, Italy.

The mutation causes the recessive form of catecholaminergic polymorphic ventricular tachycardia, or CPVT, an inherited rhythm disorder associated with cardiac arrest in children and young adults. In mice carrying two copies of the mutation, calsequestrin 2, triadin and junctin all fall to very low levels. The team writes that the mechanism behind that drop, and its contribution to the disease, were incompletely understood.

The team reports in Circulation Research that blocking calpain restored both proteins in the mutant mice and reduced ventricular tachycardia episodes in the live animals. In isolated heart cells it also reduced triggered activity, the stray electrical firing through which the mutation produces the arrhythmia.

Blocking the proteasome or autophagy, the cell's other main systems for breaking down proteins, partially restored calsequestrin 2 in newborn heart cells and in adult mice but did not restore triadin, which the authors read as a sign of separate mechanisms at work. Biochemical tests showed that calpain cuts triadin directly.

Raising triadin levels, with modified RNA in cells and a viral carrier in live mice, also raised calsequestrin 2 in the mutant animals, which the authors take as evidence that the loss of triadin is the upstream event.

The mutant hearts also showed stress in the machinery that folds proteins, along with changes in their main disposal pathways. The authors call the breakdown of triadin by calpain a key pathogenic event behind the loss of calsequestrin 2, and they describe the mouse line as closely reproducing the clinical picture seen in patients with CPVT.