Research ArticleCARDIOMYOPATHY

Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy

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Science Translational Medicine  17 Feb 2021:
Vol. 13, Issue 581, eabf0891
DOI: 10.1126/scitranslmed.abf0891

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Cell death in cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) can lead to sudden cardiac death due to myocyte cell death and ventricular dysfunction. Chelko et al. investigated the mechanism underlying exercise-induced myocyte death in mice with desmoglein-2 mutations, which are linked to ACM. They found that intracellular calcium overload in the mutant mouse hearts was associated with calpain-1 activation, calpastatin depletion, and cell death. In the mouse model and tissue from patients with ACM, mitochondrial apoptosis-inducing factor (AIF) translocation to the nucleus was implicated in the process, and treatment with an AIF-mimetic could prevent cell death. This study highlights a signaling pathway that could potentially be targeted for ACM therapy.

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