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- Title
Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy.
- Authors
Chelko, Stephen P.; Keceli, Gizem; Carpi, Andrea; Doti, Nunzianna; Agrimi, Jacopo; Asimaki, Angeliki; Beti, Carlos Bueno; Miyamoto, Matthew; Amat-Codina, Nuria; Bedja, Djahida; Wei, An-Chi; Murray, Brittney; Tichnell, Crystal; Kwon, Chulan; Calkins, Hugh; James, Cynthia A.; O'Rourke, Brian; Halushka, Marc K.; Melloni, Edon; Saffitz, Jeffrey E.
- Abstract
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. Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2mut/mut), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca2+) overload in Dsg2mut/mut hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised Dsg2mut/mut mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca2+ overload–induced necrosis. When cardiomyocytes differentiated from Dsg2mut/mut embryonic stem cells (ES-CMs) were challenged with β-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2mut/mut ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.
- Subjects
EMBRYONIC stem cells; CELL death; CARDIOMYOPATHIES; CARDIAC arrest; HEART diseases; OXIDATION-reduction reaction
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 581, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abf0891