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

Chelko, SP; Keceli, G; Carpi, A; Doti, N; Agrimi, J; Asimaki, A; Beti, CB; Miyamoto, M; Amat-Codina, N; Bedja, D; et al. Chelko, SP; Keceli, G; Carpi, A; Doti, N; Agrimi, J; Asimaki, A; Beti, CB; Miyamoto, M; Amat-Codina, N; Bedja, D; Wei, A-C; Murray, B; Tichnell, C; Kwon, C; Calkins, H; James, CA; O'Rourke, B; Halushka, MK; Melloni, E; Saffitz, JE; Judge, DP; Ruvo, M; Kitsis, RN; Andersen, P; Di Lisa, F; Paolocci, N (2021) Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy. Sci Transl Med, 13 (581). eabf0891. ISSN 1946-6242 https://doi.org/10.1126/scitranslmed.abf0891
SGUL Authors: Asimaki, Angeliki

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Abstract

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.

Item Type: Article
Additional Information: This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on Vol 13 17 Feb 2021, DOI: 10.1126/scitranslmed.abf0891.
Keywords: 11 Medical and Health Sciences, 06 Biological Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Sci Transl Med
ISSN: 1946-6242
Language: eng
Dates:
DateEvent
17 February 2021Published
27 January 2021Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
R01 HL136918National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 HL063030National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 HL137259National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 HL138475National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
T32 AG058527National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 HD086026National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
2015-MSCRFI-1622National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
19CDA34760185American Heart Associationhttp://dx.doi.org/10.13039/100000968
19CDA34760161American Heart Associationhttp://dx.doi.org/10.13039/100000968
18IPA34170446American Heart Associationhttp://dx.doi.org/10.13039/100000968
17GRNT33670405American Heart Associationhttp://dx.doi.org/10.13039/100000968
PR191593U.S. Department of Defensehttp://dx.doi.org/10.13039/100000005
16CVD04Leducq Transatlantic Network of ExcellenceUNSPECIFIED
RA15CVD04LeducqUNSPECIFIED
16CVD02Foundation LeducqUNSPECIFIED
PubMed ID: 33597260
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/113022
Publisher's version: https://doi.org/10.1126/scitranslmed.abf0891

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