| First Author | Chelko SP | Year | 2021 |
| Journal | Sci Transl Med | Volume | 13 |
| Issue | 581 | PubMed ID | 33597260 |
| Mgi Jnum | J:302341 | Mgi Id | MGI:6508138 |
| Doi | 10.1126/scitranslmed.abf0891 | Citation | Chelko SP, et al. (2021) Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy. Sci Transl Med 13(581) |
| abstractText | 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 (Dsg2 (mut/mut)), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca(2+)) overload in Dsg2 (mut/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 Dsg2 (mut/mut) mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca(2+) overload-induced necrosis. When cardiomyocytes differentiated from Dsg2 (mut/mut) embryonic stem cells (ES-CMs) were challenged with beta-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2 (mut/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. |
