Abstract
BACKGROUND: In nonischemic cardiomyopathy, mitochondrial Ca(2+) handling is involved in arrhythmogenesis by modulating diastolic sarcoplasmic reticulum (SR) Ca(2+) release. Recently, it has been reported that lysosomal Ca(2+) release can trigger an SR Ca(2+) release. We investigated whether lysosomal Ca(2+) flux through the TRPML1 (transient receptor potential mucolipin 1) channel could contribute to ischemic cardiomyopathy-related arrhythmia by causing diastolic SR Ca(2+) release. METHODS: Ischemic cardiomyopathy was induced in wild-type C57BL/6J and TRPML1 heterozygous knockdown (TRPML1±) mice by ligating the left anterior descending coronary artery. Mice were studied at 3 weeks after myocardial infarction (MI). RESULTS: After MI, the lysosomal-restricted TRPML1 Ca(2+) release channel was significantly increased in human patients with ischemic or nonischemic cardiomyopathy. TRPML1, but not the TPC2 (2-pore channel 2), was significantly upregulated by 85% in the mouse MI border zone and by 55% in a remote zone. Lysosomal number and approximation to the SR were increased after MI. Lysosomal Ca(2+) release was substantially upregulated in MI mouse cardiomyocytes compared with sham cardiomyocytes. The action potential duration was prolonged, and arrhythmogenic diastolic SR Ca(2+) release was increased in the cardiomyocytes isolated from MI mice. Blocking TRPML1 reduced action potential duration prolongation and depressed early and delayed afterdepolarizations in cardiomyocytes isolated from MI mice, while the TRPML1 agonist increased TRPML1-dependent cellular triggered activity. A TRPML1 antagonist could inhibit induced ventricular fibrillation in MI mice. Consistent with that result, genetic knockdown of TRPML1 could inhibit arrhythmic risk after MI. The effects of TRPML1-targeted drugs were not seen in control cardiomyocytes. CONCLUSIONS: Lysosomes contribute to arrhythmic risk after MI because of increased number, proximity to the SR, and induction of diastolic SR Ca(2+) release mediated by TRPML1-dependent lysosomal Ca(2+) release.