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Synchronous progression of calcium transient-dependent beating and sarcomere destruction in apoptotic adult cardiomyocytes

¹Second Department of Internal Medicine, Gifu University School of Medicine, Gifu; ²Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo; ³Second Department of Internal Medicine, Yamaguchi University School of Medicine, Ube; and ⁴Department of Food Science, Kyoto Women's University, Kyoto, Japan

Submitted 21 June 2005 ; accepted in final form 9 November 2005

During early apoptosis, adult cardiomyocytes show unusual beating, suggesting possible participation of abnormal Ca²⁺ transients in initiation of apoptotic processes in this cell type. Simultaneously with the beating, these cells show dynamic structural alteration resulting from cytoskeletal disintegration that is quite rapid. Because of the specialized structure and extensive cytoskeleton of cardiomyocytes, we hypothesized that its degradation in so short a time would require a particularly efficient mechanism. To better understand this mechanism, we used serial video microscopy to observe -adrenergic stimulation-induced apoptosis in isolated adult rat cardiomyocytes while simultaneously recording intracellular Ca²⁺ concentration and cell length. Trains of Ca²⁺ transients and corresponding rhythmic contractions and relaxations (beating) were observed in apoptotic cells. Frequencies of Ca²⁺ transients and beating gradually increased with time and were accompanied by cellular shrinkage. As the cells shrank, amplitudes of Ca²⁺ transients declined and diastolic intracellular Ca²⁺ concentration increased until the transients were lost. Beating and progression of apoptosis were significantly inhibited by antagonists against the L-type Ca²⁺ channel (nifedipine), ryanodine receptor (ryanodine), inositol 1,4,5-trisphosphate receptor (heparin), sarco(endo)plasmic Ca²⁺-ATPase (thapsigargin), and Na⁺/Ca²⁺ exchanger (KB-R7943). Electron-microscopic examination of beating cardiomyocytes revealed progressive breakdown of Z disks. Immunohistochemical analysis and Western blot confirmed that disappearance of Z disk constituent proteins (-actinin, desmin, and tropomyosin) preceded degradation of other cytoskeletal proteins. It thus appears that, in adult cardiomyocyte apoptosis, Ca²⁺ transients mediate apoptotic beating and efficient sarcomere destruction initiated by Z disk breakdown.

apoptosis; calcium regulation; cardiac myocytes; sarcomere; Z disk

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