Clofibrate-induced apoptosis is mediated by Ca2+-dependent caspase-12 activation

Sumio Matzno, Shinya Yasuda, Yuka Kitada, Takeshi Akiyoshi, Naoko Tanaka, Sachiko Juman, Kazumasa Shinozuka, Toshikatsu Nakabayashi, Kenji Matsuyama

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

The mechanism of fibrate-induced myopathy was investigated in this report. When clofibrate (30 to 300 μM) was applied to L6 rat skeletal myoblasts, dose-dependently apoptosis was observed within 24 h. In the apoptotic myoblasts, a caspase-12 cleavage was observed at 2 h and with following caspases-9 and -3-related cascade activation. In contrast, the neutral protease calpain, that is a key enzyme in ER stress-related apoptosis via caspase-12 activation, was significantly decreased during apoptosis. Next, the authors evaluated a role of calcium-dependent signal(s). When clofibrate was added into medium, cytosolic calcium concentration was rapidly and persistently increased. On the other hand, an addition of 10 mM EGTA depressed sustained calcium phase, and concurrent myoblasts apoptosis was completely inhibited. Taken together, our findings indicate that the clofibrate-induced myopathy is triggered by Ca2+ influx, then activated cytosolic caspase-12 through calpain-independent cascade, and consequently caused apoptotic DNA fragmentation.

Original languageEnglish
Pages (from-to)1892-1899
Number of pages8
JournalLife Sciences
Volume78
Issue number16
DOIs
Publication statusPublished - 2006 Mar 13
Externally publishedYes

Keywords

  • Apoptosis
  • Calcium influx
  • Clofibrate
  • Myopathy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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