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J. Biol. Chem., Vol. 279, Issue 9, 8290-8299, February 27, 2004

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Anthracyclines Induce Calpain-dependent Titin Proteolysis and Necrosis in Cardiomyocytes^*

Chee Chew Lim¶, Christian Zuppinger||, Xinxin Guo, Gabriela M. Kuster, Michiel Helmes, Hans M. Eppenberger, Thomas M. Suter||, Ronglih Liao, and Douglas B. Sawyer**

From the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, ^||Swiss Cardiovascular Center Bern, Inselspital, CH-3010 Bern, Switzerland, and Institute of Cell Biology, Swiss Federal Institute of Technology, CH-8093 Zurich, Switzerland

Titin, the largest myofilament protein, serves as a template for sarcomere assembly and acts as a molecular spring to contribute to diastolic function. Titin is known to be extremely susceptible to calcium-dependent protease degradation in vitro. We hypothesized that titin degradation is an early event in doxorubicin-induced cardiac injury and that titin degradation occurs by activation of the calcium-dependent proteases, the calpains. Treatment of cultured adult rat cardiomyocytes with 1 or 3 µmol/liter doxorubicin for 24 h resulted in degradation of titin in myocyte lysates, which was confirmed by a reduction in immunostaining of an antibody to the spring-like (PEVK) domain of titin at the I-band of the sarcomere. The elastic domain of titin appears to be most susceptible to proteolysis because co-immunostaining with an antibody to titin at the M-line was preserved, suggesting targeted proteolysis of the spring-like domain of titin. Doxorubicin treatment for 1 h resulted in 3-fold increase in calpain activity, which remained elevated at 48 h. Co-treatment with calpain inhibitors resulted in preservation of titin, reduction in myofibrillar disarray, and attenuation of cardiomyocyte necrosis but not apoptosis. Co-treatment with a caspase inhibitor did not prevent the degradation of titin, which precludes caspase-3 as an early mechanism of titin proteolysis. We conclude that calpain activation is an early event after doxorubicin treatment in cardiomyocytes and appears to target the degradation of titin. Proteolysis of the spring-like domain of titin may predispose cardiomyocytes to diastolic dysfunction, myofilament instability, and cell death by necrosis.

Received for publication, July 23, 2003 , and in revised form, December 10, 2003.

^* This work was supported in part by National Institutes of Health Grant HL 03878-02 and American Heart Association Grant 0150549N (to D. B. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a video demonstration for Fig. 8C.

^¶ Supported by the National Institutes of Health Training Grant T32 HL07224-27.

^** To whom correspondence should be addressed: Cardiovascular Division, Dept. of Medicine, Boston University Medical Center, X-320, 650 Albany St., Boston, MA 02118. Tel.: 617-638-8071; Fax: 617-414-1619; E-mail: douglas.sawyer{at}bmc.org.

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