Creatine Kinase-Overexpression Improves Myocardial Energetics, Contractile Dysfunction and Survival in Murine Doxorubicin Cardiotoxicity

Ashish Gupta, Cory Rohlfsen, Michelle K. Leppo, Vadappuram P. Chacko, Yibin Wang, Charles Jr Steenbergen, Robert George Weiss

Research output: Contribution to journalArticle

Abstract

Doxorubicin (DOX) is a commonly used life-saving antineoplastic agent that also causes dose-dependent cardiotoxicity. Because ATP is absolutely required to sustain normal cardiac contractile function and because impaired ATP synthesis through creatine kinase (CK), the primary myocardial energy reserve reaction, may contribute to contractile dysfunction in heart failure, we hypothesized that impaired CK energy metabolism contributes to DOX-induced cardiotoxicity. We therefore overexpressed the myofibrillar isoform of CK (CK-M) in the heart and determined the energetic, contractile and survival effects of CK-M following weekly DOX (5mg/kg) administration using in vivo31P MRS and 1H MRI. In control animals, in vivo cardiac energetics were reduced at 7 weeks of DOX protocol and this was followed by a mild but significant reduction in left ventricular ejection fraction (EF) at 8 weeks of DOX, as compared to baseline. At baseline, CK-M overexpression (CK-M-OE) increased rates of ATP synthesis through cardiac CK (CK flux) but did not affect contractile function. Following DOX however, CK-M-OE hearts had better preservation of creatine phosphate and higher CK flux and higher EF as compared to control DOX hearts. Survival after DOX administration was significantly better in CK-M-OE than in control animals (p

Original languageEnglish (US)
Article numbere74675
JournalPLoS One
Volume8
Issue number10
DOIs
StatePublished - Oct 1 2013

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doxorubicin
creatine kinase
Creatine Kinase
Doxorubicin
MM Form Creatine Kinase
mice
Adenosine Triphosphate
Animals
heart
Fluxes
MB Form Creatine Kinase
Phosphocreatine
Cardiotoxicity
Antineoplastic Agents
Stroke Volume
Magnetic resonance imaging
Energy Metabolism
creatine
synthesis
antineoplastic agents

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Creatine Kinase-Overexpression Improves Myocardial Energetics, Contractile Dysfunction and Survival in Murine Doxorubicin Cardiotoxicity. / Gupta, Ashish; Rohlfsen, Cory; Leppo, Michelle K.; Chacko, Vadappuram P.; Wang, Yibin; Steenbergen, Charles Jr; Weiss, Robert George.

In: PLoS One, Vol. 8, No. 10, e74675, 01.10.2013.

Research output: Contribution to journalArticle

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