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Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity.

Publication ,  Journal Article
Gupta, A; Rohlfsen, C; Leppo, MK; Chacko, VP; Wang, Y; Steenbergen, C; Weiss, RG
Published in: PLoS One
2013

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 (5 mg/kg) administration using in vivo (31)P MRS and (1)H 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<0.02). Thus CK-M-OE attenuates the early decline in myocardial high-energy phosphates and contractile function caused by chronic DOX administration and increases survival. These findings suggest that CK impairment plays an energetic and functional role in this DOX-cardiotoxicity model and suggests that metabolic strategies, particularly those targeting CK, offer an appealing new strategy for limiting DOX-associated cardiotoxicity.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

10

Start / End Page

e74675

Location

United States

Related Subject Headings

  • Ventricular Dysfunction, Left
  • Survival Analysis
  • Myocardium
  • Muscle Contraction
  • Heart
  • General Science & Technology
  • Gene Expression
  • Energy Metabolism
  • Doxorubicin
  • Creatine Kinase
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gupta, A., Rohlfsen, C., Leppo, M. K., Chacko, V. P., Wang, Y., Steenbergen, C., & Weiss, R. G. (2013). Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity. PLoS One, 8(10), e74675. https://doi.org/10.1371/journal.pone.0074675
Gupta, Ashish, Cory Rohlfsen, Michelle K. Leppo, Vadappuram P. Chacko, Yibin Wang, Charles Steenbergen, and Robert G. Weiss. “Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity.PLoS One 8, no. 10 (2013): e74675. https://doi.org/10.1371/journal.pone.0074675.
Gupta A, Rohlfsen C, Leppo MK, Chacko VP, Wang Y, Steenbergen C, et al. Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity. PLoS One. 2013;8(10):e74675.
Gupta, Ashish, et al. “Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity.PLoS One, vol. 8, no. 10, 2013, p. e74675. Pubmed, doi:10.1371/journal.pone.0074675.
Gupta A, Rohlfsen C, Leppo MK, Chacko VP, Wang Y, Steenbergen C, Weiss RG. Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity. PLoS One. 2013;8(10):e74675.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

10

Start / End Page

e74675

Location

United States

Related Subject Headings

  • Ventricular Dysfunction, Left
  • Survival Analysis
  • Myocardium
  • Muscle Contraction
  • Heart
  • General Science & Technology
  • Gene Expression
  • Energy Metabolism
  • Doxorubicin
  • Creatine Kinase