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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
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Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy

Rui A Carvalho1, Rui P B Sousa, Virgilio J J Cadete

  • 1NMR Center, Department of Biochemistry, Apartado 3126, University of Coimbra, 3001-401 Coimbra, Portugal. carvalho@ci.uc.pt

Toxicology
|February 6, 2010
PubMed

Insights

Doxorubicin (DOX) chemotherapy alters heart metabolism, shifting from fatty acid to glucose oxidation. The cardioprotective drug dexrazoxane (DZR) prevents this metabolic switch, protecting against DOX-induced cardiomyopathy.

Area of Science:

  • Biochemistry
  • Cardiology
  • Metabolomics

Background:

  • Doxorubicin (DOX) is an effective chemotherapy drug but causes dose-limiting cardiomyopathy.
  • DOX-induced cardiotoxicity is linked to mitochondrial dysfunction and impaired oxidative phosphorylation.
  • Gene expression changes suggest a metabolic shift from fatty acid oxidation to glycolysis in DOX-treated hearts.

Purpose of the Study:

  • To investigate if doxorubicin (DOX) induces a metabolic flux switch in cardiac tissue.
  • To determine if dexrazoxane (DZR) can prevent DOX-induced metabolic changes.
  • To explore if this metabolic shift is a general response to cardiac stress.

Main Methods:

  • Utilized (13)C-isotopomer analysis in isolated perfused rat hearts.
  • Administered weekly subcutaneous injections of DOX with or without DZR.
  • Performed substrate-selective isotopomer analysis and Western blots to assess metabolic pathways.

Main Results:

  • DOX treatment shifted cardiac metabolism from fatty acid oxidation to glucose and lactate/pyruvate oxidation.
  • This shift was associated with increased pyruvate dehydrogenase activity.
  • Doxorubicin inhibited long-chain fatty acid oxidation, not MCAD activity or fatty acyl-carnitine transport.
  • Dexrazoxane (DZR) co-administration largely prevented these DOX-induced metabolic alterations.
  • The observed metabolic switch is similar to other models of cardiac failure.

Conclusions:

  • Doxorubicin (DOX) induces a significant shift in cardiac substrate metabolism, favoring glycolysis over fatty acid oxidation.
  • Dexrazoxane (DZR) effectively protects the heart by preventing DOX-induced metabolic reprogramming.
  • The metabolic alterations observed in DOX-induced cardiotoxicity may represent a general compensatory mechanism in cardiac stress.

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