Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1

Circ Heart Fail. 2019 Mar;12(3):e005234. doi: 10.1161/CIRCHEARTFAILURE.118.005234.


Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines.

Keywords: anthracycline; atrophy; cardiotoxicity; doxorubicin; heart failure; mice; ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Cardiotoxicity / diagnostic imaging
  • Cardiotoxicity / etiology
  • Cardiotoxicity / genetics
  • Cardiotoxicity / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects*
  • Echocardiography
  • Gene Expression
  • Heart / diagnostic imaging
  • Heart / drug effects*
  • Heart Failure / chemically induced*
  • Heart Failure / diagnostic imaging
  • Heart Failure / genetics
  • Heart Failure / metabolism
  • Humans
  • Injections, Intraperitoneal
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Muscular Atrophy / chemically induced*
  • Muscular Atrophy / diagnostic imaging
  • Muscular Atrophy / genetics
  • Muscular Atrophy / metabolism
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Tripartite Motif Proteins / genetics*
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Up-Regulation


  • Antineoplastic Agents
  • Muscle Proteins
  • Tripartite Motif Proteins
  • Doxorubicin
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases