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

Monte Willis, Traci L. Parry, David I. Brown, Roberto I. Mota, Wei Huang, Ju Youn Beak, Michael Sola, Cynthia Zhou, Sean T. Hicks, Melissa C. Caughey, Ralph B. D'agostino, Jennifer Jordan, W. Gregory Hundley, Brian C. Jensen

Research output: Contribution to journalArticle

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Abstract

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 (R 2 =0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 μm 2 ; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R 2 =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.

Original languageEnglish (US)
Article numbere005234
JournalCirculation: Heart Failure
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Striated Muscle
Anthracyclines
Ligases
Ubiquitin
Doxorubicin
Atrophy
Heart Neoplasms
Muscular Atrophy
Dilated Cardiomyopathy
Cardiac Myocytes
Fingers
Up-Regulation
Heart Failure
Magnetic Resonance Imaging
Muscles
Therapeutics
Neoplasms

Keywords

  • anthracycline
  • atrophy
  • cardiotoxicity
  • doxorubicin
  • heart failure
  • mice
  • ubiquitin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1. / Willis, Monte; Parry, Traci L.; Brown, David I.; Mota, Roberto I.; Huang, Wei; Beak, Ju Youn; Sola, Michael; Zhou, Cynthia; Hicks, Sean T.; Caughey, Melissa C.; D'agostino, Ralph B.; Jordan, Jennifer; Hundley, W. Gregory; Jensen, Brian C.

In: Circulation: Heart Failure, Vol. 12, No. 3, e005234, 01.03.2019.

Research output: Contribution to journalArticle

Willis, M, Parry, TL, Brown, DI, Mota, RI, Huang, W, Beak, JY, Sola, M, Zhou, C, Hicks, ST, Caughey, MC, D'agostino, RB, Jordan, J, Hundley, WG & Jensen, BC 2019, 'Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1', Circulation: Heart Failure, vol. 12, no. 3, e005234. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005234
Willis, Monte ; Parry, Traci L. ; Brown, David I. ; Mota, Roberto I. ; Huang, Wei ; Beak, Ju Youn ; Sola, Michael ; Zhou, Cynthia ; Hicks, Sean T. ; Caughey, Melissa C. ; D'agostino, Ralph B. ; Jordan, Jennifer ; Hundley, W. Gregory ; Jensen, Brian C. / Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1. In: Circulation: Heart Failure. 2019 ; Vol. 12, No. 3.
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T1 - Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1

AU - Willis, Monte

AU - Parry, Traci L.

AU - Brown, David I.

AU - Mota, Roberto I.

AU - Huang, Wei

AU - Beak, Ju Youn

AU - Sola, Michael

AU - Zhou, Cynthia

AU - Hicks, Sean T.

AU - Caughey, Melissa C.

AU - D'agostino, Ralph B.

AU - Jordan, Jennifer

AU - Hundley, W. Gregory

AU - Jensen, Brian C.

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N2 - 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 (R 2 =0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 μm 2 ; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R 2 =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.

AB - 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 (R 2 =0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 μm 2 ; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R 2 =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.

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