The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases

Author:

Brandão Sofia Reis123,Reis-Mendes Ana12ORCID,Neuparth Maria João45,Carvalho Félix12ORCID,Ferreira Rita3ORCID,Costa Vera Marisa12ORCID

Affiliation:

1. Associate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal

2. UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal

3. LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal

4. Laboratory for Integrative and Translational Research in Population Health (ITR), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports, University of Porto, 4200-450 Porto, Portugal

5. TOXRUN—Toxicology Research Unit, University Institute of Health Sciences, CESPU, 4585-116 Gandra, Portugal

Abstract

The cardiotoxicity of doxorubicin (DOX) may manifest at the beginning/during treatment or years after, compromising patients’ quality of life. We intended to study the cardiac pathways one week (short-term, control 1 [CTRL1] and DOX1 groups) or five months (long-term, CTRL2 and DOX2 groups) after DOX administration in adult male CD-1 mice. Control groups were given saline, and DOX groups received a 9.0 mg/Kg cumulative dose. In the short-term, DOX decreased the content of AMP-activated protein kinase (AMPK) while the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) increased compared to CTRL1, suggesting the upregulation of fatty acids oxidation. Moreover, mitofusin1 (Mfn1) content was decreased in DOX1, highlighting decreased mitochondrial fusion. In addition, increased B-cell lymphoma-2 associated X-protein (BAX) content in DOX1 pointed to the upregulation of apoptosis. Conversely, in the long-term, DOX decreased the citrate synthase (CS) activity and the content of Beclin1 and autophagy protein 5 (ATG5) compared to CTRL2, suggesting decreased mitochondrial density and autophagy. Our study demonstrates that molecular mechanisms elicited by DOX are modulated at different extents over time, supporting the differences on clinic cardiotoxic manifestations with time. Moreover, even five months after DOX administration, meaningful heart molecular changes occurred, reinforcing the need for the continuous cardiac monitoring of patients and determination of earlier biomarkers before clinical cardiotoxicity is set.

Funder

Research Unit on Applied Molecular Biosciences—UCIBIO

Associate Laboratory Institute for Health and Bioeconomy—i4HB

LAQV-REQUIMTE Aveiro

CIAFEL

ITR—Laboratory for Integrative and Translational Research in Population Health

FCT, I.P., and the European Social Fund

Norma Transitória

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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