Small-molecule mediated MuRF1 inhibition protects from doxorubicin-induced cardiac atrophy and contractile dysfunction

• Verfasst von: Alves, Paula [VerfasserIn]
• Verfasst von: Cruz, André [VerfasserIn]
• Verfasst von: Adams, Volker [VerfasserIn]
• Verfasst von: Moriscot, Anselmo S. [VerfasserIn]
• Verfasst von: Labeit, Siegfried [VerfasserIn]
• Titel: Small-molecule mediated MuRF1 inhibition protects from doxorubicin-induced cardiac atrophy and contractile dysfunction
• Verf.angabe: Paula K. N. Alves, André Cruz, Volker Adams, Anselmo S. Moriscot, Siegfried Labeit
• E-Jahr: 2024
• Jahr: 5 December 2024
• Umfang: 9 S.
• Illustrationen: Illustrationen
• Fussnoten: Online verfügbar: 02. Oktober 2025, Artikelversion: 07. Oktober 2025 ; Gesehen am 02.04.2025
• Titel Quelle: Enthalten in: European journal of pharmacology
• Ort Quelle: New York, NY [u.a.] : Elsevier, 1967
• Jahr Quelle: 2024
• Band/Heft Quelle: 984(2024), Artikel-ID 177027, Seite 1-9
• ISSN Quelle: 1879-0712
• DOI: doi:10.1016/j.ejphar.2024.177027
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cardiac failure and atrophy
• Sach-SW: Doxorubicin chemotherapy
• Sach-SW: MuRF-1
• Sach-SW: Small molecule therapies
• Sach-SW: Titin filament
• K10plus-PPN: 1921121068

Abstract

Cancer chemotherapy induces cell stress in rapidly dividing cancer cells to trigger their growth arrest and apoptosis. However, adverse effects related to cardiotoxicity underpinned by a limited regenerative potential of the heart limits clinical application: In particular, chemotherapy with doxorubicin (DOXO) causes acute heart injury that can transition to persisting cardiomyopathy (DOXO-CM). Here, we tested if MuRF1 inhibition (“MuRFi”) was able to attenuate DOXO-CM. To mimic DOXO chemotherapy, we treated mice over four weeks with five DOXO injections, resulting in a cumulative dosage of 25 mg/kg. At day 28, mice had lower body and heart weights, reduced cardiac cross-sectional myofibrillar areas (CSAs), and disturbed functional ejection fractions (EFs) and fractional shortenings (FS) as indicated by echocardiography (ECHO). In contrast, mice with a 1 g/kg Myomed#205 spiked diet, a previously described experimental MuRFi therapy, showed lower DOXO-CM at day 28, and also reduced acute DOXO cardiac injury at day 7 (single DOXO dose; 15 mg/kg). Underlying molecular signatures using Western blot (WB) assays showed at day 28 reduced phospho-AKT (AKTp) and phospo-4EBP1 (4 EBP1p) levels following DOXO that were normalized following MuRFi treatment. Taken together, our data suggest that MuRFi treatment is suitable to attenuate DOXO-CM by preserving AKTp and 4 EBP1p levels in DOXO stressed cardiomyocytes, thereby supporting de novo protein translation and cardiomyocyte survival under translational arrest stress.