| Full text | |
| Author(s): |
Alves, Paula K. N.
;
Cruz, Andre
;
Adams, Volker
;
Moriscot, Anselmo S.
;
Labeit, Siegfried
Total Authors: 5
|
| Document type: | Journal article |
| Source: | European Journal of Pharmacology; v. 984, p. 9-pg., 2024-10-07. |
| 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. (AU) | |
| FAPESP's process: | 18/24419-4 - Effect of leucine on the expression of miR-299A and HDAC4 in the skeletal muscle of rats submitted to immobilization: implications for the control of muscle mass |
| Grantee: | Paula Ketilly Nascimento Alves |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| FAPESP's process: | 21/03066-9 - Skeletal muscle mass control by microRNA-29c manipulation: a molecular intervention approach |
| Grantee: | Anselmo Sigari Moriscot |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 17/09398-8 - Interplay betweeen myostatin and mTORC1 pathways in skeletal muscle: implications for a thyroid hormone biological action |
| Grantee: | André Cruz de Oliveira |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| FAPESP's process: | 19/08996-4 - Effects of miR-29c on skeletal muscle plasticity: implications for the control of muscle mass |
| Grantee: | William Jose da Silva |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 21/05827-7 - Effect of leucine on the expression of miR-299a and HDAC4 in the skeletal muscle of rats submitted to hind limb immobilization: implications for the control of muscle mass |
| Grantee: | Paula Ketilly Nascimento Alves |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| FAPESP's process: | 15/04090-0 - Identification and caracterization of mechanisms involved in skeletal muscle mass control and regeneration |
| Grantee: | Anselmo Sigari Moriscot |
| Support Opportunities: | Research Projects - Thematic Grants |