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| Home > Publications Database > Deregulation of m6A-RNA methylation impairs adaptive hypertrophic response and drives maladaptation via mTORC1-S6K1-hyperactivation and autophagy impairment. > print |
| Home > Publications Database > Deregulation of m6A-RNA methylation impairs adaptive hypertrophic response and drives maladaptation via mTORC1-S6K1-hyperactivation and autophagy impairment. > print |
| 001 | 282912 | ||
| 005 | 20251217170445.0 | ||
| 024 | 7 | _ | |a 10.1186/s12964-025-02509-0 |2 doi |
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| 037 | _ | _ | |a DZNE-2025-01373 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |a Annamalai, Karthika |0 0000-0002-7558-8035 |b 0 |
| 245 | _ | _ | |a Deregulation of m6A-RNA methylation impairs adaptive hypertrophic response and drives maladaptation via mTORC1-S6K1-hyperactivation and autophagy impairment. |
| 260 | _ | _ | |a London |c 2025 |b Biomed Central |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1765973747_5351 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a Pressure overload first leads to compensated hypertrophy and secondary to heart failure. m6A-RNA methylation is a fast process for the adaptation of cell composition. m6A-RNA-methylation is regulated by the demethylase, fat mass and obesity-associated protein (FTO), and FTO protein levels are diminished in heart failure. Cardiomyocyte-specific FTO-transgenic/knockout-mice have shown the relevance of FTO in pressure overload remodeling. However, its functional downstream regulatory mechanisms are still unclear. In this study, we discover the harmful signaling pathways that are triggered by m6A imbalance and FTO loss, which eventually lead to adverse cardiac remodeling and heart failure.FTOcKO animals were generated by crossing FTOfl/fl mice with [Formula: see text]-MHC Cre mice using Cre-lox system. Control and the FTOcKO animals groups were subjected to TAC (transverse aortic constriction) surgery. Echocardiography was performed 1-week post-TAC surgery. MeRIP (m6A RNA immunoprecipitation) sequencing was performed from the heart tissues of mice after one week TAC surgery. Additionally, the mechanistical interrelation between the signaling pathways during FTO loss and adverse cardiac remodeling were investigated in human iPS-CMs (hiPS-CMs).One week post-TAC surgery, FTOcKO mice showed impaired cardiac function (EF: CreC TAC (45%) vs. FTOcKO TAC (25%), p < 0.0001) and increased LVID (CreC TAC(3.9 mm) vs. FTOcKO TAC (4.8 mm), p < 0.0001), indicating a lack of adaption to pressure overload. Knockdown of FTO in hiPS-cardiomyocytes also reduced endothelin-induced hypertrophic response. MeRIP-seq data of FTOcKO mice showed that the differentially hypermethylated transcripts were associated with cardiac apoptosis inhibition (CDK1, CFLAR), mTORC1 signaling pathway (AKT1S1) and autophagy regulation (TFEB). mTORC1 was identified as a central player of dysregulation with hyperactivation of its canonical substrates phospho-S6K1 (Thr 389) and phospho-S6 (ser235/236) ex-vivo (FTOcKO) and in-vitro (FTO-KD-hiPS-CMs). Moreover, FTO-deficient cardiomyocytes cause autophagic flux impairment and defective autophagy. The effect of atrophy and induced apoptosis upon FTO-m6A imbalance could be rescued by pharmacological inhibiton of the mTORC1-S6K1 pathway.Downregulation of FTO leads to mTORC1-S6K1 hyperactivation that shift the compensative hypertrophic response to atrophy and apoptosis leading to progressive heart failure. These findings might pave the way for the development of novel therapeutic targets for the early phases of heart failure treatments.The online version contains supplementary material available at 10.1186/s12964-025-02509-0. |
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| 650 | _ | 7 | |a Apoptosis |2 Other |
| 650 | _ | 7 | |a Atrophy |2 Other |
| 650 | _ | 7 | |a Cardiac hypertrophy |2 Other |
| 650 | _ | 7 | |a Mouse |2 Other |
| 650 | _ | 7 | |a N6-methyladenosine |2 Other |
| 650 | _ | 7 | |a Pathological remodeling |2 Other |
| 700 | 1 | _ | |a Dilliker, Soniya |0 0009-0007-5118-6908 |b 1 |
| 700 | 1 | _ | |a Buchholz, Eric |b 2 |
| 700 | 1 | _ | |a Castro-Hernández, Ricardo |0 P:(DE-2719)9000512 |b 3 |u dzne |
| 700 | 1 | _ | |a Panyam, Nikita |0 0009-0009-5224-131X |b 4 |
| 700 | 1 | _ | |a Pommeranz, Alessa |b 5 |
| 700 | 1 | _ | |a Wiederhake, Pascal |b 6 |
| 700 | 1 | _ | |a Wery von Limont, Nelly |b 7 |
| 700 | 1 | _ | |a Hempel, Nina |0 P:(DE-2719)9003058 |b 8 |u dzne |
| 700 | 1 | _ | |a Ebner, Verena |b 9 |
| 700 | 1 | _ | |a Swarnkar, Surabhi |b 10 |
| 700 | 1 | _ | |a Mohamed, Belal A |b 11 |
| 700 | 1 | _ | |a Streckfuss-Bömeke, Katrin |0 0000-0001-5137-7228 |b 12 |
| 700 | 1 | _ | |a Steffens, Sabine |0 0000-0002-6892-9751 |b 13 |
| 700 | 1 | _ | |a Herzig, Stephan |b 14 |
| 700 | 1 | _ | |a Ebert, Antje |0 0000-0002-3642-242X |b 15 |
| 700 | 1 | _ | |a Fischer, Andre |0 P:(DE-2719)2000047 |b 16 |
| 700 | 1 | _ | |a Toischer, Karl |b 17 |
| 773 | _ | _ | |a 10.1186/s12964-025-02509-0 |g Vol. 23, no. 1, p. 522 |0 PERI:(DE-600)2126315-2 |n 1 |p 522 |t Cell communication and signaling |v 23 |y 2025 |x 1478-811X |
| 856 | 4 | _ | |y OpenAccess |u https://pub.dzne.de/record/282912/files/DZNE-2025-01373.pdf |
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