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@ARTICLE{Annamalai:282912,
      author       = {Annamalai, Karthika and Dilliker, Soniya and Buchholz, Eric
                      and Castro-Hernández, Ricardo and Panyam, Nikita and
                      Pommeranz, Alessa and Wiederhake, Pascal and Wery von
                      Limont, Nelly and Hempel, Nina and Ebner, Verena and
                      Swarnkar, Surabhi and Mohamed, Belal A and
                      Streckfuss-Bömeke, Katrin and Steffens, Sabine and Herzig,
                      Stephan and Ebert, Antje and Fischer, Andre and Toischer,
                      Karl},
      title        = {{D}eregulation of m6{A}-{RNA} methylation impairs adaptive
                      hypertrophic response and drives maladaptation via
                      m{TORC}1-{S}6{K}1-hyperactivation and autophagy impairment.},
      journal      = {Cell communication and signaling},
      volume       = {23},
      number       = {1},
      issn         = {1478-811X},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2025-01373},
      pages        = {522},
      year         = {2025},
      abstract     = {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.},
      keywords     = {Apoptosis (Other) / Atrophy (Other) / Cardiac hypertrophy
                      (Other) / Mouse (Other) / N6-methyladenosine (Other) /
                      Pathological remodeling (Other)},
      cin          = {AG Fischer},
      ddc          = {570},
      cid          = {I:(DE-2719)1410002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41327199},
      pmc          = {pmc:PMC12690826},
      doi          = {10.1186/s12964-025-02509-0},
      url          = {https://pub.dzne.de/record/282912},
}