PT - JOURNAL ARTICLE AU - Agnieszka A. Gorska AU - Clara Sandmann AU - Eva Riechert AU - Christoph Hofmann AU - Ellen Malovrh AU - Eshita Varma AU - Vivien Kmietczyk AU - Lonny Jürgensen AU - Verena Kamuf-Schenk AU - Claudia Stroh AU - Jennifer Furkel AU - Matthias H. Konstandin AU - Carsten Sticht AU - Etienne Boileau AU - Christoph Dieterich AU - Hugo A. Katus AU - Shirin Doroudgar AU - Mirko Völkers TI - Muscle specific translational control of Cand2 by mTORC1 regulates adverse cardiac remodeling AID - 10.1101/2020.11.29.403196 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.11.29.403196 4099 - http://biorxiv.org/content/early/2020/12/01/2020.11.29.403196.short 4100 - http://biorxiv.org/content/early/2020/12/01/2020.11.29.403196.full AB - The mechanistic target of rapamycin (mTOR) is a key regulator of pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective, however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is largely unknown. A cardiomyocyte genome-wide sequencing approach was used to define mTOR-dependent post-transcriptional gene expression control at the level of mRNA translation. This approach identified the muscle-specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene, dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we found that Cand2 links mTOR signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type-specific targeting of mTOR might have therapeutic value for adverse pathological cardiac remodeling.Cand2Cullin-associated NEDD8-dissociated protein 2CPMCount Per MillionRPKMReads Per Kilobase MillionDEGsDifferential Expressed GenesIPImmunoprecipitationmTORMechanistic Target Of RapamycinntNucleotideNRCMsNeonatal Rat Cardiac MyocytesLVLeft ventricleRPFRibosome Protected mRNA FragmentsRibo-seqRibosomal sequencingRNA-seqRNA sequencingTOP-motifTerminal oligo pyrimidin motif5’UTR5’ Untranslated RegionIRESInternal Ribosomal Entry SiteTACTransverse Aortic ConstrictionPEPhenylephrineCxCycloheximidePLAProximity Ligation AssayWTWild-typeKOKnock-outKDKnock-downOEOverexpression