Abstract
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.
Non-standard Abbreviations and acronyms
- Cand2
- Cullin-associated NEDD8-dissociated protein 2
- CPM
- Count Per Million
- RPKM
- Reads Per Kilobase Million
- DEGs
- Differential Expressed Genes
- IP
- Immunoprecipitation
- mTOR
- Mechanistic Target Of Rapamycin
- nt
- Nucleotide
- NRCMs
- Neonatal Rat Cardiac Myocytes
- LV
- Left ventricle
- RPF
- Ribosome Protected mRNA Fragments
- Ribo-seq
- Ribosomal sequencing
- RNA-seq
- RNA sequencing
- TOP-motif
- Terminal oligo pyrimidin motif
- 5’UTR
- 5’ Untranslated Region
- IRES
- Internal Ribosomal Entry Site
- TAC
- Transverse Aortic Constriction
- PE
- Phenylephrine
- Cx
- Cycloheximide
- PLA
- Proximity Ligation Assay
- WT
- Wild-type
- KO
- Knock-out
- KD
- Knock-down
- OE
- Overexpression