Pim1 Maintains Telomere Length In Mouse Cardiomyocytes By Inhibiting Tgf Beta Signalling

Aims Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and upregulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating tetomere length is the transforming growth factor beta (TGF beta) signalling pathway where inhibiting TGF beta signalling maintains telomere Length. The relationship between Pim1 and TGF beta has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGF beta signalling pathways in proliferating A549 cells and post-mitotic cardiomyocytes.Methods and results Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGF beta signalling in re A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGF beta signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGF beta pathway genes.Conclusion Pim1 maintains tetomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGF beta pathway downstream effectors Smad2 and Smad3, which prevents repression of telomerase reverse transcriptase. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.[GRAPHICS].