Aims Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and upregulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase... Show moreAims 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]. Show less
Cell culture models play an important role in biomedical research and will continue to do so given the growing opposition to vivisection and the limited predictive value of animal models for... Show moreCell culture models play an important role in biomedical research and will continue to do so given the growing opposition to vivisection and the limited predictive value of animal models for human disease. Moreover, cell culture models can be easily established to mimic physiological or pathological processes, which is difficult to accomplish using in silico models. While non-cellular in vitro models are highly suitable for studying simple biochemical processes, cell culture models recapitulate many of the complex regulatory circuits governing protein activity in vivo and hence allow investigation of diverse physiological processes. Also, cell culture models offer the possibility to address fundamental research questions in a much more simplified, specific and controllable manner than can be achieved using in vivo models. Show less
