Background: Telomerase has initially been described as a nuclear enzyme counteracting telomere erosion. Although this process is relevant only in cells with high proliferative capacity, the catalytic subunit of telomerase, Telomerase Reverse Transcriptase (TERT) has also been found in post-mitotic tissues. There, it is present not only in cell nuclei, but also mitochondria. The fact that TERT deficiency impairs respiration in heart mitochondria clearly demonstrates that TERT is relevant for mitochondrial functions. As TERT has protective functions in the cardiovascular system we generated new mouse models, which contain TERT in all tissues only in mitochondria (mitoTERT mice) or cell nuclei (nucTERT mice), to differentiate between the functions of TERT in these two cellular compartments.

 

Results: Both mouse lines did not show phenotypic abnormalities and had basal cardiac functions identical to wildtype and TERT knockout animals. In addition, immune cell composition and metabolic parameters were not different. However, mitochondrial respiration in the heart was impaired in knockout and nucTERT mice compared to wildtype animals, whereas it was improved in mitoTERT animals. Moreover, mitoTERT mice were protected against myocardial ischemia/reperfusion injury as evident from smaller infarcts after 2 days of reperfusion, reduced scar size after 7 days, an attenuated decrease in ejection fraction and reduced left ventricular dilation after 28 days. These effects were mirrored in improvements in functional parameters of the parental cell types of the heart, namely cardiomyocytes, endothelial cells relevant for vascularization and fibroblasts, which, after myocardial infarction, have to differentiate into myofibroblasts to substitute for dead cardiomyocytes and are required to form a stable scar. To find a therapeutic option for those results, we made use of the telomerase activator TA-65. We found that TA-65 increased mitochondrial TERT, but not nuclear TERT. To assess the effects of this plant compound in vivo, we fed mice for 10 days with TA-65, which led to an increase in respiration in heart mitochondria similar to the one observed in mitoTERT mice.

 

Conclusion: With our new, unique mouse models we demonstrated for the first time that mitochondrial, but not nuclear TERT is protective after myocardial infarction. The improved mitochondrial respiration in the heart after TA-65 supplementation implies that this food supplement could have therapeutic potential in myocardial infarction.