Mice with shortened cardiac telomeres recapitulate functional and transcriptional features of human ischemic and dilated cardiomyopathy

M. Brandt (Mainz)¹, S. Khraisat (Mainz)¹, Q. Luo (Mainz)¹, M. Mayerle (Stanford)², U. Raaz (Göttingen)³, P. Tsao (Stanford)⁴, P. Wenzel (Darmstadt)⁵, H. Blau (Stanford)^2
1Universitätsmedizin der Johannes Gutenberg-Universität Mainz Kardiologie 1, Zentrum für Kardiologie Mainz, Deutschland; ²Stanford University School of Medicine Baxter Laboratory for Stem Cell Biology Stanford, USA; ³Universitätsmedizin Göttingen Herzzentrum, Klinik für Kardiologie und Pneumologie Göttingen, Deutschland; ⁴Stanford University School of Medicine Division of Cardiovascular Medicine Stanford, USA; ⁵Klinikum Darmstadt Medizinische Klinik I Darmstadt, Deutschland

Mice have significantly longer telomeres than humans. Mice engineered to lack components of telomerase exhibit cardiac dysfunction, increased p53 activation and DNA damage, and mitochondrial dysfunction, all hallmarks of the telomere-p53-mitochondrion model of cardiac dysfunction. The combined effects of telomere shortening, p53 activation, and mitochondrial dysfunction can lead to an increase in senescent and apoptotic cardiomyocytes, weakening heart muscle and reducing contractility and cardiac efficiency. Cardiomyocyte death also triggers fibrotic remodeling, further impairing cardiac function. However, a characterization of the underlying transcriptional profile of telomere-shortened cardiomyocytes is lacking, and the general clinical relevance of this model to heart failure remains to be established.
We conducted cardiac assessment of early and advanced generation telomerase RNA-component deficient mice (mTR-/-). We characterized cardiomyocyte function and compared the cardiomyocyte-specific (mTR-/-) transcriptomic profile to reexisting human and murine datasets of dilated cardiomyopathy and ischemic heart failure.
mTR-/- mice with shortened telomeres exhibited impaired cardiac and cardiomyocyte mitochondrial function. Analysis of telomere-shortened cardiomyocytes revealed that TP53 activation and PGC-1α suppression are key events. We also identified increased inflammatory and stress signals, suggesting that telomere shortening triggers inflammation and aging, and novel factors such as TREX1, and RNASEH2B.
Comparison analysis revealed that both specific regulators and the complete transcriptional profile show a statistically robust overlap with virtually all available murine and human ischemic and dilated cardiomyopathy datasets. Together these data help establish the clinical relevance of the mTR-/- mouse model and telomere attrition to human heart failure and suggest potential therapeutic targets for future testing.