Telomerase Reverse Transcriptase Promotes Cardiac Muscle Cell Proliferation, Hypertrophy, and Survival

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 18; pp. 10308 - 10313
• Main Authors: Oh, Hidemasa, Taffet, George E., Youker, Keith A., Entman, Mark L., Overbeek, Paul A., Michael, Lloyd H., Schneider, Michael D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.08.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Animals; Apoptosis; Apoptosis - physiology; Base Sequence; Biological Sciences; Cardiomegaly - enzymology; Cardiomegaly - etiology; Cell cycle; Cell Division - physiology; Cell growth; Cell Size - physiology; Cell Survival - physiology; Cells, Cultured; DNA; DNA Primers - genetics; DNA-Binding Proteins; Gene Expression Regulation, Developmental; Heart; Histones; Humans; Hypertrophy; Mice; Mice, Transgenic; Myocardium; Myocardium - cytology; Myocardium - enzymology; Phosphorylation; Rats; Space life sciences; Telomerase - genetics; Telomerase - physiology; Telomere - ultrastructure; Telomeres; TERT protein; Non-programmatic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.191169098

Cardiac muscle regeneration after injury is limited by "irreversible" cell cycle exit. Telomere shortening is one postulated basis for replicative senescence, via down-regulation of telomerase reverse transcriptase (TERT); telomere dysfunction also is associated with greater sensitivity to apoptosis. Forced expression of TERT in cardiac muscle in mice was sufficient to rescue telomerase activity and telomere length. Initially, the ventricle was hypercellular, with increased myocyte density and DNA synthesis. By 12 wk, cell cycling subsided; instead, cell enlargement (hypertrophy) was seen, without fibrosis or impaired function. Likewise, viral delivery of TERT was sufficient for hypertrophy in cultured cardiac myocytes. The TERT virus and transgene also conferred protection from apoptosis, in vitro and in vivo. Hyperplasia, hypertrophy, and survival all required active TERT and were not seen with a catalytically inactive mutation. Thus, TERT can delay cell cycle exit in cardiac muscle, induce hypertrophy in postmitotic cells, and promote cardiac myocyte survival.