Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival

Cardiac muscle regeneration after injury is limited by "irreversible" cell cycle exit. Telomere shortening is one postulated basis for replicative sen escence, via down-regulation of telomerase reverse transcriptase (TERT); te lomere dysfunction also is associated with greater sensitivity to apoptosis . Forced expression of TERT in cardiac muscle in mice was sufficient to res cue telomerase activity and telomere length. Initially, the ventricle was h ypercellular, with increased myocyte density and DNA synthesis. By 12 wk, c ell cycling subsided; instead, cell enlargement (hypertrophy) was seen, wit hout fibrosis or impaired function. Likewise, viral delivery of TERT was su fficient for hypertrophy in cultured cardiac myocytes. The TERT virus and t ransgene also conferred protection from apoptosis, in vitro and in vivo. Hy perplasia, hypertrophy, and survival all required active TERT and were not seen with a catalytically inactive mutation. Thus, TERT can delay cell cycl e exit in cardiac muscle, induce hypertrophy in postmitotic cells, and prom ote cardiac myocyte survival.