Hidemasa Oh ^{1, 3}, George E. Taffet ^{2, 3}, Keith A. Youker ^{2, 3}, Mark L. Entman ^{2, 3}, Paul A. Overbeek ⁴, Lloyd H. Michael ^{2, 3}, and Michael D. Schneider ^{1, 2, 3, 4, 5, @}.

¹ Center for Cardiovascular Development and the ² DeBakey Heart Center Graduate Program in Cardiovascular Sciences, Departments of ³ Medicine, ⁴ Molecular and Cellular Biology, and ⁵ Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030

Edited by Robert A. Weinberg, Whitehead Institute for Biomedical Research, Cambridge, MA, and approved July 5, 2001 (received for review April 5, 2001)

^@ To whom reprint requests should be addressed at: Baylor College of Medicine, One Baylor Plaza, Room 506C, Houston, TX 77030.E-mail: michaels@bcm.tmc.edu

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.

1. Frenster JH, and Herstein PH, "Gene De-Repression", New Eng. J. Med. 288: 1224-1229 (June 7, 1973).