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 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.
Oh
H
H
Center for Cardiovascular Development, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Taffet
G E
GE
Youker
K A
KA
Entman
M L
ML
Overbeek
P A
PA
Michael
L H
LH
Schneider
M D
MD
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology; D002455:Cell Division / Q000502:physiology; D048429:Cell Size / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology*; D051381:Rats; D019098:Telomerase / Q000235:genetics / Q000502:physiology*; D016615:Telomere / Q000648:ultrastructure
D017931:DNA Primers; D004268:DNA-Binding Proteins; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse