Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure.
Hypertrophy allows the heart to adapt to workload but culminates in later pump failure; how it is achieved remains uncertain. Previously, we showed that hypertrophy is accompanied by activation of cyclin T/Cdk9, which phosphorylates the C-terminal domain of the large subunit of RNA polymerase II, stimulating transcription elongation and pre-mRNA processing; Cdk9 activity was required for hypertrophy in culture, whereas heart-specific activation of Cdk9 by cyclin T1 provoked hypertrophy in mice. Here, we report that alphaMHC-cyclin T1 mice appear normal at baseline yet suffer fulminant apoptotic cardiomyopathy when challenged by mechanical stress or signaling by the G-protein Gq. At pathophysiological levels, Cdk9 activity suppresses many genes for mitochondrial proteins including master regulators of mitochondrial function (peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), nuclear respiratory factor-1). In culture, cyclin T1/Cdk9 suppresses PGC-1, decreases mitochondrial membrane potential, and sensitizes cardiomyocytes to apoptosis, effects rescued by exogenous PGC-1. Cyclin T1/Cdk9 inhibits PGC-1 promoter activity and preinitiation complex assembly. Thus, chronic activation of Cdk9 causes not only cardiomyocyte enlargement but also defective mitochondrial function, via diminished PGC-1 transcription, and a resulting susceptibility to apoptotic cardiomyopathy.
Sano
Motoaki
M
Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX 77030, USA.
Wang
Sam C
SC
Shirai
Manabu
M
Scaglia
Fernando
F
Xie
Min
M
Sakai
Satoshi
S
Tanaka
Toru
T
Kulkarni
Prathit A
PA
Barger
Philip M
PM
Youker
Keith A
KA
Taffet
George E
GE
Hamamori
Yasuo
Y
Michael
Lloyd H
LH
Craigen
William J
WJ
Schneider
Michael D
MD
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051265:NF-E2-Related Factor 1; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C503684:CCNT1 protein, human; C503685:Ccnt1 protein, mouse; C503686:Ccnt1 protein, rat; D056906:Cyclin T; D016213:Cyclins; D004268:DNA-Binding Proteins; D051265:NF-E2-Related Factor 1; C495633:NRF1 protein, human; C495632:Nfe2l1 protein, rat; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D015534:Trans-Activators; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9; D012319:RNA Polymerase II