Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure.
While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.
Lee
Hyoung-gon
HG
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America. hyoung-gon.lee@case.edu
Chen
Qun
Q
Wolfram
Julie A
JA
Richardson
Sandy L
SL
Liner
Anna
A
Siedlak
Sandra L
SL
Zhu
Xiongwei
X
Ziats
Nicholas P
NP
Fujioka
Hisashi
H
Felsher
Dean W
DW
Castellani
Rudy J
RJ
Valencik
Maria L
ML
McDonald
John A
JA
Hoit
Brian D
BD
Lesnefsky
Edward J
EJ
Smith
Mark A
MA
D000818:Animals; D017209:Apoptosis; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D004579:Electron Transport; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006984:Hypertrophy; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
D016271:Proto-Oncogene Proteins c-myc