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2016 ; 118
(8
): 1208-22
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Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in
Fatal Dilated Cardiomyopathy
#MMPMID26976650
Zhou J
; Ahmad F
; Parikh S
; Hoffman NE
; Rajan S
; Verma VK
; Song J
; Yuan A
; Shanmughapriya S
; Guo Y
; Gao E
; Koch W
; Woodgett JR
; Madesh M
; Kishore R
; Lal H
; Force T
Circ Res
2016[Apr]; 118
(8
): 1208-22
PMID26976650
show ga
RATIONALE: Cardiac myocyte-specific deletion of either glycogen synthase kinase
(GSK)-3? and GSK-3? leads to cardiac protection after myocardial infarction,
suggesting that deletion of both isoforms may provide synergistic protection.
This is an important consideration because of the fact that all GSK-3-targeted
drugs, including the drugs already in clinical trial target both isoforms of
GSK-3, and none are isoform specific. OBJECTIVE: To identify the consequences of
combined deletion of cardiac myocyte GSK-3? and GSK-3? in heart function. METHODS
AND RESULTS: We generated tamoxifen-inducible cardiac myocyte-specific mice
lacking both GSK-3 isoforms (double knockout). We unexpectedly found that cardiac
myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial
echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment,
double-knockout hearts leads to excessive dilatative remodeling and ventricular
dysfunction. Further experimentation with isolated adult cardiac myocytes and
fibroblasts from double-knockout implicated cardiac myocytes intrinsic factors
responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult
cardiac myocytes resulted in induction of mitotic catastrophe, a previously
unreported event in cardiac myocytes. Double-knockout cardiac myocytes showed
cell cycle progression resulting in increased DNA content and multinucleation.
However, increased cell cycle activity was rivaled by marked activation of DNA
damage, cell cycle checkpoint activation, and mitotic catastrophe-induced
apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in
isolated adult cardiac myocytes. CONCLUSIONS: Together, our findings suggest that
cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis, and its
loss is incompatible with life because of cell cycle dysregulation that
ultimately results in a severe fatal dilated cardiomyopathy.