AIMS: The present study was designed to examine the impact of chronic Akt 
activation on endoplasmic reticulum (ER) stress-induced cardiac mechanical 
anomalies, if any, and the underlying mechanism involved.
RESULTS: Wild-type and transgenic mice with cardiac-specific overexpression of 
the active mutant of Akt (Myr-Akt) were subjected to the ER stress inducer 
tunicamycin (1 or 3 mg/kg). ER stress led to compromised echocardiographic 
(elevated left ventricular end-systolic diameter and reduced fractional 
shortening) and cardiomyocyte contractile function, intracellular Ca(2+) 
mishandling, and cell survival in wild-type mice associated with mitochondrial 
damage. In vitro ER stress induction in murine cardiomyocytes upregulated the ER 
stress proteins Gadd153, GRP78, and phospho-eIF2α, and promoted reactive oxygen 
species production, carbonyl formation, apoptosis, mitochondrial membrane 
potential loss, and mitochondrial permeation pore (mPTP) opening associated with 
overtly impaired cardiomyocyte contractile and intracellular Ca(2+) properties. 
Interestingly, these anomalies were mitigated by chronic Akt activation or the 
ER chaperon tauroursodeoxycholic acid (TUDCA). Treatment with tunicamycin also 
dephosphorylated Akt and its downstream signal glycogen synthase kinase 3β 
(GSK3β) (leading to activation of GSK3β), the effect of which was abrogated by 
Akt activation and TUDCA. The ER stress-induced cardiomyocyte contractile and 
mitochondrial anomalies were obliterated by the mPTP inhibitor cyclosporin A, 
GSK3β inhibitor SB216763, and ER stress inhibitor TUDCA.
INNOVATION: This research reported the direct relationship between ER stress and 
cardiomyocyte contractile and mitochondrial anomalies for the first time.
CONCLUSION: Taken together, these data suggest that ER stress may compromise 
cardiac contractile and intracellular Ca(2+) properties, possibly through the 
Akt/GSK3β-dependent impairment of mitochondrial integrity.