Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mTOR-mediated signaling and cardiac function.
Mammalian target of rapamycin (mTOR) is a key regulator for cell growth through modulating components of the translation machinery. Previously, numerous pharmacological studies using rapamycin suggested that mTOR has an important role in regulating cardiac hypertrophic growth. To further investigate this assumption, we have generated two lines of cardiac specific mTOR transgenic mice, kinase-dead (kd) mTOR and constitutively active (ca) mTOR, using alpha-myosin heavy chain promoter. alpha-Myosin heavy chain (alphaMHC)-mTORkd mice had a near complete inhibition of p70 S6k and 4E-BP1 phosphorylation, whereas alphaMHC-mTORca had a significant increase in p70 S6k and 4E-BP1 phosphorylation. Although the cardiac function of alphaMHC-mTORkd mice was significantly altered, the cardiac morphology of these transgenic mice was normal. The cardiac hypertrophic growth in response to physiological and pathological stimuli was not different in alphaMHC-mTORkd and alphaMHC-mTORca transgenic mice when compared with that of nontransgenic littermates. These findings suggest that the mTOR-mediated signaling pathway is not essential to cardiac hypertrophic growth but is involved in regulating cardiac function. Additional analysis of cardiac responses to fasting-refeeding or acute insulin administration indicated that alphaMHC-mTORkd mice had a largely impaired physiological response to nutrient energy supply and insulin stimulation.
Shen
Wei-Hua
WH
Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology and Neonatology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Chen
Zhuang
Z
Shi
Shu
S
Chen
Hanying
H
Zhu
Wuqiang
W
Penner
Anne
A
Bu
Guixue
G
Li
Wei
W
Boyle
David W
DW
Rubart
Michael
M
Field
Loren J
LJ
Abraham
Robert
R
Liechty
Edward A
EA
Shou
Weinian
W
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D039642:Eukaryotic Initiation Factors; D005786:Gene Expression Regulation; D006984:Hypertrophy; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D007328:Insulin; D010750:Phosphoproteins; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases