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The Role of mTOR in Cardiac Function.

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Title:The Role of mTOR in Cardiac Function.
Authors:Shimada, Briana K.
Contributors:Cell & Molecular Biology (department)
Date Issued:Aug 2017
Publisher:University of Hawaiʻi at Mānoa
Abstract:Despite many therapeutic advances, the rate of heart failure after myocardial
infarction remains very high. Therefore, there is still significant need to develop better
therapeutics to treat heart failure. One potential mark is the protein, mechanistic target
of rapamycin (mTOR), a key signaling kinase for most cell types. Overexpression of
mTOR has been previously shown by our lab as sufficient to protect the heart against
different stressors including ischemia-reperfusion (I/R) injury, TAC-induced hypertrophy,
and metabolic syndrome and obesity. As our laboratory is most concerned with the role
of mTOR in I/R injury, in this dissertation I wanted to determine if mTOR was necessary
for cardioprotection in I/R against various pathological settings, including diabetes
mellitus (DM).
To do this, I generated a tamoxifen-inducible, cardiac muscle specific mTOR
knockout (CKO) mouse model to evaluate the loss of mTOR in functional studies,
especially I/R injury. I initially characterized heart physiology in the CKO mouse at
baseline using echocardiography. Preliminary in vivo I/R injury and ex vivo Langendorff
I/R using acute inhibition of mTOR by Torin1 administration suggested mTOR was
necessary to protect the heart as the recovery of the CKO group was significantly worse
than that of littermate controls in both settings. However, when CKO hearts were
subjected to I/R using the ex vivo system, CKO hearts surprisingly exhibited had better
cardiac function following I/R than control hearts. This was also the case in a mouse
model of obesity and hyperglycemia. CKO hearts also had irregular contractility, a
finding that led to the investigation of Ca2+ handling in these CKO mice. Cardiomyocytes
(CM) isolated from CKO mice displayed weaker contractions and smaller calcium (Ca2+)
transients as well as a reduction in relative SR Ca2+ content. Insulin also blunted the
recovery of these mice, showing mTOR is at least partially necessary for
cardioprotection against I/R injury. The findings in this study may be caused by
decreased expression of the IP3R, which plays an important role in regulating Ca2+
transfer from the ER to the mitochondria, since that was found to be lower in the
SR/mitochondria fraction of CKO hearts. However, a clear mechanism for explaining
these results still needs to be identified. A novel role for mTOR in Ca2+ handling and
contraction could bring new insights into potential therapeutics for treating and
managing heart failure.
Description:Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017.
URI:http://hdl.handle.net/10125/62239
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: Ph.D. - Cell and Molecular Biology


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