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mTOR signaling in mice with dysfunctional cardiac ryanodine receptor ion channel

Authors Huang T, Zou M, Pasek DA, Meissner G

Received 1 December 2014

Accepted for publication 5 February 2015

Published 20 May 2015 Volume 2015:8 Pages 43—51

DOI https://doi.org/10.2147/JRLCR.S78410

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Professor Trevor W. Stone


Tai-Qin Huang,* Min-Xu Zou,* Daniel A Pasek, Gerhard Meissner 

Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA

*These authors contributed equally to this work

Abstract: Simultaneous substitution of three amino acid residues in the calmodulin binding domain (W3587A/L3591D/F3603A, ADA) of the cardiac ryanodine receptor ion channel (RyR2) impairs calmodulin inhibition of RyR2 and causes cardiac hypertrophy and early death of Ryr2ADA/ADA mice. To determine the physiological significance of growth promoting signaling molecules, the protein and phosphorylation levels of Ser/Thr kinase mTOR and upstream and downstream signaling molecules were determined in hearts of wild-type and Ryr2ADA/ADA mice. Phosphorylation of mTOR at Ser-2448, and mTOR downstream targets p70S6 kinase at Thr-389, S6 ribosomal protein at Ser-240/244, and 4E-BP1 at Ser-65 were increased. However, there was no increased phosphorylation of mTOR upstream kinases PDK1 at Ser-241, AKT at Thr-308, AMPK at Thr-172, and ERK1/2 at Thr-202/Tyr204. To confirm a role for mTOR signaling in the development of cardiac hypertrophy, rapamycin, an inhibitor of mTOR, was injected into wild-type and mutant mice. Rapamycin decreased mouse heart-to-body weight ratio, improved cardiac performance, and decreased phosphorylation of mTOR and downstream targets p70S6K and S6 in 10-day-old Ryr2ADA/ADA mice but did not extend longevity. Taken together, the results link a dysfunctional RyR2 to an altered activity of signaling molecules that regulate cardiac growth and function.

Keywords: calmodulin, cardiac hypertrophy, rapamycin, RyR2

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