Open AccessSelective enhancement of cardiomyocyte efficiency results in a pernicious heart condition
Author(s) -
Jody Groenendyk,
Qian Wang,
Cory S. Wagg,
Dukgyu Lee,
Alison Robinson,
Amy Barr,
Peter E. Light,
Gary D. Lopaschuk,
Luis B. Agellon,
Marek Michalak
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0236457
Subject(s) - ex vivo , ventricle , medicine , contractility , cardiac function curve , in vivo , transgene , cardiology , glycolysis , heart failure , endocrinology , biology , biochemistry , metabolism , microbiology and biotechnology , gene
Transgenic mice with selective induction of calreticulin transgene expression in cardiomyocytes (Cardiac CRT+ ) were analyzed. Cardiac CRT+ cardiomyocytes showed increased contractility and Ca 2+ transients. Yet, in vivo assessment of cardiac performance, and ischemic tolerance of Cardiac CRT+ mice demonstrated right ventricle dilation and reduced cardiac output, increased QT interval and decreased P amplitude. Paradoxically, ex vivo working hearts from Cardiac CRT+ mice showed enhanced ischemic cardio-protection and cardiac efficiency. Under aerobic conditions, Cardiac CRT+ hearts showed less efficient cardiac function than sham control hearts due to an increased ATP production from glycolysis relative to glucose oxidation. During reperfusion, this inefficiency was reversed, with Cardiac CRT+ hearts exhibiting better functional recovery and increased cardiac efficiency compared to sham control hearts. On the other hand, mechanical stretching of isolated cardiac fibroblasts activated the IRE1α branch of the unfolded protein response pathway as well as induction of Col1A2 and TGFβ gene expression ex vivo , which were all suppressed by tauroursodeoxycholic acid.