Journal
CELL REPORTS
Volume 17, Issue 12, Pages 3292-3304Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.11.066
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Funding
- NIH [HL125807, AR062128, UH3EB017103, EB001046, HL080494, HL128810, HL084553]
- John S. Ladue Foundation
- Leducq Foundation
- Sarnoff Foundation
- Howard Hughes Medical Institute
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AMP-activated protein kinase (AMPK) is a metabolic enzyme that can be activated by nutrient stress or geneticmutations. Missense mutations in the regulatory subunit, PRKAG2, activate AMPK and cause left ventricular hypertrophy, glycogen accumulation, and ventricular pre-excitation. Using human iPS cell models combined with three-dimensional cardiac microtissues, we show that activating PRKAG2 mutations increase microtissue twitch force by enhancing myocyte survival. Integrating RNA sequencing with metabolomics, PRKAG2 mutations that activate AMPK remodeled global metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism instead of glycolysis. As in patients with PRKAG2 cardiomyopathy, iPS cell and mouse models are protected from cardiac fibrosis, and we define a crosstalk between AMPK and post-transcriptional regulation of TGF beta isoform signaling that has implications in fibrotic forms of cardiomyopathy. Our results establish critical connections among metabolic sensing, myocyte survival, and TGF beta signaling.
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