Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis.
Document Type
Article
Publication Date
12-20-2016
JAX Source
Cell Rep 2016 Dec 20; 17(12):3292-3304.
Volume
17
Issue
12
First Page
3292
Last Page
3304
ISSN
2211-1247
PMID
28009297
Grant
HL125807
Abstract
AMP-activated protein kinase (AMPK) is a metabolic enzyme that can be activated by nutrient stress or genetic mutations. 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 TGFβ isoform signaling that has implications in fibrotic forms of cardiomyopathy. Our results establish critical connections among metabolic sensing, myocyte survival, and TGFβ signaling. Cell Rep 2016 Dec 20; 17(12):3292-3304.
Recommended Citation
Hinson J,
Chopra A,
Lowe A,
Sheng C,
Gupta R,
Kuppusamy R,
O'Sullivan J,
Rowe G,
Wakimoto H,
Gorham J,
Zhang K,
Musunuru K,
Gerszten R,
Wu S,
Chen C,
Seidman J,
Seidman C.
Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis. Cell Rep 2016 Dec 20; 17(12):3292-3304.