Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis

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. [Display omitted] •PRKAG2 cardiomyopathy mutations activate AMPK in human iPS models•AMPK transcriptionally regulates glucose handling and mitochondrial biogenesis•AMPK enhances cardiac microtissue forces by increased myocyte survival•AMPK inhibits TGF-beta 2 production and fibrosis in vivo Hinson et al. now use human iPS models of PRKAG2 cardiomyopathy combined with engineered cardiac microtissues to reveal key links between metabolic sensing by AMPK and myocyte survival, metabolism, and TGF-beta signaling.