Dataset Information

FTO-Dependent N6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair.

ABSTRACT: BACKGROUND:Despite its functional importance in various fundamental bioprocesses, studies of N6-methyladenosine (m6A) in the heart are lacking. Here, we show that the FTO (fat mass and obesity-associated protein), an m6A demethylase, plays a critical role in cardiac contractile function during homeostasis, remodeling, and regeneration. METHODS:We used clinical human samples, preclinical pig and mouse models, and primary cardiomyocyte cell cultures to study the functional role of m6A and FTO in the heart and in cardiomyocytes. We modulated expression of FTO by using adeno-associated virus serotype 9 (in vivo), adenovirus (both in vivo and in vitro), and small interfering RNAs (in vitro) to study its function in regulating cardiomyocyte m6A, calcium dynamics and contractility, and cardiac function postischemia. We performed methylated (m6A) RNA immunoprecipitation sequencing to map transcriptome-wide m6A, and methylated (m6A) RNA immunoprecipitation quantitative polymerase chain reaction assays to map and validate m6A in individual transcripts, in healthy and failing hearts, and in myocytes. RESULTS:We discovered that FTO has decreased expression in failing mammalian hearts and hypoxic cardiomyocytes, thereby increasing m6A in RNA and decreasing cardiomyocyte contractile function. Improving expression of FTO in failing mouse hearts attenuated the ischemia-induced increase in m6A and decrease in cardiac contractile function. This is performed by the demethylation activity of FTO, which selectively demethylates cardiac contractile transcripts, thus preventing their degradation and improving their protein expression under ischemia. In addition, we demonstrate that FTO overexpression in mouse models of myocardial infarction decreased fibrosis and enhanced angiogenesis. CONCLUSIONS:Collectively, our study demonstrates the functional importance of the FTO-dependent cardiac m6A methylome in cardiac contraction during heart failure and provides a novel mechanistic insight into the therapeutic mechanisms of FTO.

SUBMITTER: Mathiyalagan P

PROVIDER: S-EPMC6400591 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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FTO-Dependent N<sup>6</sup>-Methyladenosine Regulates Cardiac Function During Remodeling and Repair.

Mathiyalagan Prabhu P Adamiak Marta M Mayourian Joshua J Sassi Yassine Y Liang Yaxuan Y Agarwal Neha N Jha Divya D Zhang Shihong S Kohlbrenner Erik E Chepurko Elena E Chen Jiqiu J Trivieri Maria G MG Singh Rajvir R Bouchareb Rihab R Fish Kenneth K Ishikawa Kiyotake K Lebeche Djamel D Hajjar Roger J RJ Sahoo Susmita S

Circulation 20190101 4

<h4>Background</h4>Despite its functional importance in various fundamental bioprocesses, studies of N<sup>6</sup>-methyladenosine (m6A) in the heart are lacking. Here, we show that the FTO (fat mass and obesity-associated protein), an m6A demethylase, plays a critical role in cardiac contractile function during homeostasis, remodeling, and regeneration.<h4>Methods</h4>We used clinical human samples, preclinical pig and mouse models, and primary cardiomyocyte cell cultures to study the functiona ...[more]

PMID: 29997116

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Project description:BackgroundAdolescent idiopathic scoliosis (AIS) is characterized by low lean mass without vertebral deformity. The cause-and-effect relationship between scoliosis and paraspinal muscle imbalance has long puzzled researchers. Although FTO has been identified as a susceptibility gene for AIS, its potential role in the asymmetry of paraspinal muscles has not been fully elucidated.MethodsWe investigated the role of Fto in murine myoblast proliferation, migration, and myogenic differentiation. We examined its precise regulatory influence on murine muscle fiber remodeling in vitro and in vivo. We identified the downstream target gene of Fto by screening key regulators of murine muscle fiber remodeling and identified its m6A reader. Deep paraspinal muscle samples were obtained from the concave and convex sides of AIS patients with or without Schroth exercises, and congenital scoliosis served as a control group. We compared the content of type I fibers, expression patterns of fast- and slow-type genes, and levels of FTO expression.ResultsFTO contributed to maintain the formation of murine slow-twitch fibers both in vitro and in vivo. These effects were mediated by the demethylation activity of FTO, which specifically demethylated NFATC1 and prevented YTHDF2 from degrading it. We found a significant reduction in type I fibers, mRNA levels of MYH7 and MYH7B, and expression of FTO on the concave side of AIS. The percentage of type I fibers showed a positive correlation with the expression level of FTO. The asymmetric patterns observed in AIS were consistent with those seen in congenital scoliosis, and the asymmetry of FTO expression and fiber type in AIS was largely restored by Schroth exercises.ConclusionsFTO supports the formation of murine slow-twitch fibers in an NFATC1-YTHDF2 dependent manner. The consistent paraspinal muscle features seen in AIS and congenital scoliosis, as well as the reversible pattern of muscle fibers and expression of FTO in AIS suggest that FTO may contribute to the muscle fiber remodeling secondary to scoliosis.

Dataset Information

FTO-Dependent N6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair.

Publications

FTO-Dependent N<sup>6</sup>-Methyladenosine Regulates Cardiac Function During Remodeling and Repair.

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