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Exercise promotes a cardioprotective gene program in resident cardiac fibroblasts
Janet K. Lighthouse, … , Alex Rosenberg, Eric M. Small
Janet K. Lighthouse, … , Alex Rosenberg, Eric M. Small
Published January 10, 2019
Citation Information: JCI Insight. 2019;4(1):e92098. https://doi.org/10.1172/jci.insight.92098.
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Research Article Cardiology Cell biology

Exercise promotes a cardioprotective gene program in resident cardiac fibroblasts

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Abstract

Exercise and heart disease both induce cardiac remodeling, but only disease causes fibrosis and compromises heart function. The cardioprotective benefits of exercise have been attributed to changes in cardiomyocyte physiology, but the impact of exercise on cardiac fibroblasts (CFs) is unknown. Here, RNA-sequencing reveals rapid divergence of CF transcriptional programs during exercise and disease. Among the differentially expressed programs, NRF2-dependent antioxidant genes — including metallothioneins (Mt1 and Mt2) — are induced in CFs during exercise and suppressed by TGF-β/p38 signaling in disease. In vivo, mice lacking Mt1/2 exhibit signs of cardiac dysfunction in exercise, including cardiac fibrosis, vascular rarefaction, and functional decline. Mechanistically, exogenous MTs derived from fibroblasts are taken up by cultured cardiomyocytes, reducing oxidative damage–dependent cell death. Importantly, suppression of MT expression is conserved in human heart failure. Taken together, this study defines the acute transcriptional response of CFs to exercise and disease and reveals a cardioprotective mechanism that is lost in disease.

Authors

Janet K. Lighthouse, Ryan M. Burke, Lissette S. Velasquez, Ronald A. Dirkx Jr., Alessandro Aiezza II, Christine S. Moravec, Jeffrey D. Alexis, Alex Rosenberg, Eric M. Small

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Figure 1

Evaluating the fibroblast response to physiological and pathological cardiac remodeling.

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Evaluating the fibroblast response to physiological and pathological car...
(A) Experimental timeline (days) of inducing and assessing remodeling and isolating CFs (red) for RNA-Seq and subsequent analysis in C57BL/6 animals. (B) Heart weight/body weight (HW/BW) ratio of sedentary and swim-trained animals. (C) qPCR analysis of primary CFs from mice subjected to the indicated treatment. (D) Analysis of fragments per kilobase of transcript per million mapped reads (FPKM) from RNA-Seq data for indicated ECM genes. (E) Analysis of FPKM from RNA-Seq data for CF and myofibroblast markers. Statistics in B–E were performed using 1-way ANOVA and Tukey’s post-hoc test (n = 3 except for control where n = 5). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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