Exercise promotes a cardioprotective gene program in resident cardiac fibroblasts
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
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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Research Article Cardiology Cell biology

Exercise promotes a cardioprotective gene program in resident cardiac fibroblasts

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 2

Gene expression profiling of pathological and physiological CFs.

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Gene expression profiling of pathological and physiological CFs. (A) PCA...
(A) PCA of log-transformed FPKM data from 19 individual CF samples from C57BL/6 animals of the indicated treatment group using the first and second principal components (PCs). There were 8500 of 23,359 genes included, where at least 5 of the 19 samples had a FPKM > 1. No other feature selection was performed. (B) Spearman correlation and average linkage of the same 19 samples in A indicates consistency between biological replicates, which cluster in a hierarchical manner. (C) Ingenuity Pathway Analysis (IPA) of CFs at 10-day TAC (disease) versus control (top) or 10-day swim (exercise) versus control (bottom). The gray bars indicate that there is no activity pattern available identified in IPA, despite highly significant association of the genes within the pathway. Orange, positive z-score; white, zero z-score; blue, negative z-score; gray, no pattern. Vertical red line indicates a Benjamini-Hochberg–corrected P = 0.01. (D) Predicted upstream regulators from 10-day swim versus 10-day TAC are shown that have overlap P < 0.001 (red line). Red and green triangles indicate direction of change in expression in exercise versus disease, if significant. Red and blue text in C and D indicate myofibroblast regulation and detoxification pathways, respectively, and indicate a mechanistic link between TF and IPA canonical pathway.