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Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming
Mattia Quattrocelli, … , Joseph Bass, Elizabeth M. McNally
Mattia Quattrocelli, … , Joseph Bass, Elizabeth M. McNally
Published December 19, 2019
Citation Information: JCI Insight. 2019;4(24):e132402. https://doi.org/10.1172/jci.insight.132402.
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Research Article Metabolism Muscle biology

Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming

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Abstract

In humans, chronic glucocorticoid use is associated with side effects like muscle wasting, obesity, and metabolic syndrome. Intermittent steroid dosing has been proposed in Duchenne Muscular Dystrophy patients to mitigate the side effects seen with daily steroid intake. We evaluated biomarkers from Duchenne Muscular Dystrophy patients, finding that, compared with chronic daily steroid use, weekend steroid use was associated with reduced serum insulin, free fatty acids, and branched chain amino acids, as well as reduction in fat mass despite having similar BMIs. We reasoned that intermittent prednisone administration in dystrophic mice would alter muscle epigenomic signatures, and we identified the coordinated action of the glucocorticoid receptor, KLF15 and MEF2C as mediators of a gene expression program driving metabolic reprogramming and enhanced nutrient utilization. Muscle lacking Klf15 failed to respond to intermittent steroids. Furthermore, coadministration of the histone acetyltransferase inhibitor anacardic acid with steroids in mdx mice eliminated steroid-specific epigenetic marks and abrogated the steroid response. Together, these findings indicate that intermittent, repeated exposure to glucocorticoids promotes performance in dystrophic muscle through an epigenetic program that enhances nutrient utilization.

Authors

Mattia Quattrocelli, Aaron S. Zelikovich, Zhen Jiang, Clara Bien Peek, Alexis R. Demonbreun, Nancy L. Kuntz, Grant D. Barish, Saptarsi M. Haldar, Joseph Bass, Elizabeth M. McNally

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Figure 2

Epigenomic programs in steroid-treated dystrophic mouse muscles.

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Epigenomic programs in steroid-treated dystrophic mouse muscles.
(A) PCA...
(A) PCA of H3K27ac profiles derived from quadriceps myofibers. Weekly vs. daily prednisone regimens cluster from each other and from vehicle-treated controls. (B) Motif enrichment analysis highlights GRE, KRE, and MEF2 as acetylation-enriched motifs after weekly prednisone, while FOXO3 motifs were enriched after daily prednisone. (C) Concordant genes enriched for both H3K27ac and expression included Klf15 and Mef2C after weekly prednisone, while daily prednisone promoted acetylation and expression of Foxo3 and other atrophy genes. (D) Representative H3K27ac markings across gene loci of interest demonstrated divergent acetylation enrichment with respect to weekly or daily prednisone (signal is tags/bp normalized to 1e7 reads; red arrows, gain; blue arrow, loss of H3K27ac signal). (E) Pathway analysis showed that pulsatile weekly prednisone increased transcription of genes regulating glucose, fatty acid, and BCAA metabolism. H3K27ac ChIP-seq showed GR enrichment after both weekly and daily steroids, but it showed increased enrichment of KRE and MEF2 sites only after weekly prednisone. ChIP-qPCR confirmed enriched occupancy for GR, KLF15, and MEF2C on the same sites (n = 3 mice/group for K27ac ChIP-seq, n = 5 mice/group for RNA-seq; q value, Benjamini-Hochberg test).

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ISSN 2379-3708

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