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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 3

Pulsatile weekly prednisone acts through a GR-, KLF15-, and MEF2C-mediated transcriptional program and requires epigenetic remodeling.

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Pulsatile weekly prednisone acts through a GR-, KLF15-, and MEF2C-mediat...
(A) Genetic loss of Klf15 disrupts the transcriptional and metabolic changes induced by weekly prednisone in muscle, including Mef2C upregulation. (B) Luciferase reporter plasmids were electroporated into mdx myofibers, carrying regulatory regions from Mef2c, Pfkm, Ech1, and Bckdha loci. Prednisone pulse and Klf15 overexpression had additive effects in increasing GRE-KRE activation. Prednisone pulse, Klf15, and Mef2C overexpression had additive effects on MEF2 activation. Changes were lost after specific deletion of target sites (Δ). Histograms depict single values and mean ± SEM; n = 3 mice/group (A), n = 8 muscles/group (B). *P < 0.05 vs. own vehicle control, $P < 0.05 vs single-factor treatment, 1-way ANOVA with Tukey’s multiple comparison.

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