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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 5

Pulsatile glucocorticoids enhanced nutrient utilization for mitochondrial respiration in dystrophic muscle.

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Pulsatile glucocorticoids enhanced nutrient utilization for mitochondria...
(A) PCA of 171 metabolites showed treatment-specific clustering of muscle tissues. (B) Heatmaps of metabolite levels showed that pulsatile prednisone activated consumption of glucose, BCAA, and glutamine, increasing ATP and phosphocreatine levels. (C) Muscle respirometry showed that weekly prednisone led to higher basal oxygen consumption in the presence of either glucose, palmitate, or valine. (D) Weekly prednisone increased BCKDHA levels and reduced its phosphorylation in muscle. (E) Weekly prednisone increased glucose uptake in muscle, as shown by 2-NBDG uptake in live dystrophic myofibers. (F) Weekly prednisone increased whole-body insulin sensitivity, while daily regimen induced insulin resistance. Curves depict mean ± SEM; histograms depict single values and mean ± SEM; box plots, Tukey distribution; n = 3 mice/group (A and B), n = 6 mice/group (C–F). *P < 0.05 vs. vehicle, 2-way ANOVA with Tukey’s multiple comparison (C), 1-way ANOVA with Tukey’s multiple comparison (D and E). #P < 0.05 vs. vehicle, 2-way ANOVA.

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