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.
| Original language | English (US) |
|---|---|
| Article number | e132402 |
| Journal | JCI Insight |
| Volume | 4 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 19 2019 |
Funding
Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Next-generation sequencing was performed at the NUSeq core at Center for Genetic Medicine of Northwestern University. Live animal multimodal imaging was performed at the Center for Advanced Molecular Imaging of Northwestern University. Metabolic cage testing was performed by the Northwestern Comprehensive Metabolic Core. We thank Christopher Newgard (Duke University, Durham, North Carolina, USA) for helpful suggestions. This work was supported by NIH U54 AR052646, NIH RO1 NS047726, NU 320-8235910-30027355-01, the Parent Project for Muscular Dystrophy, and the American Heart Association. MQ is supported by NIH K01 DK121875 (NIDDK) and MDA-AANEM development grant no. 479350. SMH was supported by NIH R01 DK093821.
ASJC Scopus subject areas
- General Medicine
