Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming

Autor: Elizabeth M. McNally, Nancy L. Kuntz, Alexis R. Demonbreun, Mattia Quattrocelli, Zhen Jiang, Clara Bien Peek, Saptarsi M. Haldar, Aaron S. Zelikovich, Joseph Bass, Grant D. Barish
Rok vydání: 2019
Předmět:
Epigenomics
Male
0301 basic medicine
medicine.medical_specialty
Duchenne muscular dystrophy
Kruppel-Like Transcription Factors
KLF15
Epigenesis
Genetic
Mice
03 medical and health sciences
0302 clinical medicine
Glucocorticoid receptor
Internal medicine
medicine
Animals
Humans
Metabolomics
Epigenetics
Child
Muscle
Skeletal
Glucocorticoids
Histone Acetyltransferases
MEF2 Transcription Factors
business.industry
Nutrients
General Medicine
Metabolism
medicine.disease
Anacardic Acids
Muscular Dystrophy
Duchenne
Disease Models
Animal
Cross-Sectional Studies
030104 developmental biology
Endocrinology
Gene Expression Regulation
Pulse Therapy
Drug
030220 oncology & carcinogenesis
Mice
Inbred mdx
Prednisone
Drug Therapy
Combination
Metabolic syndrome
business
Biomarkers
Glucocorticoid
Research Article
medicine.drug
Zdroj: JCI Insight. 4
ISSN: 2379-3708
DOI: 10.1172/jci.insight.132402
Popis: 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.
Databáze: OpenAIRE
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