Muscle mitochondrial remodeling by intermittent glucocorticoid drugs requires an intact circadian clock and muscle PGC1α

Sci Adv. 2022 Feb 18;8(7):eabm1189. doi: 10.1126/sciadv.abm1189. Epub 2022 Feb 18.

Abstract

Exogenous glucocorticoids interact with the circadian clock, but little attention is paid to the timing of intake. We recently found that intermittent once-weekly prednisone improved nutrient oxidation in dystrophic muscle. Here, we investigated whether dosage time affected prednisone effects on muscle bioenergetics. In mice treated with once-weekly prednisone, drug dosing in the light-phase promoted nicotinamide adenine dinucleotide (NAD+) levels and mitochondrial function in wild-type muscle, while this response was lost with dark-phase dosing. These effects depended on a normal circadian clock since they were disrupted in muscle from [Brain and muscle Arnt-like protein-1 (Bmal1)]-knockout mice. The light-phase prednisone pulse promoted BMAL1-dependent glucocorticoid receptor recruitment on noncanonical targets, including Nampt and Ppargc1a [peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α)]. In mice with muscle-restricted inducible PGC1α ablation, bioenergetic stimulation by light-phase prednisone required PGC1α. These results demonstrate that glucocorticoid "chronopharmacology" for muscle bioenergetics requires an intact clock and muscle PGC1α activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • Animals
  • Circadian Clocks*
  • Glucocorticoids / pharmacology
  • Mice
  • Mitochondria / metabolism
  • Muscles
  • NAD
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Prednisone

Substances

  • ARNTL Transcription Factors
  • Glucocorticoids
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • NAD
  • Prednisone