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

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 mitochondria! 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 Amt-like protein-1 (Bmal1)]-knockout mice. The light-phase prednisone pulse promoted BMAL1-dependent glucocorticoid receptor recruitment on noncanonical targets, including Nampt and Ppargcla [peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1 alpha)]. In mice with muscle-restricted inducible PGC1 alpha ablation, bioenergetic stimulation by light-phase prednisone required PGC1 alpha. These results demonstrate that glucocorticoid chronopharmacology for muscle bioenergetics requires an intact clock and muscle PGC1 alpha activity.

Automated summary

This study found that the timing of glucocorticoid intake can affect their effects on muscle bioenergetics. In mice, prednisone dosing during the light phase promoted NAD(+) levels and mitochondrial function, while dosing during the dark phase did not have the same effect. These results suggest that the circadian clock and muscle PGC1 alpha activity are important factors in glucocorticoid chronopharmacology for muscle bioenergetics.