Intermittent dosing of prednisone, once weekly in the light phase of the day, had a positive effect on muscle bioenergetics in mice, according to the results of a new study published in Science Advances.
The researchers noted these effects were lost with dark-phase dosing, suggesting that to be effective in diseases such as Duchenne muscular dystrophy (DMD), glucocorticoid treatment will require a functioning circadian clock and muscle peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α).
“Here, we compared the effects of light-phase versus dark-phase dosage on prednisone effects on muscle bioenergetics,” the researchers wrote. “Our study provides evidence for circadian-dependent mechanisms of exogenous glucocorticoid effects on muscle mitochondrial function, identifying epigenetic and circadian mechanisms to account for their role as bioenergetic facilitators of skeletal muscle.”
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Specifically, the researchers found that exposure to prednisone during the light phase improved muscle endurance in terms of treadmill performance and reduced fatigue due to repetitive leg muscle contractions in the mice—improvements that did not occur with dark-phase dosing in time-matched controls.
They also observed improved nutrient utilization and stronger mitochondrial bioenergetics in muscle tissue. The team used mass spectrometry to determine that the effects of prednisone correlated with increases in muscle NAD+ and in muscle tissue respiration during the light phase.
The authors noted that prednisone was selected as an exogenous glucocorticoid drug due to its rapid uptake in muscle tissue and limited half-life. Valerone, a new glucocorticoid derivative, is currently in trials for patients with DMD, but the team suspects the time-dependent pharmacology of valerone will probably be different from that of prednisone due to its different glucocorticoid receptor activation activity from prednisone.
However, they expect the interesting effects observed in this study to open new lines of research into ways to achieve the desired effects on muscle tissue without off-target drug events.
Quattrocelli M, Wintzinger M, Miz K et al. Muscle mitochondrial remodeling by intermittent glucocorticoid drugs requires an intact circadian clock and muscle PGC1α. Sci Adv. 2022;8(7):1189. doi:10.1126/sciadv.abm1189