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

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.

Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids

“…The possible role of strain-specific genetic modifiers on glucocorticoid action in heart remains an important open question. However, we wish to emphasize that the treatment effects through GR and BMAL1 on cardiomyocyte NAD + content were evident on the 6J strain; well correlated with the time-of-intake effects on mitochondrial function and rescue; matched what we previously observed in skeletal muscle on the same sub-strain [ 15 ]. Furthermore, the bioenergetic effects of chronic intermittent dosing in vivo correlated with functional improvements after MI.…”

“…Indeed, chronic once-daily glucocorticoid intake in the human population increases the chance of heart failure events in a dose-dependent manner [ 14 ]. It is therefore possible that the combination of circadian time-of-intake and dosing intermittence, at least in our experimental conditions, increased the bioenergetic effects in heart without inducing or even counteracting metabolic stress, a notion strongly supported by our prior studies in WT normal and obese mice [ 15 , 16 ]. Human-relevant promising indications were recently reported by an exploratory open-label clinical trial in non-Duchenne patients with intermittent prednisone dosing at 7–9PM, which roughly corresponds to our mice injections in the early light-phase.…”

“…Synthetic glucocorticoids are used chronically by > 2.5M people in the US [ 13 ], but their regular once-daily intake promotes metabolic syndrome and cardiovascular diseases in a dose-dependent manner [ 14 ]. Opposite to once-daily dosing, we discovered that intermittent dosing (once-weekly) of glucocorticoids improves function and mitochondrial capacity in skeletal muscle in normal and metabolic stress conditions [ 15 , 16 ]. Dosing intermittence could therefore reverse the adverse benefits/risks ratio of chronic steroid regimens for the heart.…”

Balanced Free Essential Amino Acids and Resistance Exercise Training Synergistically Improve Dexamethasone-Induced Impairments in Muscle Strength, Endurance, and Insulin Sensitivity in Mice

“…Therefore, we suggest that EAA supplementation is useful for maintaining muscle mass and function in patients who routinely use DEX treatment. However, there are several limitations in the current study, including potential differences regarding timing of treatment [ 37 ] and sex difference [ 38 ]. Furthermore, it is important to confirm our findings in clinical outcome trials.…”

Narrative Review: Glucocorticoids in Alcoholic Hepatitis—Benefits, Side Effects, and Mechanisms

“…sAH livers had a marked dysregulation of non-canonical GR-target genes ( Figure 1 A), including retinoic acid receptor-related orphan receptor alpha (RORA, ↓76%), ERBB receptor feedback inhibitor 1 (ERRFI1, ↓80%) [ 114 ], 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3, ↓74%) [ 4 ], hydroxy acid oxidase 2 (HAO2, ↓83%), nicotinamide phosphoribosyl-transferase (NAMPT, ↓93%) [ 115 ], and G0/G1 switch gene 2 (G0S2, ↑105%) [ 45 ]. The orphan receptor RORα protects against non-alcoholic steatohepatitis by inhibiting lipogenesis and inflammation [ 116 , 117 , 118 ].…”