LAUSR

Glucocorticoid steroids are circadian regulators of energy balance and tissue metabolism. Chronic daily intake of synthetic glucocorticoids commonly promotes insulin resistance and metabolic syndrome. In dystrophic mice, we previously showed that frequency of glucocorticoid intake determines their effects on muscle metabolism. We also found that, compared to daily intake, once-weekly intermittent administration of these drugs reduced obesity and metabolic stress biomarkers in persons with muscular dystrophy. In newer experiments, we sought to understand whether the muscle effects of pulsatile glucocorticoids extend to conditions of metabolic stress. We first investigated the muscle-autonomous effects of a single pulse of glucocorticoids. To avoid interferences from other tissues, we developed an ex vivo system to interrogate the steady-state basal metabolism in isolated wildtype muscle. Considering the intrinsic circadian regulation of glucocorticoids, we compared opposite circadian times of drug exposure in muscles isolated at day-time versus night-time of test mice. We found that within 4 hours from ex vivo exposure, prednisone increased the mitochondrial respiratory capacity rate in muscle tissue but, strikingly, only in muscle from the day-time phase. We then restricted in vivo prednisone regimens (intermittent versus daily) to the day-time of mice with dietary obesity, established with 12 weeks of ad libitum high-fat diet (60% kcal from fat). Opposite to daily regimen, intermittent diurnal prednisone promoted strength and mitochondrial oxidation in muscle of obese mice. Moreover, this correlated with partial counteraction of weight accrual and hyperglycemia, while daily prednisone exacerbated dietary obesity. In summary, our data indicate that circadian time and dosing frequency can upend our current understanding of glucocorticoids and provide a novel strategy to boost nutrient utilization in persons with metabolic stress. Disclosure M. Quattrocelli: None. M. Wintzinger: None. R. M. Rathbun: None. Funding National Institutes of Health (K01DK121875); Cincinnati Children9s Research Foundation