ROLE OF CIRCADIAN RHYTHM AND INTERMITTENT DOSING IN MUSCLE TRIGLYCERIDE LIPASE INDUCTION BY GLUCOCORTICOIDS

点击翻译按钮获取中文摘要

PROJECT SUMMARY Glucocorticoid (GC) steroids are a primal signal for circadian regulation of energy metabolism in our body. The circadian rhythm regulates not only the endogenous GCs, but also the effects of exogenous synthetic GCs. Triacylglycerol metabolism is particularly relevant for circadian regulation of muscle biology, as intramyocellular triacylglycerols (IMTGs) are the most abundant lipid elevated by circadian misalignment in healthy young men. However, the circadian-specific effects of GC modulation on IMTG metabolism are still unknown. Strikingly, in contrast to the dysmetabolic effects of once-daily GCs, intermittent once-weekly GCs promoted muscle metabolism and force production in dystrophic mice, correlating with a mitigation of metabolic stress in GC- treated dystrophic patients. Chronic GC intake has a prevalence of >2.5M people in the US. Therefore, there is an unmet need to discriminate the beneficial versus deleterious mechanisms of GC treatments. In WT mice, we found that light-phase-specific intermittent prednisone decreased IMTGs in conditions of diet-induced obesity and aging, whereas dark-phase-specific GC dosing abrogated these pro-metabolic effects. The treatment-driven IMTG decrease correlated with increases in muscle mass, AKT phosphorylation and force production. Transcriptomic profiling of treated aging muscle showed upregulation of adipose triacylglycerol lipase (ATGL). GCs activate ATGL in fat tissue but the role of ATGL in the muscle response to GCs is still unknown. Moreover, the extent to which muscle ATGL is required for GC effects on IMTGs and the associated muscle remodeling is still unknown. We have now generated mice with muscle-specific inducible ATGL ablation (imATGL-KO). In contrast to constitutive KO, these mice will unveil muscle ATGL effects without developmental or postnatal compensations. Here we will use this new model to test the hypothesis that muscle ATGL is required for the intermittent GC effects on muscle IMTGs depending on circadian time and intermittent frequency of GC intake. We will also test the extent to which muscle ATGL mediates the light-phase GC effects on muscle remodeling and glucose uptake. In Aim 1 we will determine the role of muscle ATGL in the circadian-specific effects of GCs on IMTG metabolism. We hypothesize that muscle-specific ATGL is required for the exogenous GC effects on IMTGs depending on light-phase-restricted exposure, i.e. opposite to endogenous GC rhythm. We will test this in our imATGL-KO mice, measuring IMTGs in response to circadian modulation of exogenous and endogenous GCs. In Aim 2 we will elucidate the role of muscle ATGL in the frequency-specific effects of GCs on muscle metabolism. We hypothesize that muscle ATGL links IMTG breakdown to the favorable versus unfavorable muscle programs induced by intermittent versus daily dosing of light-phase-specific GCs. We will test this in our imATGL-KO mice, measuring IMTGs and muscle glucose uptake after intermittent versus daily prednisone. Our study identifies mechanisms to reconvert GCs from metabolically toxic drugs to metabolic agonists in muscle. We will also test the novel concept of muscle ATGL as effector of circadian hormonal signals like GCs.