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

昼夜节律和间歇给药在糖皮质激素诱导肌肉甘油三酯脂肪酶中的作用

• 批准号: 10657826
• 负责人: Mattia Quattrocelli
• 金额: $ 12.3万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657826
• 关键词: Ablation; Adipose tissue; Aging; Agonist; Biology; Chronic; Circadian Rhythms; Circadian desynchrony; Collaborations; Compensation; Darkness; Development; Dose; Energy Metabolism; Equilibrium; Exercise Tolerance; Fatty acid glycerol esters; Frequencies; Glucocorticoids; Hydrolysis; Intake; Intramuscular; Knock-out; Knockout Mice; Light; Link; Lipase; Lipids; Liver; Macronutrients Nutrition; Measures; Mediating; Metabolic; Metabolic stress; Metabolic syndrome; Metabolism; Modeling; Mus; Muscle; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Patients; Persons; Pharmaceutical Preparations; Phase; Phosphorylation; Prednisone; Prevalence; Production; Proto-Oncogene Proteins c-akt; Regimen; Regulation; Role; Signal Transduction; Steroids; Stress; Testing; Time; Tissues; Transgenic Model; Triglycerides; Up-Regulation; Wild Type Mouse; circadian; circadian regulation; diet-induced obesity; exercise capacity; glucose uptake; hormonal signals; light effects; muscle aging; muscle form; muscle metabolism; novel; postnatal; programs; protective effect; response; transcriptomic profiling; uptake; young man

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.

项目总结 糖皮质激素(GC)是人体能量代谢昼夜节律调节的原始信号。这个 昼夜节律不仅调节内源性GCs，还调节外源性合成GCs的作用。 三酰甘油代谢与肌肉生物学的昼夜调节特别相关，因为肌细胞内 三酰甘油(IMTGs)是健康年轻男性中因昼夜节律失调而升高的最丰富的血脂。 然而，GC对IMTG代谢的昼夜节律性调节作用尚不清楚。令人惊讶的是，在 与每天一次的GC的代谢障碍作用不同，间歇性的每周一次的GCs促进肌肉 营养不良小鼠的代谢和力量产生，与GC-1代谢性应激的缓解相关 治疗营养不良患者。在美国，长期摄入糖皮质激素的人数高达250万。因此，有 一个尚未得到满足的需要，即区分GC治疗的有益和有害机制。在WT小鼠中，我们 研究发现，在饮食诱导肥胖的情况下，特定光期间歇强的松能降低IMTGs 和衰老，而暗阶段特定的GC剂量消除了这些促进代谢的作用。以治疗为导向 IMTG降低与肌肉质量、AKT磷酸化和FORCE产生增加相关。 经处理的衰老肌肉的转录图谱显示脂肪三酰甘油脂肪酶(ATGL)上调。 GCS激活脂肪组织中的ATGL，但ATGL在肌肉对GCS的反应中的作用尚不清楚。此外， GC对IMTG和相关肌肉重塑的影响需要肌肉ATGL的程度是 仍然未知。我们现在已经产生了肌肉特异性可诱导ATGL消融(imATGL-KO)的小鼠。在……里面 与结构性KO相比，这些小鼠将在没有发育或出生后的情况下揭示肌肉ATGL效应 补偿。在这里，我们将使用这个新的模型来检验这个假设，即肌肉ATGL是 间歇性GC对肌肉IMTGs的影响取决于昼夜节律时间和间歇性GC摄入频率。 我们还将测试肌肉ATGL在多大程度上调节光相GC对肌肉重塑的影响 和葡萄糖摄取。在目标1中，我们将确定肌肉ATGL在GCs的昼夜节律性效应中的作用 对IMTG代谢的影响。我们假设肌肉特异性ATGL是外源性GC作用所必需的。 IMTGs依赖于光相位限制的暴露，即与内源GC节律相反。我们将对此进行测试 在我们的imATGL-KO小鼠中，测量IMTGs对外源性和内源性的昼夜调节的反应 GCS。在目标2中，我们将阐明肌肉ATGL在GCs对肌肉的频率特异性效应中的作用 新陈代谢。我们假设肌肉ATGL将IMTG分解与有利和不利联系起来 间歇性服用与每日服用特定光相GC所诱导的肌肉程序。我们将在我们的 IMATGL-KO小鼠，测量间歇与每日强的松后的IMTGs和肌肉葡萄糖摄取。我们的 研究确定了在肌肉中将GC从代谢毒性药物重新转化为代谢激动剂的机制。 我们还将测试肌肉ATGL作为昼夜节律激素信号效应器的新概念，如GC。

项目成果

The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.

人类基因变异 rs6190 揭示了 Foxc1 和 Arid5a 作为肌肉中糖皮质激素受体的新型促代谢靶点。

• DOI: 10.1101/2024.03.28.586997
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Prabakaran,AshokDaniel;Chung,Hyun-Jy;McFarland,Kevin;Govindarajan,Thirupugal;ElAbdellaouiSoussi,Fadoua;Durumutla,HimaBindu;Villa,Chiara;Piczer,Kevin;Latimer,Hannah;Werbrich,Cole;Akinborewa,Olukunle;Horning,Robert;Quattrocelli,
• 通讯作者: Quattrocelli,