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.

项目概要 糖皮质激素 (GC) 类固醇是人体能量代谢昼夜节律调节的原始信号。这 昼夜节律不仅调节内源性GC，还调节外源性合成GC的作用。 三酰甘油代谢与肌肉生物学的昼夜节律调节特别相关，因为肌细胞内 三酰甘油（IMTG）是健康年轻男性中因昼夜节律失调而升高的最丰富的脂质。 然而，GC 调节对 IMTG 代谢的昼夜节律特异性影响仍不清楚。引人注目的是，在 与每日一次 GC 的代谢失调效应相反，间歇性每周一次 GC 可以促进肌肉生长 营养不良小鼠的代谢和力量产生，与 GC-代谢应激的减轻相关 治疗营养不良患者。在美国，慢性 GC 摄入的患病率超过 250 万人。因此，有 区分 GC 治疗的有益与有害机制的需求尚未得到满足。在 WT 小鼠中，我们 发现光相特异性间歇性泼尼松可降低饮食引起的肥胖情况下的 IMTG 和衰老，而暗相特异性 GC 剂量消除了这些促代谢作用。治疗驱动 IMTG 的降低与肌肉质量、AKT 磷酸化和力量产生的增加相关。 经治疗的老化肌肉的转录组分析显示脂肪三酰甘油脂肪酶（ATGL）上调。 GC 激活脂肪组织中的 ATGL，但 ATGL 在肌肉对 GC 反应中的作用仍不清楚。而且， GC 对 IMTG 的影响以及相关的肌肉重塑需要肌肉 ATGL 的程度为 仍然未知。我们现在已经培育出具有肌肉特异性诱导 ATGL 消融 (imATGL-KO) 的小鼠。在 与组成型 KO 相比，这些小鼠无需发育或出生后即可展现肌肉 ATGL 效应 补偿。在这里，我们将使用这个新模型来检验肌肉 ATGL 是 间歇性 GC 对肌肉 IMTG 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 介导光相 GC 对肌肉重塑的影响程度 和葡萄糖摄取。在目标 1 中，我们将确定肌肉 ATGL 在 GC 昼夜节律特异性影响中的作用 IMTG 代谢。我们假设肌肉特异性 ATGL 是外源 GC 作用所必需的 IMTG 取决于光相位限制暴露，即与内源 GC 节律相反。我们将测试这个 在我们的 imATGL-KO 小鼠中，测量 IMTG 对外源性和内源性昼夜节律调节的反应 GC。在目标 2 中，我们将阐明肌肉 ATGL 在 GC 对肌肉的频率特异性影响中的作用 代谢。我们假设肌肉 ATGL 将 IMTG 分解与有利与不利联系起来 间歇性与每日服用轻相特异性 GC 诱导的肌肉计划。我们将在我们的 imATGL-KO 小鼠，测量间歇性泼尼松与每日泼尼松后的 IMTG 和肌肉葡萄糖摄取量。我们的 研究确定了将GC从代谢毒性药物重新转化为肌肉中代谢激动剂的机制。 我们还将测试肌肉 ATGL 作为昼夜节律激素信号（如 GC）效应器的新概念。

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。

• 发表时间: 2024-03-31
• 作者: Prabakaran, Ashok Daniel;Chung, Hyun;McFarland, Kevin;Govindarajan, Thirupugal;El Abdellaoui Soussi, Fadoua;Durumutla, Hima Bindu;Villa, Chiara;Piczer, Kevin;Latimer, Hannah;Werbrich, Cole;Akinborewa, Olukunle;Horning, Robert;Quattrocelli
• 通讯作者: Quattrocelli