Estrogen-Related Receptor Pathways in Skeletal Muscle

 描述(申请人提供)：骨骼肌在维持血糖和脂肪的动态平衡方面起着关键作用，并对全身能量消耗起着重要作用。身体状况不佳和缺乏运动是患2型糖尿病的风险因素，2型糖尿病是一种流行程度的疾病。相反，体育运动通过增强胰岛素敏感性和改善血脂参数，有效地改善新陈代谢健康。有趣的是，运动的能力、新陈代谢的益处和对运动的反应在不同的人之间差异很大，在某些疾病状态下会降低。因此，阐明决定肌肉功能和适合度(从而实现运动)并调节运动诱导的骨骼肌反应的机制，对于寻找新的靶向肌肉和改善代谢健康的方法非常重要。雌激素相关受体家族(ERR、ERR和ERR)调节氧化代谢和其他对能量平衡至关重要的途径。作为核受体家族的成员，ERRS有容纳合成配体的口袋，因此可以作为治疗的靶点。我们的初步数据显示，该家族的三个成员都在骨骼肌中表达，并被运动信号激活。我们还表明，错误共同决定了对骨骼肌代谢和收缩特性至关重要的基因的表达。在这项拟议的工作中，我们将利用骨骼肌中缺乏ERRS的小鼠，来确定ERR、ERR和ERR在骨骼肌基础状态和耐力运动适应性反应中的细胞和生理功能。我们还将在体内使用功能获得和功能丧失的方法来描述Perm1的生理功能和作用机制，Perm1是一种新的ERR下游效应因子，我们最近发现它调节骨骼肌的氧化能力。总体而言，我们希望为实现和塑造骨骼肌对耐力运动的适应性反应的调控机制提供新的见解，并提供与氧化代谢和肌肉功能受损的疾病状态相关的途径，如胰岛素抵抗和2型糖尿病、疾病相关或损伤导致的肌肉萎缩，以及年龄相关的肌肉退化。我们的发现将对指导未来使用ERR/激动剂来增强肌肉功能和/或从运动中获益的努力具有重要意义。

 DESCRIPTION (provided by applicant): Skeletal muscle plays key roles in glucose and lipid homeostasis, and contributes to whole body energy expenditure. Poor physical fitness and inactivity are risk factors for developing type 2 diabetes, a disease reaching epidemic proportions. Conversely, physical activity is effective in improving metabolic health, by enhancing insulin sensitivity and improving lipid parameters. Interestingly, both the capacity for exercise, and the metabolic benefits and responses to exercise, vary greatly among individuals and are decreased in some disease states. Thus, elucidating the mechanisms that determine muscle function and fitness (and thereby enable exercise), and mediate exercise-induced skeletal muscle responses, is important for finding new ways to target muscle and improve metabolic health. The family of estrogen-related receptors (ERR, ERR and ERR) regulates oxidative metabolism and other pathways important for energy homeostasis. As members of the nuclear receptor family, ERRs have pockets that accommodate synthetic ligands and can thus be targeted therapeutically. Our preliminary data show that all three members of the family are expressed in skeletal muscle and activated by exercise signals. We also show that ERRs collectively determine the expression of genes important for metabolic and contractile properties of skeletal muscle. In the proposed work, we will use mice lacking ERRs specifically in skeletal muscle, to define the cellular and physiologic functions of ERR, ERR and ERR in skeletal muscle, at the basal state and in adaptive responses to endurance exercise. We will also use gain- and loss-of- function approaches in vivo to delineate the physiological function and mechanism of action of Perm1, a novel ERR downstream effector that we recently identified as regulating skeletal muscle oxidative capacity. Overall, we expect to provide novel insights into regulatory mechanisms that enable and shape skeletal muscle adaptive responses to endurance exercise, and to inform on pathways relevant to disease states where oxidative metabolism and muscle function are compromised, such as insulin resistance and type 2 diabetes, disease-associated or injury-caused muscle atrophies, and age-related muscle degeneration. Our findings will be important for guiding future efforts to use ERR/ agonists o enhance muscle function and/or benefits from exercise.