Estrogen-Related Receptor Pathways in Skeletal Muscle

 描述（由申请人提供）：骨骼肌在葡萄糖和脂质体内平衡中起关键作用，并有助于全身能量消耗。身体素质差和缺乏活动是发展2型糖尿病的危险因素，这种疾病已达到流行病的程度。相反，体力活动通过增强胰岛素敏感性和改善脂质参数，有效改善代谢健康。有趣的是，运动能力以及代谢益处和对运动的反应在个体之间差异很大，并且在某些疾病状态下会降低。因此，阐明决定肌肉功能和健身（从而使运动），并介导运动诱导的骨骼肌反应的机制，对于寻找靶向肌肉和改善代谢健康的新方法是重要的。雌激素相关受体家族（ERRα、ERRβ和ERRγ）调节氧化代谢和其他对能量稳态很重要的辅助途径。作为核受体家族的成员，ERR具有容纳合成配体的口袋，因此可以在治疗上靶向。我们的初步数据表明，该家族的所有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，ERRs共同决定了骨骼肌的代谢和收缩特性的重要基因的表达。在拟议的工作中，我们将定义ERRs在骨骼肌中的细胞和生理功能，在基础状态和耐力运动的反应中，使用缺乏ERRs的小鼠，特别是在肌肉中。我们还将深入了解ERRs重塑肌肉的机制，通过阐明ERR诱导的蛋白Perm 1的生理作用和作用机制，我们最近确定了PGC-1/ERR下游效应器对线粒体生物合成和氧化能力的调节很重要。总的来说，我们希望提供新的见解，使和塑造骨骼肌适应性反应耐力运动的调节机制，并阐明与氧化代谢和肌肉功能受损的疾病相关的途径，如胰岛素抵抗和2型糖尿病，疾病相关或损伤引起的肌肉萎缩，和年龄相关的肌肉退化。我们的发现对于指导未来使用ERR配体来增强肌肉功能和/或从运动中获益的努力将是重要的。

 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 (ERRα, ERRβ and ERRγ) regulates oxidative metabolism and other ancillary 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 define the cellular and physiologic functions of ERRs in skeletal muscle, at the basal state and in the response to endurance exercise, using mice lacking ERRs specifically in muscle. We will also gain insights into the mechanisms by which ERRs remodel muscle, by elucidating the physiological role and mechanism of action of the ERR-induced protein Perm1, which we recently identified as a PGC-1/ERR downstream effector important for the regulation of mitochondrial biogenesis and 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 elucidate pathways relevant to diseases with compromised oxidative metabolism and muscle function, 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 ligands to enhance muscle function and/or benefits from exercise.