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Estrogen-Related Receptor Pathways in Skeletal Muscle

骨骼肌中雌激素相关受体途径

基本信息

批准号：
9029852
负责人：
Anastasia Kralli
金额：
$ 43.2万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-28 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029852
关键词：
Acute Adipose tissue Affect Biogenesis Cell Respiration Chronic Disease Complex Contractile Proteins Data Defect Disease Energy Metabolism Environment Epidemic Exercise Family Family member Future Gene Expression Gene Targeting Genes Glucose Grant Health Homeostasis Individual Injury Insulin Resistance Ions Lead Ligands Lipids MAP Kinase Gene MAPK14 gene Mediating Metabolic Mitochondria Mus Muscle Muscle Fibers Muscle function Muscular Atrophy Non-Insulin-Dependent Diabetes Mellitus Nuclear Orphan Receptor Nuclear Receptors Oxidative Stress Pathway interactions Performance Phosphorylation Phosphotransferases Physical Fitness Physical activity Physiological Physiology Play Property Proteins Publishing Regulation Research Risk Factors Role Running Shapes Signal Pathway Signal Transduction Skeletal Muscle Testing Therapeutic Therapeutic Intervention Training Work age related amino acid metabolism base calmodulin-dependent protein kinase II estrogen-related receptor fitness flexibility improved in vivo insight insulin sensitivity interest loss of function member muscle aging muscle degeneration muscle metabolism novel programs public health relevance receptor respiratory response

项目摘要

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.