Redefining the Role of FKBP12 in Skeletal Muscle

重新定义 FKBP12 在骨骼肌中的作用

基本信息

批准号：
10359698
负责人：
Robert T Dirksen
金额：
$ 56.22万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-22 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359698
关键词：
Affect Automobile Driving Binding Body fat Bone Density Calcineurin Couples Coupling Data Development Dose Excision Exercise Exhibits FK506 Fatigue Feedback Glucose Goals High Fat Diet Human Immunoprecipitation Immunosuppression Insulin Intervention Ligands Lipids LoxP-flanked allele Mass Spectrum Analysis Mediating Membrane Metabolism Mitochondria Modeling Molecular Monitor Mus Muscle Muscle Fibers Muscle function Mutation Myopathy Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Patients Performance Persons Pharmaceutical Preparations Phenotype Phosphorylation Production Publishing Reaction Resistance Respiratory Diaphragm Role Ryanodine Receptor Calcium Release Channel Sarcoplasmic Reticulum Signal Transduction Sirolimus Site Skeletal Muscle Strenuous Exercise Tacrolimus Binding Protein 1A Tacrolimus Binding Proteins Testing Therapeutic Weight Gain Work calmodulin-dependent protein kinase II diet and exercise dosage improved inhibitor muscle aging muscle metabolism novel strategies novel therapeutic intervention side effect uptake

项目摘要

Abstract Mice with a skeletal muscle (SkM)-specific decrease in the small 12 kDa FK506 binding protein, FKBP12, (FKD mice) display improved endurance, insulin-mediated glucose clearance, and bone mineral density, as well as decreased body fat and resistance to weight gain on a high fat diet. Low doses of rapamycin and SLF (synthetic ligand for FKBP12) that displace FKBP12 from its binding partners mimic the effects of FKBP12 deficiency in SkM, suggesting these drugs have potential as interventions to improve muscle function and metabolism. The primary target of FKBP12 in SkM is the sarcoplasmic reticulum (SR) Ca2+ release channel, RyR1, which controls the release of Ca2+ from intracellular stores during excitation-contraction coupling (ECC). Partial removal of FKBP12 from RyR1 (genetically or by treatment with low doses of rapamycin or SLF) increases both the amplitude of the myoplasmic Ca2+ transient and Ca2+ influx into the muscle fiber during repetitive stimulation. Both enhanced SR Ca2+ release and increased Ca2+ influx associated with partial removal of FKBP12 from RyR1 are blocked by inhibitors of calmodulin-dependent protein kinase II (CaMKII) and store-operated Ca2+ entry (SOCE). However, the mechanisms by which increases in Ca2+ release and influx result in improved muscle function and metabolism remain unknown. We hypothesize the existence of a tunable feedback loop that functionally couples ECC, SOCE, and mitochondrial Ca2+ uptake to modulate muscle function and metabolism. The specific aims of this application are to: A1. Define the roles of FKBP12 and RyR1 phosphorylation in regulating the amplitude of the Ca2+ transient during repetitive stimulation and improving SkM performance and metabolism. 2. Define the feedback loop that enhances Ca2+ store refilling and ATP production to sustain the improved muscle performance and metabolism in FKBP12 deficient mice. 3. Evaluate the therapeutic potential of SLF to improve muscle function and metabolism. Our long-term goal is to develop interventions to improve muscle function in people who cannot perform strenuous exercise due to age, muscle disease, obesity and/or have type II diabetes.

抽象的小的12 kDa FK506结合蛋白FKBP12的小鼠（SKM）特异性降低（FKD小鼠）表现出改善的耐力，胰岛素介导的葡萄糖清除率和骨矿物质密度，如同时减少体内脂肪和高脂饮食中体重增加的能力。低剂量的雷帕霉素和SLF （FKBP12的合成配体）从其结合伴侣中取代FKBP12 SKM的不足，表明这些药物具有改善肌肉功能和的干预措施的潜力代谢。 SKM中FKBP12的主要目标是肌质网（SR）Ca2+释放通道， RYR1，它控制激发收缩偶联（ECC）期间细胞内存储中Ca2+的释放。从RYR1（遗传学或低剂量雷帕霉素或SLF处理）部分去除FKBP12 在肌胞浆Ca2+瞬态的振幅和Ca2+涌入肌肉纤维的幅度都增加了重复刺激。增强的SR Ca2+释放和与部分相关的Ca2+涌入增加从RYR1中去除FKBP12被钙调蛋白依赖性蛋白激酶II（CAMKII）的抑制剂阻止和商店经营的CA2+条目（SOCE）。但是，Ca2+释放增加的机制和涌入导致肌肉功能改善，代谢仍然未知。我们假设存在可调反馈循环，该循环在功能上将ECC，SOCE和线粒体Ca2+摄取均为调节肌肉功能和代谢。此应用程序的具体目的是：A1。定义FKBP12的角色在重复刺激和改善SKM性能和代谢。 2。定义增强CA2+存储补充的反馈循环和ATP产生，以维持FKBP12缺乏小鼠的肌肉性能和代谢的改善。 3。评估SLF改善肌肉功能和代谢的治疗潜力。我们的长期目标是制定干预措施以改善因年龄而无法进行剧烈运动的人的肌肉功能，肌肉疾病，肥胖和/或患有II型糖尿病。