Redefining the Role of FKBP12 in Skeletal Muscle

重新定义 FKBP12 在骨骼肌中的作用

• 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
• 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

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 骨骼肌 (SkM) 特异性减少的小鼠 12 kDa FK506 结合蛋白 FKBP12 （FKD 小鼠）显示出改善的耐力、胰岛素介导的葡萄糖清除率和骨矿物质密度，如 以及减少体内脂肪和抵抗高脂肪饮食的体重增加。低剂量雷帕霉素和 SLF （FKBP12 的合成配体）将 FKBP12 从其结合伙伴中取代，模拟 FKBP12 的效果 SkM 缺乏，表明这些药物有潜力作为干预措施来改善肌肉功能和 代谢。 SkM 中 FKBP12 的主要靶标是肌浆网 (SR) Ca2+ 释放通道， RyR1，在兴奋-收缩耦合 (ECC) 过程中控制细胞内储存的 Ca2+ 的释放。 从 RyR1 中部分去除 FKBP12（通过基因或低剂量雷帕霉素或 SLF 治疗） 增加肌质 Ca2+ 瞬时幅度和 Ca2+ 流入肌纤维的幅度 重复刺激。 SR Ca2+ 释放增强，Ca2+ 流入增加，与部分相关 钙调蛋白依赖性蛋白激酶 II (CaMKII) 抑制剂可阻断从 RyR1 中去除 FKBP12 和商店操作的 Ca2+ 输入 (SOCE)。然而，Ca2+释放增加的机制和 流入是否会改善肌肉功能和新陈代谢仍然未知。我们假设存在一个 可调反馈环路，功能性耦合 ECC、SOCE 和线粒体 Ca2+ 摄取以进行调节 肌肉功能和新陈代谢。该应用程序的具体目标是： A1。定义 FKBP12 的角色 和 RyR1 磷酸化在重复刺激期间调节 Ca2+ 瞬变幅度 改善 SkM 性能和新陈代谢。 2. 定义增强 Ca2+ 储存补充的反馈回路 和 ATP 产生以维持 FKBP12 缺陷小鼠肌肉性能和新陈代谢的改善。 3. 评估 SLF 改善肌肉功能和新陈代谢的治疗潜力。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。