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.

摘要 骨骼肌(SKM)特异性降低小鼠12 kDa FK506结合蛋白FKBP12， (FKD小鼠)表现出更好的耐力、胰岛素介导的葡萄糖清除和骨密度，如 以及减少身体脂肪和抵抗高脂肪饮食的体重增加。低剂量雷帕霉素和系统性红斑狼疮 (FKBP12的合成配体)从其结合伙伴上取代FKBP12，模拟FKBP12的作用 SKM缺乏，表明这些药物有可能作为干预措施来改善肌肉功能和 新陈代谢。FKBP12在SKM中的主要靶点是肌浆网(SR)钙释放通道， RyR1，在兴奋收缩偶联(ECC)过程中控制细胞内钙离子的释放。 部分去除RyR1中的FKBP12(通过基因或低剂量雷帕霉素或SLF治疗) 增加肌浆钙瞬变的幅度和钙离子流入肌纤维的幅度 重复刺激。肌浆网钙离子释放和钙内流增加均与部分性激素相关 钙调素依赖的蛋白激酶II(CaMKII)抑制剂阻断RyR1中FKBP12的去除 和存储操作的钙离子进入(SOCE)。然而，增加钙释放和钙离子的机制 内流是否会改善肌肉功能和新陈代谢尚不清楚。我们假设存在一个 可调节的反馈环，功能上耦合ECC、SOCE和线粒体钙摄取以调节 肌肉功能和新陈代谢。本申请的具体目的是：A1。定义FKBP12的角色 和RyR1磷酸化在调节重复刺激过程中钙瞬变的幅度和 改善SKM的性能和新陈代谢。2.定义增强钙存储再充值的反馈环路 以及ATP的产生，以维持FKBP12缺陷小鼠改善的肌肉表现和代谢。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，改善因年龄原因不能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。