甲状腺老化通过TH/TRα/PINK1诱导骨骼肌自稳态失衡致肌少症机制研究

肌少症与甲状腺老化密切关联。已知骨骼肌是甲状腺激素(TH)最大靶器官，TH对其调节依赖于甲状腺信号三联征（TRIAD）。我们借助衰老模型研究发现，甲状腺激素受体α（TRα）是TRIAD增龄性改变核心因子；伴随衰老基因p16，p21，p53表达升高，骨骼肌量下降，MyHC亚型发生变化，线粒体自噬相关基因PINK1受抑；通过基因芯片与生物信息技术发现具有甲状腺激素反应元件的miR-183-5p随增龄升高，靶基因是自噬相关基因PINK1。据上我们假设：TRα是TRIAD老化关键因子，TRα与TH在骨骼肌细胞核内结合，锚定激活miR-183-5p，后者通过调控PINK1基因，引起线粒体自噬损伤，肌细胞修复障碍。课题拟通过体内/体外模型、基因芯片与数据分析、Pull-down分析等，研究并阐述甲状腺老化通过TH/TRα/PINK1诱导骨骼肌自稳态失衡致肌少症的发生机制，为寻找肌少症治疗靶点提供思路。

The mechanism of sarcopenia is still unclear though senescent thyroid with age showed intimate relationship with it. It had been demonstrated that skeletal muscle was the most important target of thyroid hormone (TH), and TH could regulate it through thyroid signaling pathway, while the signaling triad (TRIAD), i.e transmembrane transporter, intracellular deiodination and TR-mediated gene transcription, constitute the basis for cellular customization of this signaling. In our primary experiment with skeletal muscle of geriatric mouse, it was found thyroid receptor α (TRα) was the prominent points of aged TRIAD, which showed suppressive expression of its gene and protein and intensive dysfunction. Previously, we also found, accompanying with increased expression of geriatric genes, such as p16, p21 and p53, the muscle mass, strength and muscle function were all reduced, and the ratio of subtypes of myosin heavy chain(MyHC) displayed typically senescent phenomena, and PINK1, a distinct gene of mitochondrial autophagy, was showed decreased. With the technique of gene chip and bioinformatic analysis technique, we found miR-183-5p, consistantly increased with age, and TH could act it through its specific TH/TRα promoter. Furthermore, it would be the regulator of PINK1 with the prediction of bioinformation. To date, we hypothesis that TRα acts the pivotal role in geriatric TRIAD, and senescent TRα , combining with TH, could promote and activate miR-183-5p in the nuclear of skeletal muscle cells, while the activated miR-183-5p exporting from nuclear, suppresses the gene of PINK1 and induces abnormality of mitophagy which destroys homeostasis of skeletal muscle and induces sarcopenia. In this project, we would utilize a series of molecular biological techniques such as Western-blot, immunofluorescence, siRNA, chromatin immunoprecipitation assay, microarray analysis and RNA pull-down assay to discuss the mechanism of sarcopenia induced by senescent thyroid through TH/TRα/PINK1 pathway, thus we hope to provide a novel approach in preventing sarcopenia from the new perspective of thyroid.