Irisin作为增龄相关骨骼肌线粒体功能血清生物标志物的研究

Mitochondrial function plays a key role in development of sarcopenia. It is significantly to explore the potential serum marker of skeletal muscle mitochondrial functional dependence during aging. We have found that mitohormesis and reactive oxygen species (ROS) involved in the production of myokines in skeletal muscle in response to exercise. In present study, we try to confirm the hypothesis that Irisin is an independent predictor of skeletal muscle mitochondrial functional dependence during aging. First, we will study the correlation between the level of Irisin in serum and aging dependence skeletal muscle mitohormesis remodeling, and to study the activation mode of Irisin and its association with muscle fibers type. Second, we will explore the energy sensing mechanism of Irisin. PGC-1α activity may be conversely regulated by the Sirt1 deacetylase, which activates PGC-1α, and the GCN5 acetyltransferase, which may represses PGC-1a activity. Finally, we also want to explore the relationship between Irisin and ROS. The cross-talk between p38 MAPK and NFκB may be contributed to the potential handoff mechanism between activation and inactivation of PGC-1α. The present study may provide a worthy diadynamic criteria for sarcopenia and other mitochondrial dysfunction related muscle disease.

线粒体稳态与衰老性肌萎缩的发生密切相关，探寻可反映增龄进程中骨骼肌线粒体功能变化的潜在血清生物标志物具有重要意义。我们前期发现活性氧（ROS）及线粒体稳态参与了骨骼肌Myokines释放。本研究从转化运动医学视角，探索"血清Irisin作为增龄相关骨骼肌线粒体功能变化的独立预测因子"这一新命题。具体研究：① 探讨血清Irisin与增龄相关骨骼肌线粒体稳态重构的相关性，与肌纤维类型的关系，及其诱导方式；② 探讨运动诱导骨骼肌分泌Irisin 与线粒体能量代谢的关联机制，即SIRT1和GCN5介导的PGC-1α可逆性乙酰化反应；③ 探讨运动诱导骨骼肌分泌Irisin 与线粒体ROS的关联机制，即不同水平ROS通过调控p38 MAPK活化效应和NFκB拮抗效应的平衡对PGC-1α表达的影响。本研究将为衰老性肌萎缩等线粒体功能相关骨骼肌疾病提供有价值的诊断指标。

本研究从转化运动医学视角，以“血清Irisin作为增龄相关骨骼肌线粒体功能变化的独立预测因子” 为核心科学问题，分别通过in vivo和in vitro实验，系统探讨线粒体稳态、氧化还原信号和FNDC5/Irisin合成的相互关系。主要发现：1）首次证明线粒体稳态通过产生不同水平ROS，干预P38MAPK/NFκB的平衡关系，双向调控PGC-1α表达及其下游骨骼肌Irisin的合成和分泌；2）首次证明线粒体稳态水平通过输出不同水平ATP，干预SIRT1/GCN5的平衡关系，双向调控PGC-1α表达及其下游骨骼肌Irisin的合成和分泌；3）初步在增龄模型中证明Irisin作为骨骼肌线粒体功能的血清标志物可能性；4）首次利用电穿孔注射PGC-1α DNA片段技术模拟运动，证明可通过干预外周器官（骨骼肌）线粒体稳态，以Irisin为载体，远程改变内脏器官（心脏）功能的微创治疗策略。