BK通道通过线粒体损伤调控骨骼肌退变的机制研究

肌少症发病机制尚未完全阐明，并缺少有效的实验动物模型。课题组前期研究发现，骨骼肌特异性敲除BK通道的小鼠（CKO鼠）肌肉含量和肌力降低，病理显示肌纤维水肿，线粒体明显肿胀、嵴消失。与肌少症相似。进一步研究显示，CKO鼠成肌细胞的线粒体活性氧（ROS）生成增加，呼吸链复合体III的活性下降，RNA-Seq结果显示复合体III的核心亚基UQCRC2表达下降。故提出假说：BK通道通过与UQCRC2作用影响呼吸链复合体活性，引起ROS增多，损伤线粒体，导致肌肉功能退变。本项目拟通过以上CKO小鼠和成肌细胞为主要研究对象，采用病理学、分子生物学、电生理学等多种研究方法，在分子、细胞和整体水平验证假说，阐明BK通道在骨骼肌退变中的作用和机制，探讨BK开放剂的治疗作用。为肌肉退行性病变的机制提出新观点，为肌少症研究提供潜在药物筛选靶标和动物模型。

The underlying mechanism of sarcopenia has been poorly illustrated and there has been none well-accepted animal model of muscle mass loss. Our group found that conditioned knockout the expression of large conductance calcium activated potassium channels (BK channels) in skeletal muscle in mice lead to the decreased muscle mass and strength, muscle fiber pathologically swelling along with the mitochondria swelling and loss of ridge under electronic microscope. Furthermore, we found that in BK channels deficient myoblasts, the production of mitochondrial reactive oxygen species (ROS) significantly increased, the activity of mitochondrial respiratory china complex Ⅲ decreased and the critical component of mitochondrial respiratory china complex Ⅲ, Ubiquinol cytochrome c reductase core protein 2 (UQCRC2) down-expressed revealed in RNA-seq. Thus, we suppose that the dysfunction of skeletal muscle is contributed to the ROS-injured mitochondria in which the excess ROS is produced by interaction between BK channels and UQCRC2. This project aims to illuminate the mechanism of BK channels in skeletal muscle degeneration using BK channels deficient myoblasts and conditioned knockout mice with pathological, molecular biological, electrophysiological research approaches. Our project will provide a new view in BK channels involved muscle degeneration and testify whether the BK channels stimulator can alleviate or reverse muscle disorder. Hopefully, BK channels will be a potential treatment target and the genetic knockout mice will be a helpful model for sarcopenia researches.