FGF-21激活PI3K/AKT信号通路调控颏舌肌的肌纤维转化

The upper airway dilator (represented by the genioglossus) dysfunction is an important pathogenesis of OSAHS, and it is characterized by the transformation from the slow-twitch muscles resistant to fatigue to the fast-twitch muscles prone to fatigue. Previous studies showed that the fibroblast growth factor-21 (FGF-21) can independently regulate the glucolipid metabolism, and can regulate the skeletal muscle fiber conversion by activating the PI3K/AKT signaling pathway. However, the relationship between FGF-21 and OSAHS has not been reported. Our preliminary studies observe the elevated level of serum FGF-21 in patients with OSAHS and find that it is positively correlated with the severity of OSAHS. In vitro studies also find that FGF-21 can promote muscle fiber hypertrophy of C2C12 myoblasts. Thus we can deduce that FGF-21 may promote the transformation of the muscle fibers of the genioglossus by activating the PI3K/AKT signaling pathways, resulting in dysfunction of the genioglossus. This project will use AKT gene knockout mice model for in vivo and in vitro tests on the basis of the preliminary studies. And its purpose is to verify the function of FGF-21 through the PI3K/AKT signaling pathway in regulating genioglossus fiber conversion so as to reveal the mechanism of the genioglossus dysfunction and to provide new ideas for OSAHS prevention and treatment.

以颏舌肌为代表的上气道扩张肌功能异常是OSAHS的重要发病机制，主要表现为耐疲劳的慢肌向易疲劳的快肌转化。既往研究发现成纤维细胞生长因子-21 (FGF-21) 能够独立调节糖-脂代谢，并通过激活PI3K/AKT信号通路在肥胖-胰岛素抵抗中调控骨骼肌的肌纤维转化，但FGF-21与OSAHS的关系及其作用机制尚未见报道。我们的前期研究发现OSAHS患者血清FGF-21水平升高，并与OSAHS的严重程度成正相关；体外研究也发现FGF-21可促进C2C12成肌细胞的肌纤维肥大。为此，我们推测FGF-21可能通过激活PI3K/AKT信号通路促进颏舌肌的肌纤维转化，导致颏舌肌的功能异常。本项目拟在前期研究的基础上，利用AKT基因敲除小鼠模型，通过体内和体外试验，验证FGF-21是否通过PI3K/AKT信号通路调控颏舌肌的肌纤维转化,揭示颏舌肌功能受损的机制，为OSAHS的防治提供新的思路。

以颏舌肌为代表的上气道扩张肌功能异常是OSAHS的重要发病机制，主要表现为耐疲劳的慢肌向易疲劳的快肌转化。既往研究发现成纤维细胞生长因子-21 (FGF-21) 能够独立调节糖-脂代谢，并通过激活PI3K/AKT信号通路在肥胖-胰岛素抵抗中调控骨骼肌的肌纤维转化。我们的前期研究发现OSAHS患者血清FGF-21水平升高，并与OSAHS的严重程度成正相关。为此，我们推测FGF-21可能通过激活PI3K/AKT信号通路促进颏舌肌的肌纤维转化，导致颏舌肌的功能异常。本项目，从体外试验的层面探讨了FGF-21对颏舌肌肌纤维转化的影响，初步揭示FGF-21调控PI3K/AKT信号通路导致颏舌肌肌纤维转化的可能机制;本研究从 FGF-21 这个新视点为揭示颏舌肌肌纤维转化的发生机制奠定基础，为 OSAHS 及其并发症的防治提供新的思路。