肌联蛋白(titin, TTN)是人体中分子量最大的蛋白质,不仅在肌节结构稳定和弹性势能的储存上发挥作用,而且在肌肥大和蛋白质质量控制中发挥重要调控作用。基于TTN-Z盘区、I带区和M 线区构成的蛋白质复合物被认为起着机械传感器的作用,在张力的刺激下动态调整肌细胞肥厚信号的传导。TTN 在运动后诱导骨骼肌重塑,通过蛋白质保护和质量控制修复与降解受损TTN。在适宜机械运动刺激下,TTN 机械感应复合体被激活,进而诱导一系列肥厚反应;不适宜负荷运动后,损伤严重的TTN 通过T-Cap与MDM2的相互作用、近端Ig区与Calpain1相互作用、N2A 区和M 线区与Calpain3相互作用及M 线结构域的MuRF1结合位点促进其降解。本文以骨架蛋白TTN 作为骨骼肌重塑的关键信号中枢为切入点,首先阐述TTN 的基本结构,进而深入分析不同分区在肌肥大和蛋白质质量控制中的作用机制。

Titin (TTN), the largest protein by molecular weight in humans, extends beyond its roles in providing structural stability to the sarcomere and storing elastic potential energy. It also plays a crucial regulatory role in muscle hypertrophy and protein quality control. The protein complex encompassing the Z-disk, I-band, and M-line regions of TTN acts as a mechanosensor, dynamically modulating the transduction of myocellular hypertrophic signaling in response to mechanical tension. TTN induces skeletal muscle remodeling after exercise, mediating the repair and degradation of damaged TTN through protein protection and quality control mechanisms. Under appropriate mechanical stimulation, the TTN mechanosensory complex is activated, thereby triggering a series of hypertrophic responses. Conversely, following overload exercise, severely damaged TTN promotes its degradation through interactions of T-cap with MDM2, the proximal Ig region with calpain 1, and the N2A and M-line regions with calpain 3, as well as engagement of the MuRF1 binding site within the M-line domain. In this article, we delve into the role of the cytoskeletal protein TTN as a central signaling hub for skeletal muscle remodeling. Initially, the basic structure of TTN is elucidated, followed by an in-depth analysis of the mechanisms by which different regions contribute to muscle hypertrophy and protein quality control.