Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA.
Hum Mol Genet. 2019 Feb 1;28(3):386-395. doi: 10.1093/hmg/ddy341.
Syntrophins are a family of modular adaptor proteins that are part of the dystrophin protein complex, where they recruit and anchor a variety of signaling proteins. Previously we generated mice lacking α- and/or β2-syntrophin but showed that in the absence of one isoform, other syntrophin isoforms can partially compensate. Therefore, in the current study, we generated mice that lacked α, β1 and β2-syntrophins [triple syntrophin knockout (tKO) mice] and assessed skeletal and cardiac muscle function. The tKO mice showed a profound reduction in voluntary wheel running activity at both 6 and 12 months of age. Function of the tibialis anterior was assessed in situ and we found that the specific force of tKO muscle was decreased by 20-25% compared with wild-type mice. This decrease was accompanied by a shift in fiber-type composition from fast 2B to more oxidative fast 2A fibers. Using echocardiography to measure cardiac function, it was revealed that tKO hearts had left ventricular cardiac dysfunction and were hypertrophic, with a thicker left ventricular posterior wall. Interestingly, we also found that membrane-localized dystrophin expression was lower in both skeletal and cardiac muscles of tKO mice. Since dystrophin mRNA levels were not different in tKO, this finding suggests that syntrophins may regulate dystrophin trafficking to, or stabilization at, the sarcolemma. These results show that the loss of all three major muscle syntrophins has a profound effect on exercise performance, and skeletal and cardiac muscle dysfunction contributes to this deficiency.
连接蛋白是一类模块化衔接蛋白，是抗肌萎缩蛋白蛋白复合物的组成部分，在复合物中它们可以募集和锚定多种信号蛋白。此前我们生成了缺乏α-和/或β2-连接蛋白的小鼠，但研究表明在缺失一种同工型时，其他连接蛋白同工型可以部分代偿。因此，在本研究中，我们生成了缺乏α、β1 和 β2-连接蛋白的小鼠（三重连接蛋白敲除（tKO）小鼠），并评估了骨骼肌和心肌功能。tKO 小鼠在 6 个月和 12 个月大时的自愿轮跑活动明显减少。我们在体评估了比目鱼肌的功能，发现 tKO 肌肉的比特定力比野生型小鼠降低了 20-25%。这种下降伴随着纤维型组成从快 2B 向更氧化的快 2A 纤维的转变。使用超声心动图测量心脏功能，结果显示 tKO 心脏左心室功能障碍且呈肥大状态，左心室后壁增厚。有趣的是，我们还发现 tKO 小鼠的骨骼肌和心肌中的膜定位的抗肌萎缩蛋白表达较低。由于 tKO 中的抗肌萎缩蛋白 mRNA 水平没有差异，这一发现表明连接蛋白可能调节抗肌萎缩蛋白向肌膜的转运或稳定。这些结果表明，三种主要的肌肉连接蛋白缺失对运动表现有深远影响，骨骼肌和心肌功能障碍导致了这种缺陷。
