Institute of Physiology II, University of Muenster, Muenster, 48149 Germany.
BioCAT, Department of Biology, Illinois Institute of Technology, Chicago, IL 60616.
Proc Natl Acad Sci U S A. 2022 Nov 29;119(48):e2209441119. doi: 10.1073/pnas.2209441119. Epub 2022 Nov 21.
Skeletal muscle force production is increased at longer compared to shorter muscle lengths because of length-dependent priming of thick filament proteins in the contractile unit before contraction. Using small-angle X-ray diffraction in combination with a mouse model that specifically cleaves the stretch-sensitive titin protein, we found that titin cleavage diminished the length-dependent priming of the thick filament. Strikingly, a titin-sensitive, length-dependent priming was also present in thin filaments, which seems only possible via bridge proteins between thick and thin filaments in resting muscle, potentially myosin-binding protein C. We further show that these bridges can be forcibly ruptured via high-speed stretches. Our results advance a paradigm shift to the fundamental regulation of length-dependent priming, with titin as the key driver.
骨骼肌的力产生在较长的肌肉长度下比在较短的肌肉长度下增加，这是因为在收缩前，收缩单位中的粗丝蛋白依赖长度进行了预激活。我们使用小角度 X 射线衍射结合一种特异性切割伸展敏感的肌联蛋白蛋白的小鼠模型发现，肌联蛋白的切割减少了粗丝的长度依赖性预激活。引人注目的是，细丝中也存在肌联蛋白敏感的、长度依赖性的预激活，这似乎仅通过休息肌肉中粗丝和细丝之间的桥接蛋白（可能是肌球蛋白结合蛋白 C）才成为可能。我们进一步表明，这些桥接蛋白可以通过高速拉伸被强行破坏。我们的结果推动了长度依赖性预激活的基本调控范式的转变，肌联蛋白是关键的驱动因素。
