成肌细胞的机械转导和肌管形态依赖于 BAG3 对 YAP 和 TAZ 的调节。
Myoblast mechanotransduction and myotube morphology is dependent on BAG3 regulation of YAP and TAZ.
机构信息
Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO, USA; BioFrontiers Institute, University of Colorado, Boulder, CO, USA.
Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO, USA; BioFrontiers Institute, University of Colorado, Boulder, CO, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
出版信息
Biomaterials. 2021 Oct;277:121097. doi: 10.1016/j.biomaterials.2021.121097. Epub 2021 Aug 25.
Skeletal muscle tissue is mechanically dynamic with changes in stiffness influencing function, maintenance, and regeneration. We modeled skeletal muscle mechanical changes in culture with dynamically stiffening hydrogels demonstrating that the chaperone protein BAG3 transduces matrix stiffness by redistributing YAP and TAZ subcellular localization in muscle progenitor cells. BAG3 depletion increases cytoplasmic retention of YAP and TAZ, desensitizing myoblasts to changes in hydrogel elastic moduli. Upon differentiation, muscle progenitors depleted of BAG3 formed enlarged, round myotubes lacking the typical cylindrical morphology. The aberrant morphology is dependent on YAP/TAZ signaling, which was sequestered in the cytoplasm in BAG3-depleted myotubes but predominately nuclear in cylindrical myotubes of control cells. Control progenitor cells induced to differentiate on soft (E' = 4 and 12 kPa) hydrogels formed circular myotubes similar to those observed in BAG3-depleted cells. Inhibition of the Hippo pathway partially restored myotube morphologies, permitting nuclear translocation of YAP and TAZ in BAG3-depleted myogenic progenitors. Thus, BAG3 is a critical mediator of dynamic stiffness changes in muscle tissue, coupling mechanical alterations to intracellular signals and inducing changes in gene expression that influence muscle progenitor cell morphology and differentiation.
骨骼肌组织在力学上是动态的，其僵硬度的变化会影响功能、维持和再生。我们通过使水凝胶动态变硬来模拟骨骼肌力学变化，结果表明，伴侣蛋白 BAG3 通过重新分配 YAP 和 TAZ 的亚细胞定位来传递基质僵硬度，从而改变肌肉祖细胞。BAG3 的耗竭会增加 YAP 和 TAZ 的细胞质保留，使成肌细胞对水凝胶弹性模量的变化不敏感。分化后，BAG3 耗尽的肌肉祖细胞形成了增大的、圆形的肌管，缺乏典型的圆柱形形态。这种异常形态依赖于 YAP/TAZ 信号通路，在 BAG3 耗尽的肌管中，该信号通路被隔离在细胞质中，而在对照组细胞的圆柱形肌管中，该信号通路主要位于核内。在软（E'=4 和 12 kPa）水凝胶上诱导分化的对照组祖细胞形成了类似在 BAG3 耗尽的细胞中观察到的圆形肌管。Hippo 通路的抑制部分恢复了肌管形态，使 BAG3 耗尽的成肌祖细胞中的 YAP 和 TAZ 发生核易位。因此，BAG3 是肌肉组织动态僵硬度变化的关键介质，它将机械变化与细胞内信号联系起来，并诱导影响肌肉祖细胞形态和分化的基因表达变化。
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