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.

骨骼肌组织是机械动态的，刚度的变化会影响功能、维持和再生。我们用动态硬化水凝胶模拟了培养中的骨骼肌机械变化，证明伴侣蛋白 BAG3通过重新分配肌肉祖细胞中的 YAP 和 TAZ 亚细胞定位来转导基质刚度BAG3 消耗增加 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. 分化后，耗尽 BAG3 的肌肉祖细胞形成增大的圆形肌管，缺乏典型的圆柱形形态。异常形态取决于 YAP/TAZ 信号，它被隔离在 BAG3 耗尽的肌管的细胞质中，但在对照细胞的圆柱形肌管中主要是细胞核。在软（E' = 4 和 12 kPa）水凝胶上诱导分化的对照祖细胞形成类似于在 BAG3 耗尽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，允许YAP和TAZ在BAG3耗尽的肌源性祖细胞中进行核易位。因此，BAG3 是肌肉组织动态刚度变化的关键介质，