Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.

中文翻译：

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骨细胞连接蛋白 43 通道调节骨-肌肉串扰

骨骼肌肉串扰在骨骼生物力学功能、多种病理状况的进展以及局部和远处细胞环境的调节中起着重要作用。以前的工作表明，成骨细胞中连接蛋白 (Cx) 43 的缺失，因此，骨细胞，间接损害骨骼肌的形成和功能。然而，Cx43 形成的间隙连接通道 (GJs) 和半通道 (HCs) 在骨-肌肉串扰中的各自作用却知之甚少。为此，我们使用了两种表达显性失活突变体 Δ130-136（GJs 和 HCs 功能被抑制）和 R76W（仅 GJs 功能被阻断）的 Cx43 骨细胞特异性转基因小鼠模型，以确定这两种类型的邻近骨骼肌上的 Cx43 通道。在 Δ130-136 小鼠中阻断骨细胞 Cx43 GJs 和 HCs 会降低快肌质量，同时肌肉蛋白质合成减少和肌肉蛋白质降解增加。R76W 和 Δ130-136 小鼠都表现出肌肉收缩力下降，伴随着典型的快肌肌肉的快到慢纤维转变。体外结果进一步表明，在用来自 R76W 和 Δ130-136 小鼠的原代骨细胞条件培养基 (PO CM) 处理后，C2C12 成肌细胞的肌管形成受到抑制。此外，转基因小鼠的循环和 PO CM 中的前列腺素 E2 (PGE2) 水平显着降低。有趣的是，向转基因小鼠注射 PGE2 可挽救快肌质量和功能。然而，这对蛋白质的合成和降解几乎没有影响。这些发现表明了一种通道特异性反应：抑制骨细胞 Cx43 HCs 会降低快肌骨骼肌质量，同时减少蛋白质合成和增加蛋白质降解。相比之下，Cx43 GJs 的阻塞导致快肌骨骼肌收缩力和肌生成降低，PGE2 部分解释了测量的差异。