The regulation of skeletal muscle growth following pro-hypertrophic stimuli requires a coordinated response by different cell types that leads to extracellular matrix (ECM) remodeling and increases in muscle cross-sectional area. Indeed, matricellular proteins serve a key role as communication vehicles that facilitate the propagation of signaling stimuli required for muscle adaptation to environmental challenges. We found that the matricellular protein cellular communication network factor 2 (CCN2), also known as connective tissue growth factor (CTGF), is induced during a time course of overload-driven skeletal muscle hypertrophy in mice. To elucidate the role of CCN2 in mediating the hypertrophic response, we utilized genetically engineered mouse models for myofiber-specific CCN2 gain- and loss-of-function and then examined their response to mechanical stimuli through muscle overload. Interestingly, myofiber-specific deletion of CCN2 blunted muscle's hypertrophic response to overload without interfering with ECM deposition. On the other hand, when in excess through transgenic CCN2 overexpression, CCN2 was efficient in promoting overload-induced aberrant ECM accumulation without affecting myofiber growth. Altogether, our genetic approaches highlighted independent ECM and myofiber stress adaptation responses, and positioned CCN2 as a central mediator of both. Mechanistically, CCN2 acts by regulating focal adhesion kinase (FAK) mediated transduction of overload-induced extracellular signals, including interleukin 6 (IL6), and their regulatory impact on global protein synthesis in skeletal muscle. Overall, our study highlights the contribution of muscle-derived extracellular matrix factor CCN2 for proper hypertrophic muscle growth.

促肥大刺激后骨骼肌生长的调节需要不同细胞类型的协调反应，从而导致细胞外基质 (ECM) 重塑和肌肉横截面积增加。事实上，基质细胞蛋白作为促进肌肉适应环境挑战所需的信号刺激传播的通讯工具发挥着关键作用。我们发现基质细胞蛋白细胞通讯网络因子 2 (CCN2)，也称为结缔组织生长因子 (CTGF)，在小鼠超负荷驱动的骨骼肌肥大的时间过程中被诱导。为了阐明 CCN2 在介导肥大反应中的作用，我们利用基因工程小鼠模型来检测肌纤维特异性 CCN2 功能的获得和丧失，然后通过肌肉超负荷检查它们对机械刺激的反应。有趣的是，CCN2 的肌纤维特异性缺失减弱了肌肉对超负荷的肥大反应，而不会干扰 ECM 沉积。另一方面，当通过转基因 CCN2 过表达过量时，CCN2 可有效促进超载诱导的异常 ECM 积累，而不影响肌纤维生长。总之，我们的遗传方法强调了独立的 ECM 和肌纤维应激适应反应，并将 CCN2 定位为两者的中心介质。从机制上讲，CCN2 通过调节粘着斑激酶 (FAK) 介导的过载诱导的细胞外信号转导起作用，包括白细胞介素 6 (IL6)，及其对骨骼肌中全球蛋白质合成的调节影响。总的来说，我们的研究强调了肌肉来源的细胞外基质因子 CCN2 对适当的肥大肌肉生长的贡献。