Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 473 W 12th Ave, Columbus, OH 43210, USA.
Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 473 W 12th Ave, Columbus, OH 43210, USA.
Matrix Biol. 2022 Feb;106:1-11. doi: 10.1016/j.matbio.2022.01.003. Epub 2022 Jan 16.
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肉生长的调节需要不同细胞类型的协调反应，导致细胞外基质（ECM）重塑和肌肉横截面积增加。事实上，细胞基质蛋白作为通讯媒介，在肌肉适应环境挑战所需的信号刺激的传播中起着关键作用。我们发现细胞通讯网络因子 2（CCN2），也称为结缔组织生长因子（CTGF），在小鼠的过载驱动的骨骼肌肉肥大的时程中被诱导。为了阐明 CCN2 在介导肥大反应中的作用，我们利用肌纤维特异性 CCN2 获得和功能丧失的基因工程小鼠模型，然后通过肌肉过载来检查它们对机械刺激的反应。有趣的是，肌纤维特异性 CCN2 缺失会削弱肌肉对过载的肥大反应，而不干扰 ECM 沉积。另一方面，当通过转基因 CCN2 过表达过量时，CCN2 有效地促进过载诱导的异常 ECM 积累，而不影响肌纤维生长。总之，我们的遗传方法强调了 ECM 和肌纤维应激适应反应的独立性，并将 CCN2 定位为两者的中心介质。从机制上讲，CCN2 通过调节由细胞外信号（包括白细胞介素 6（IL6））诱导的焦点黏附激酶（FAK）介导的转导，调节肌肉中蛋白质合成的全局。总的来说，我们的研究强调了肌肉衍生的细胞外基质因子 CCN2 对适当的肥大肌肉生长的贡献。
