Adaptation to mechanical load, leading to enhanced force and power output, is a characteristic feature of skeletal muscle. Formation of new myonuclei required for efficient muscle hypertrophy relies on prior activation and proliferation of muscle stem cells (MuSCs). However, the mechanisms controlling MuSC expansion under conditions of increased load are not fully understood. Here we demonstrate that interstitial mesenchymal progenitors respond to mechanical load and stimulate MuSC proliferation in a surgical mouse model of increased muscle load. Mechanistically, transcriptional activation of Yes-associated protein 1 (Yap1)/transcriptional coactivator with PDZ-binding motif (Taz) in mesenchymal progenitors results in local production of thrombospondin-1 (Thbs1), which, in turn, drives MuSC proliferation through CD47 signaling. Under homeostatic conditions, however, CD47 signaling is insufficient to promote MuSC proliferation and instead depends on prior downregulation of the Calcitonin receptor. Our results suggest that relayed signaling between mesenchymal progenitors and MuSCs through a Yap1/Taz-Thbs1-CD47 pathway is critical to establish the supply of MuSCs during muscle hypertrophy.

适应机械负荷，导致增强的力量和功率输出，是骨骼肌的一个特征。有效肌肉肥大所需的新肌核的形成依赖于肌肉干细胞 (MuSC) 的先前激活和增殖。然而，在负载增加的情况下控制 MuSC 膨胀的机制尚不完全清楚。在这里，我们证明间质间充质祖细胞在肌肉负荷增加的手术小鼠模型中对机械负荷有反应并刺激 MuSC 增殖。从机制上讲，间充质祖细胞中 Yes 相关蛋白 1 (Yap1)/具有 PDZ 结合基序 (Taz) 的转录共激活因子的转录激活导致血小板反应蛋白-1 (Thbs1) 的局部产生，进而通过 CD47 信号传导驱动 MuSC 增殖. 然而，在稳态条件下，CD47 信号传导不足以促进 MuSC 增殖，而是依赖于降钙素受体的先前下调。我们的研究结果表明，间充质祖细胞和 MuSC 之间通过 Yap1/Taz-Thbs1-CD47 通路传递的信号对于在肌肉肥大期间建立 MuSC 的供应至关重要。