Relayed Signaling between Mesenchymal Progenitors and Muscle Stem Cells Ensures Adaptive Stem Cell Responses to Increased Mechanical Load

Adaptation to mechanical load leading to enhanced force and power output is a characteristic feature of skeletal muscles. Formation of new myonuclei, eventually required for efficient muscle hypertrophy, relies on prior activation and proliferation of muscle stem cells (MuSCs). However, the mechanisms controlling MuSC expansion in 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 model of increased muscle load. Mechanistically, transcriptional activation of Yap1/Taz in mesenchymal progenitors results in local production of thrombospondin-1 that in turn drives MuSC proliferation through CD47 signaling. In homeostatic conditions, however, CD47 signaling is insufficient to promote MuSC proliferation and instead depends on prior downregulation of the Calcitonin receptor. Taken together, 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 MuSC during muscle hypertrophy.