Regulation of muscle hypertrophy through granulin: Relayed communication among mesenchymal progenitors, macrophages, and satellite cells

Skeletal muscles exert remarkable regenerative or adaptive capacities in response to injuries or mechanical loads. However, the cellular networks underlying muscle adaptation are poorly understood compared to those underlying muscle regeneration. We employed single-cell RNA sequencing to investigate the gene expression patterns and cellular networks activated in overloaded muscles and compared these results with those observed in regenerating muscles. The cellular composition of the 4-day overloaded muscle, when macrophage infiltration peaked, closely resembled that of the 10-day regenerating muscle. In addition to the mesenchymal progenitor-muscle satellite cell (MuSC) axis, interactome analyses or targeted depletion experiments revealed communications between mesenchymal progenitors-macrophages and macrophages-MuSCs. Furthermore, granulin, a macrophage-derived factor, inhibited MuSC differentiation, and Granulin-knockout mice exhibited blunted muscle hypertrophy due to the premature differentiation of overloaded MuSCs. These findings reveal the critical role of granulin through the relayed communications of mesenchymal progenitors, macrophages, and MuSCs in facilitating efficient muscle hypertrophy. [Display omitted] •Mesenchymal progenitors recruit monocytes/Møs in overloaded muscle•Number of MuSC-derived myonuclei decreased in Mø-suppressed mice•Mø-derived granulin acts on MuSCs and inhibits myogenic differentiation•Granulin-null mice exhibit blunted muscle hypertrophy Zhang et al. conducted single-cell RNA sequencing of overloaded muscles and revealed the relayed signaling among mesenchymal progenitors-macrophages (Møs)-muscle satellite cells (MuSCs). Among Mø-derived factors, they found that granulin crosses the basal lamina, directly acts on MuSCs, and promotes MuSC expansion by suppressing the expression of MyoD and myogenin.