Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle

Ectopic fat deposition in skeletal muscle is closely associated with several disorders, however, the origin of these adipocytes is not clear, nor is the mechanism of their formation. Satellite cells function as adult muscle stem cells but are proposed to possess multipotency. Here, we prospectively identify PDGFRα⁺ mesenchymal progenitors as being distinct from satellite cells and located in the muscle interstitium. We show that, of the muscle-derived cell populations, only PDGFRα⁺ cells show efficient adipogenic differentiation both in vitro and in vivo. Reciprocal transplantations between regenerating and degenerating muscles, and co-culture experiments revealed that adipogenesis of PDGFRα⁺ cells is strongly inhibited by the presence of satellite cell-derived myofibres. These results suggest that PDGFRα⁺ mesenchymal progenitors are the major contributor to ectopic fat cell formation in skeletal muscle, and emphasize that interaction between muscle cells and PDGFRα⁺ mesenchymal progenitors, not the fate decision of satellitecells, has a considerable impact on muscle homeostasis.