Diverse effector and regulatory functions of fibro/adipogenic progenitors during skeletal muscle fibrosis in muscular dystrophy

Fibrosis is a prominent pathological feature of skeletal muscle in Duchenne muscular dystrophy (DMD). The commonly used disease mouse model, mdx5cv, displays progressive fibrosis in the diaphragm but not limb muscles. We use sin-gle-cell RNA sequencing to determine the cellular expression of the genes involved in extracellular matrix (ECM) production and degradation in the mdx5cv diaphragm and quadriceps. We find that fibro/adipogenic progenitors (FAPs) are not only the primary source of ECM but also the predominant cells that express important ECM regulatory genes, including Ccn2, Ltbp4, Mmp2, Mmp14, Timp1, Timp2, and Loxs. The effector and regulatory functions are exerted by diverse FAP clusters which are different between diaphragm and quadriceps, indicating their activation by different tissue microenvironments. FAPs are more abundant in diaphragm than in quadriceps. Our findings suggest that the development of anti-fibrotic therapy for DMD should target not only the ECM production but also the pro-fibrogenic regulatory functions of FAPs.

Automated summary

Fibrosis is observed in the diaphragm of mdx5cv mouse model for DMD, but not in the limb muscles. Single-cell RNA sequencing reveals that fibro/adipogenic progenitors (FAPs) are the main source of ECM and also express important ECM regulatory genes. FAPs are more abundant in the diaphragm than in the quadriceps, suggesting that anti-fibrotic therapy for DMD should target ECM production and the regulatory functions of FAPs.