The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice.
Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skele- tal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regard- less of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors. Overall design: To investigate the role of AR in mesenchymal progenitors, PDGFRa-CreER and ARL2/Y mice were crossed to selectively delete AR gene in mesenchymal progenitors expressing PDGFRa. To determine the effects of AR on gene expression, we performed RNA-Seq from PDGFRa+ cells in LA/BC muscles of both control (PDGFRa-CreER;AR+/Y)  and mutant (PDGFRa-CreER;ARL2/Y) mice. To determine the AR target genes, we used CUT&RUN method for AR and trimethylated lysine 4 from histone H3 (H3K4me3) in mesenchymal progenitors isolated from C57BL/6J male mice treated with DHT 2 hours before sampling.