Excessive BMP3b suppresses skeletal muscle differentiation

Bone morphogenetic protein (BMP)-3b, also known as growth differentiation factor (GDF)-10, belongs to the transforming growth factor (TGF)-β superfamily. Despite being named a BMP, BMP3b is considered as an intermediate between the TGFβ/activin/myostatin and BMP/GDF subgroups of the TGFβ superfamily. Myoblast differentiation is tightly regulated by various cytokines, including the TGFβ superfamily members. However, despite BMP3b supporting the maintenance of skeletal myofibers, myoblast differentiation induced by BMP3b remains unclear. In this study, BMP3 expression levels in isolated satellites were very low compared to those in the skeletal muscle tissues. We analyzed cardiotoxin-induced muscle regeneration. Intact muscle fiber size was larger in BMP3b null mice than in wild-type mice; however, regenerated muscle fiber size did not differ between the null and wild-type mice. Next, we analyzed the satellite cell-specific BMP3b-overexpressing (BMP3b Tg) mice. Intact fiber size was increased in BMP3b Tg mice. However, regenerating tibialis anterior muscle size was reduced in BMP3b Tg mice compared to that in control mice. BMP3b overexpression in C2C12 cells stimulated Smad2/3 signaling. Moreover, BMP3b overexpression and conditioned medium of BMP3b-expressing Chinese hamster ovary cells strongly suppressed myoblast differentiation by repressing transactivation. Overall, our data suggest that BMP3b is not necessary for muscle regeneration; however, excessive BMP3b interferes with muscle regeneration by suppressing myoblast differentiation.